REVIEW ARTICLE. Andres Duarte-Rojo, 1 Astrid Ruiz-Margain, 3 Aldo J. Monta~no-Loza, 4 Ricardo U. Macıas-Rodrıguez, 3 Arny Ferrando, 2 and W.

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1 REVIEW ARTICLE Exercise and Physical Activity for Patients With End-Stage Liver Disease: Improving Functional Status and Sarcopenia While on the Transplant Waiting List Andres Duarte-Rojo, 1 Astrid Ruiz-Margain, 3 Aldo J. Monta~no-Loza, 4 Ricardo U. Macıas-Rodrıguez, 3 Arny Ferrando, 2 and W. Ray Kim 5 1 Division of Gastroenterology and Hepatology and 2 Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR; 3 Department of Gastroenterology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico; 4 Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Canada; and 5 Division of Gastroenterology and Hepatology, Stanford School of Medicine, Stanford, CA Sarcopenia and physical deconditioning are frequent complications in patients with cirrhosis and end-stage liver disease (ESLD). They are the end result of impaired dietary intake, chronic inflammation, altered macronutrient and micronutrient metabolism, and low physical activity. Frailty is the end result of prolonged sarcopenia and physical deconditioning. It severely affects a patient s functional status and presents in approximately 1 in 5 patients on the liver transplantation waiting list. Sarcopenia, poor physical fitness/cardiopulmonary endurance (CPE), and frailty are all associated with increased mortality in ESLD. Clinical trials addressing the usefulness of exercise in patients with cirrhosis have shown that it improves the metabolic syndrome, sarcopenia, CPE, health-related quality of life, and hepatic venous pressure gradient. Although evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing, based on existing literature from multiple medical subspecialties, we believe that an exercise program coupled to a tailored nutritional intervention benefits both cardiopulmonary and musculoskeletal functions, ultimately translating into improved functional status, sense of well-being, and possibly less complications from portal hypertension. In conclusion, although supervised exercise training is the prevailing approach to manage ESLD patients, such intervention is not sustainable or feasible for most patients. Innovative home-based physical activity interventions may be able to effectively reach a larger number of patients. Liver Transplantation AASLD. Received June 7, 2017; accepted September 9, Management of patients with decompensated cirrhosis and end-stage liver disease (ESLD) has become more standardized over the last couple of decades. Refinement Abbreviations: 6MWT, 6-minute walk test; ACC/AHA, American College of Cardiology/American Heart Association; ACSM, American College of Sports Medicine; ADA, American Diabetes Association; ADL, activities of daily living; ALT, alanine aminotransferase; ASMI, appendicular skeletal muscle index; BCAA, branched-chain amino acid; BIA, bioelectrical impedance analysis; b.i.w., twice a week; BMI, body mass index; CLDQ, chronic liver disease questionnaire; CPE, cardiopulmonary endurance; CPET, cardiopulmonary exercise testing; Cr, creatinine; CT, computed tomography; CTP, Child-Turcotte-Pugh; DXA, dual X-ray absorptiometry; DHHS, US Department of Health and Human Services; ESLD, end-stage liver disease; FFMI, fat-free mass index; FIS, fatigue impacts scale; HE, hepatic encephalopathy; HOMA-IR, homeostasis model assessment for insulin resistance; HR, hazard ratio; HRQoL, healthrelated quality of life; HVPG, hepatic venous pressure gradient; ICU, intensive care unit; IL6, interleukin 6; ISI, insulin resistance index; 122 REVIEW ARTICLE in therapeutic techniques has decreased mortality from ascites and its complications, whereas improved understanding of the pathophysiology of portal hypertension is helping reach better treatment goals for acute kidney injury and hepatic encephalopathy (HE). Likewise, treatment of specific diseases, such as hepatitis C, hepatitis B, and locoregional therapy for hepatocellular carcinoma, have all facilitated stabilization of disease toward a more favorable outcome, on occasions including successful liver transplantation (LT). However, mortality for patients with ESLD continues to be high, and in 2015, over 3000 patients in the United States were unable to reach LT as a consequence of progressing disease or death. Acute-on-chronic liver disease and infectious complications are leading indications for hospital admission and prolonged hospital stay, severely affecting an ESLD patient s functional status and mortality. In recent years, more attention has been given to

2 LIVER TRANSPLANTATION, Vol. 24, No. 1, 2018 conditions indirectly resulting from ESLD and prolonged illness, including malnutrition, sarcopenia, poor functional status, and frailty (Fig. 1). Although interrelated, each of these conditions can independently affect a patient s functional status and mortality. In the present review, we will summarize the evidence on the relevance of these complications in ESLD, while providing a framework for a possible change in practice aiming to improve functionality and survival in LT candidates through an exercise intervention. Sarcopenia and Malnutrition Malnutrition is a highly prevalent complication in ESLD patients. It is a complex condition that includes L3, 3rd lumbar vertebra; L4, 4th lumbar vertebra; LT, liver transplantation; MADRS, Montgomery-Asberg depression rating scale; MELD, Model for End-Stage Liver Disease; MELD-Na, Model for End-Stage Liver Disease sodium; NEAT, nonexercise activity thermogenesis; NH 3, ammonia; PhA, phase angle; PMA, psoas muscle area; PMI, psoas muscle index; QUICKI, quantitative insulin sensitivity check index; RCT, randomized controlled trial; SF-36, short-form 36; SMI, skeletal muscle index; SMM, skeletal muscle mass; TIPS, transjugular intrahepatic portosystemic shunt; t.i.w., thrice a week; TNF-a, tumor necrosis factor a; TPA, total psoas area; TPMT, transversal psoas muscle thickness; US, ultrasound; VE, ventilation; VCO 2, carbon dioxide output; VO 2peak, peak oxygen uptake; WC, waist circumference. Address reprint requests to Andres Duarte-Rojo, M.D., M.S., D.Sc., Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, 4301 West Markham #567, Little Rock, AR Telephone: ; FAX: ; aduarterojo@uams.edu Andres Duarte-Rojo receives financial support from the University of Arkansas for Medical Sciences College of Medicine Clinician Scientist Program. Andres Duarte-Rojo has received research grants from Ocera Therapeutics, Gilead Sciences, and Vital Therapies and consults for Gilead Sciences. Aldo J. Monta~no-Loza has received research grants from Tobira Therapeutics, Gilead Sciences, and Takeda and consults for Intercept. Arny Ferrando has received research grants from National Pork Board, Egg Nutrition Center, National Institutes of Health, and Department of Defense; holds an intellectual property patent that is licensed to 8IP; and consults for the Center for Applied Health Sciences. W. Ray Kim consults for Gilead Sciences, Merck, AbbVie, Intercept, and Conatus. Copyright VC 2017 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt FIG. 1. Conceptual framework on the interdependence between physical fitness and nutritional status in patients with cirrhosis and ESLD. Physical deconditioning, determined by a low CPE, and sarcopenia, an objective surrogate for progressive malnutrition, are cofactors leading to functional deterioration. As physical deconditioning progresses, patients exercise less and use less energy as part of NEAT. Frailty is conceptualized as the extreme of functional deterioration where both physical deconditioning and sarcopenia/malnutrition are present at their severest forms. CPE and sarcopenia are herein considered intermediate outcomes leading to clinical outcomes with increased relevance, from functional deterioration to death. the decrease of muscle and fat mass, body weight loss, increased proinflammatory cytokines, anorexia, and fatigue, resulting in sarcopenia. (1,2) Sarcopenia is defined as the generalized loss of muscle mass, muscle strength, and muscle function, and it is directly related to adverse outcomes in this population. (1) Evaluating malnutrition in patients with ESLD is a challenging task given that many of the markers associated with malnutrition are intrinsically affected in liver disease (eg, albumin, prealbumin, lymphopenia); therefore, skeletal muscle evaluation (mass, function, and quality) provides an objective means to determine nutritional status in patients with ESLD. The gold standard for the assessment of sarcopenia in ESLD patients is computed tomography (CT), which measures the total cross-sectional area of the abdominal skeletal muscles at the 3rd lumbar vertebra (L3) level, and when normalized to the patient s height, yields the skeletal muscle index (SMI). (3) Several other methods can be used to assess sarcopenia by reflecting muscle mass directly or indirectly with validated cutoffs in the population. Dual X-ray absorptiometry (DXA) is an imaging method that measures both bone mineral and soft tissue content, allowing REVIEW ARTICLE 123

3 LIVER TRANSPLANTATION, January 2018 calculation of the fat-free mass index (FFMI), where values of FFMI below the 10th percentile are considered diagnostic for sarcopenia. When ascites is present, the appendicular skeletal muscle index (ASMI) can be calculated instead, and an ASMI below 2 standard deviations from the mean of a reference population is considered as sarcopenia. (4) Apart from imaging methods, there are some bedside methods commonly used for assessment of muscle mass. Bioelectrical impedance examines the resistance and reactance of an electric current through body tissues, and it predicts values of fat-free mass, fat mass, and intracellular and extracellular water. The latter has been shown to be influenced by the presence of ascites; therefore, direct markers such as phase angle (PhA) or body cell mass are preferred over the predicted values. Bioelectrical impedance derived PhA is a nutritional marker that reflects the integrity of cellular membranes and water cell distribution (ie, by relating resistance and reactance), what in nutritional terms translates into muscle and fat mass. Therefore, values of PhA below the cutoff established for the population are considered diagnostic for muscle/fat mass depletion and malnutrition and are not affected by fluid overload. (1,5) Mid-arm muscle circumference is a simple anthropometric method that reflects the amount of muscle mass by deducting the amount of measured fat in the triceps and bone width. The diagnosis of sarcopenia can be established when this value is below the 10th percentile from a reference population. (6) Hand grip strength is a technique that measures the amount of static force on a dynamometer and predicts muscle function. This technique requires the active involvement of the patient and is not useful in patients with HE. Values of hand grip strength below the 10th percentile of the reference population are considered abnormal. (7) Physical Fitness and Cardiopulmonary Endurance Some terminology needs to be properly defined in order to better understand the advantage of an exercise intervention in ESLD and how endpoints have been evaluated in clinical trials. According to the Institute of Medicine, physical fitness is a state of well-being with a low risk of premature health problems and adequate energy to participate in a variety of physical activities. In this regard, physical activity makes reference to body movement produced by the contraction of skeletal muscle, whereas exercise refers to planned, structured, and repetitive movement aiming to improve or maintain physical fitness. Thus, these 3 concepts are interrelated in such a way that physical activity and exercise facilitate physical fitness, the latter was defined in terms of successful performance of physical duties. Given that physical fitness is a broad and complex concept, cardiopulmonary endurance (CPE), the ability of the heart and lungs to meet skeletal muscle demands during extended exercise, is traditionally used in clinical trials as the surrogate endpoint to quantify changes from an exercise intervention aiming to improve aerobic fitness. The most commonly used methods to evaluate CPE in cirrhosis are cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT). CPET is performed on a treadmill or in a stationary cycle ergometer, and the patient is monitored for heart rate, blood pressure, electrocardiogram changes, and symptoms, while the workload progressively increases. Simultaneously, the gas exchange is measured yielding results of oxygen uptake, ventilation (VE), and carbon dioxide output (VCO 2 ). From these, maximum oxygen uptake (or its working equivalent, peak oxygen uptake [VO 2peak ]) is the most frequently used parameter of CPE. (8) The 6MWT is a simple test where the patient is asked to walk quickly on a flat surface during 6 minutes, with the distance covered used as the endpoint. The test is easy to perform and essentially requires a 30-meter hallway, a pulse oximeter, and a stopwatch. (9) Clinical Factors Associated With Sarcopenia and Physical Deconditioning in ESLD The etiology of sarcopenia and physical deconditioning in patients with ESLD is multifactorial, resulting from a combination of impaired dietary intake, malabsorption, altered macronutrient and micronutrient metabolism, and low physical activity. (10) Decreased dietary intake could result from early satiety, delayed gastric emptying, nausea, anorexia, enforced dietary restrictions (sodium and protein restriction), altered taste perception due to zinc deficiency, and chronic alcohol consumption. (11-13) Moreover, increases in the tumor 124 REVIEW ARTICLE

4 LIVER TRANSPLANTATION, Vol. 24, No. 1, 2018 necrosis factor a (TNF-a) and leptin are frequent in patients with ESLD and might contribute to anorexia. (14,15) Malabsorption is also multifactorial resulting from impaired gut motility, bile acid deficiency, pancreatic insufficiency, small intestinal bacterial overgrowth, and bowel edema from portal enteropathy. (10-16) Impaired carbohydrate metabolism due to hyperinsulinemia and impaired hepatic glycogen synthesis are key contributors to altered macronutrient metabolism. In fact, patients with ESLD enter into a catabolic or starvation state during an overnight fast. Rapid depletion of muscle and hepatic glycogen, free fatty acid oxidation, and production of ketone bodies are observed within 10 hours, as compared with 3 days in healthy subjects. (8,9) Finally, regular physical activity is needed to protect patients with ESLD from sarcopenia. However, most patients have a rather sedentary lifestyle and self-assessments do not reliably indicate actual performance. (17) Molecular Mechanisms of Sarcopenia in ESLD Patients with ESLD have an increase in fatty acid oxidation and gluconeogenesis early in the fasting or postabsorptive state. (18) Becauseglucoseisadesired substrate in most cellular tissues and fatty acid carbon cannot be used for gluconeogenesis, amino acids are used for this metabolic pathway. (19) Proteolysis from the skeletal muscle produces aromatic and branched-chain amino acids (BCAAs) that become the principal source of substrate for gluconeogenesis. Accelerated starvation response and increased gluconeogenesis as metabolic abnormalities that cause muscle wasting is supported by the low respiratory quotient found in patients with ESLD and sarcopenia. (18) Myostatin (myokine also known as growth differentiation factor 8) is a protein produced and released by myocytes that acts on muscle cells in an autocrine fashion to inhibit myogenesis, muscle cell growth, and differentiation. Increased expression of myostatin in plasma and skeletal muscle has been reported in patients with ESLD. (20) Interestingly, high ammonia (NH 3 ) levels in patients with ESLD seems to be associated with sarcopenia through upregulation of myostatin, impaired protein synthesis, and increased autophagy. (19) Other factors associated with sarcopenia in ESLD include low testosterone concentrations due to increased aromatase activity and decreased growth hormone levels in the skeletal muscle. (21,22) Clinical Implications of Sarcopenia and Physical Fitness Changes in skeletal muscle mass and physical fitness have been strongly correlated with adverse clinical outcomes (Table 1). (3,24,42) A recent meta-analysis evaluating the impact of CT-assessed sarcopenia that included 19 studies with 3803 ESLD patients showed an independent association between sarcopenia and wait-list and post-lt mortality. The pooled hazard ratios (HRs) of sarcopenia were 1.72 (P ) and 1.84 (P ) for wait-list and post-lt mortality, respectively, independent of the Model for End-Stage Liver Disease (MELD) score. (43) Though not consistently reported in studies, (25,26,44) sepsis may be one of the explanations behind a higher mortality in patients with sarcopenia. (24) In order to standardize cut points for sarcopenia, a recent multicenter study across 5 academic transplant centers in North America included almost 400 adult patients with ESLD awaiting LT. This study validated the association of sarcopenia and mortality and established cutoff values for ESLD patients awaiting LT using the CT-SMI (39 cm 2 /m 2 for women and 52 cm 2 /m 2 for men). (3) Using these cutoff values, a recent study identified sarcopenia as an independent predictor for HE after transjugular intrahepatic portosystemic shunt (TIPS), outperforming traditional risk factors such as age, covert HE, and history of overt HE. (45) Practical methods available at bedside to assess sarcopenia have not been widely studied in cirrhosis. In a study including 249 patients with a mean follow-up of 34 months, we identified a PhA independently associated with increased mortality (HR ; P ) in patients with cirrhosis. (46) In a subsequent study, a low PhA was also associated with incidental HE. (47) Although these findings support the use of bioelectrical impedance (PhA) as a malnutrition prognostic marker in cirrhosis, studies comparing this technique to CT-SMI are warranted to demonstrate validity in the determination of sarcopenia. Importantly, modified scoring systems incorporating sarcopenia have shown promising results. (30,48) Using the CT-SMI, we have reported that sarcopenia was independently associated with a 2-fold risk of REVIEW ARTICLE 125

5 LIVER TRANSPLANTATION, January 2018 TABLE 1. Studies Describing Sarcopenia, CPE, and Frailty in Patients With Chronic Liver Disease Author/Year Feature n Prevalence Definition Method of Assessment Clinical Implication Englesbe et al. (23) (2010) Sarcopenia % Lowest quartile TPA CT Low TPA was associated with mortality after LT. Montano-Loza et al. (24) (2012) Sarcopenia % L3 SMI 38.5 cm 2 /m 2 for women and 52.4 cm 2 /m 2 for men CT Sarcopenia was independently associated with mortality. Tandon et al. (25) (2012) Sarcopenia % L3 SMI 38.5 cm 2 /m 2 for women and 52.4 cm 2 / m 2 for men Meza-Junco et al. (26) (2013) Sarcopenia % L3 SMI 38.5 cm 2 /m 2 for women and 52.4 cm 2 /m 2 for men CT CT Sarcopenia was associated with increased LT wait-list mortality. Sarcopenia was independently associated with mortality. Krell et al. (27) (2013) Sarcopenia % Lowest tertile TPA CT Lower TPA was associated with higher risk for post-lt infectious complications and mortality. Cruz et al. (28) (2013) Sarcopenia % SMI at L3-L4 CT SMI was significantly associated with survival after LT. DiMartini et al. (29) (2013) Sarcopenia % SMI at L3-L4 CT Muscle mass predicted ICU stay, total length of stay, and days of intubation. Durand et al. (30) (2014) Sarcopenia 562 NA TPMT/height at umbilicus CT TPMP index was predictive of mortality in patients with cirrhosis. Masuda et al. (31) (2014) Sarcopenia % PMA at L3 CT Sarcopenia was an independent prognostic factor for post-lt septic episodes and mortality. Tsien et al. (32) (2014) Sarcopenia 53 Pre-LT: 62% Post-LT: 87% Jeon et al. (33) (2015) Sarcopenia 145 Pre-LT: 36% Post-LT: 46% Carey et al. (34) (2017) Sarcopenia 396 Women: 33% Men: 50% Sex- and age-dependent 5th percentile of SMI Sex- and age-specific 5th percentile of PMI at L4 SMI 39 cm 2 /m 2 for women and 50 cm 2 / m 2 for men CT CT CT Pre-LT sarcopenia and post-lt muscle loss were associated with higher mortality. Elevated sarcopenia prevalence following LT was associated with higher mortality. Sarcopenia was independently associated with LT wait-list mortality. Belarmino et al. (4) (2017) Sarcopenia % DXA-ASMI 7 kg/m 2 DXA Sarcopenia in combination with handgrip strength was a predictor of mortality. Kalafateli et al. (35) (2017) Sarcopenia % Lowest quartile L3-PMI (34 cm 2 /m 2 for men and 26 cm 2 / m 2 for women) CT Dharancy et al. (36) (2008) CPE % VO 2peak < 60% predicted Incremental maximal cycle ergometer exercise Sarcopenia was associated with longer hospital stay and elevated risk of infections. Shorter survival and longer post-lt hospital stay were observed in patients with impaired aerobic capacity. 126 REVIEW ARTICLE

6 LIVER TRANSPLANTATION, Vol. 24, No. 1, 2018 TABLE 1. Continued Author/Year Feature n Prevalence Definition Method of Assessment Clinical Implication Carey et al. (37) (2010) CPE 121 N/A 6MWT < 250 meter 6MWT Higher mortality was observed in patients with low 6MWT. Lai et al. (38) (2017) Frailty 536 N/A Poor frailty index scores (>80th percentile) Grip strength, chair stands, and balance Tandon et al. (39) (2016) Frailty % Clinical Frailty Scale > 4 Rapid 1-minute bedside screen Sinclair et al. (40) (2017) Frailty % Fried Frailty score 3 Lai et al. (41) (2014) Frailty % Fried Frailty score 3 Combination of grip strength, gait speed, exhaustion, weight loss, and physical activity Consists of 5 components including gait speed, exhaustion, physical activity, unintentional weight loss, and weakness Combined MELD-Na and frailty index was a better predictor of wait-list mortality compared with the MELD-Na. Frailty was an independent predictor of the length of hospital stay and mortality. Frailty was an independent predictor of hospitalization and length of hospital stay. Frailty increased the risk of wait-list mortality. mortality, and that the modification of MELD to include sarcopenia (MELD-sarcopenia) was associated with improvement in the prediction of mortality in ESLD patients. (48) The observed benefit of modifying MELD was greatest in patients with low MELD scores, who are at a low risk of death (Fig. 2A). The importance of sarcopenia was reflected by the fact that if it is present, it is equivalent to adding 10 points to the MELD score. (48) Some studies indicate sarcopenia has been linked with higher mortality after LT, (23,28,29,31) whereas others have not found this association. (30,44) Sarcopenia was found to correlate with other post-lt outcomes such as infection, length of hospital, and intensive care unit (ICU) stay, (31,44) and patients with sarcopenia had higher occurrences of post-lt infections as compared with those without sarcopenia. (27,44) Sarcopenic obesity and myosteatosis, the convergence of sarcopenia and obesity, and an increase in skeletal muscle fatty infiltration, respectively, are 2 recently described body composition abnormalities that have also been associated with increased mortality in patients with cirrhosis. (42) Physical fitness, measured in terms of CPE, has also been associated with mortality in ESLD patients (Table 1). A study performing CPET in 135 LT candidates showed that 88% of patients had impaired fitness, with severe impairment (VO 2peak < 60% or predicted value) in 54% of patients. An inverse correlation was described between VO 2peak and MELD, and VO 2peak was predictive of 1-year wait-list survival (65% if severely impaired versus 96% if not; P ), even in patients with a MELD > 17. (36) The 6MWT was evaluated in 121 LT candidates and was significantly lower than a reference population. The 6MWT was inversely correlated with MELD score, and those patients in the lower tertile (<250 meters) were found to have higher waitlist mortality. In fact, every 100-meter decrease in performance predicted a 2-fold increase in mortality. (34) REVIEW ARTICLE 127

7 LIVER TRANSPLANTATION, January 2018 FIG. 2. C-statistics for 3- and 12-month mortality prediction in (A) patients with chronic liver disease comparing the use of MELD score and MELD1sarcopenia in the whole cohort (n 5 669; P and P , respectively) and in those with a MELD score < 15 (n 5 438; P and P , respectively); and (B) in patients listed for LT comparing MELD-Na, the frailty index score, and its combination (n 5 536; P values not reported). Physical Frailty in Patients With ESLD Physical frailty in patients with ESLD is characterized by sarcopenia, malnutrition, and physical deconditioning with a poor functional status. Tests of physical frailty have also been correlated with poor clinical outcomes in ESLD, again underlining the importance of complementing measures of muscle mass with those of muscle function (Table 1). (38,39) Importantly, frailty indexes improve prognostic performance of conventional scores (ie, MELD, Child-Turcotte-Pugh [CTP]) and should facilitate clinical decisions in ESLD patients. A study on 294 LT-listed patients using validated geriatric constructs identified frailty as an independent mortality predictor. For every 1-unit change, wait-list mortality increased by 19%-45%, though predictive usefulness was particularly helpful in those with MELD < 18. (41) More recently, the same group validated a novel frailty index score for LT-listed patients (consisting of grip strength, chair stands, and balance) showing that, when combined with Model for End-Stage Liver Disease sodium (MELD- Na; MELD-Na1Frailty), it outperformed risk prediction with MELD-Na alone (Fig. 2B), allowing reclassification of 19% of patients with or without predicted death/delisting. (38) These findings might have some practical implications, for instance, some patients with irreversible frailty might benefit from strategies to reduce the waiting time for LT, such as living donor related transplant or acceptance of high-risk donors. (38) Interventions Targeting Sarcopenia and Physical Fitness Given the challenges associated with defining and reversing sarcopenia, prevention during early stages of liver disease should be the main goal. Corrective measures should be taken to address sarcopenia, poor physical fitness, or frailty. Some considerations are discussed below. PHARMACOLOGICAL Testosterone was the focus of many early trials because it was found to be significantly decreased in men with cirrhosis. Recently, a 1-year controlled clinical trial of intramuscular testosterone in male ESLD patients with low serum testosterone demonstrated that testosterone safely increased muscle mass. (49) This finding was supported by a second trial using a transdermal approach. (50) These therapies would benefit only a subset of ESLD patients, though there is no specific recommendation on the use of androgen replacement therapy in ESLD, and longterm safety is unknown. A study with in vitro and in vivo data suggests that NH 3 -lowering treatment with L-ornithine-L-aspartate restores net protein balance, which could directly impact muscle mass in patients. (51) This agent is not available in the United States, and although a newer compound 128 REVIEW ARTICLE

8 LIVER TRANSPLANTATION, Vol. 24, No. 1, 2018 recently tested in a phase 2 clinical trial, ornithine phenylacetate, could potentially decrease hyperammonemia, it is unknown whether the concomitant urinary loss of phenylacetylglutamine would have a negative nutritional impact. Until more data from randomized clinical trials are available, these agents cannot be recommended for the treatment of sarcopenia. NUTRITIONAL Dietary management should be implemented for every sarcopenic patient, with regular follow-up to evaluate response. A dedicated nutritional team for ESLD patients is recommended, given the difficulties inherent to nutritional education and compliance. As a guideline, it is recommended to aim for an energy intake of kcal/kg/day and a protein intake of g/kg/day, although in patients with proven sarcopenia, 1.5 g/kg/day may be preferred. Protein intake should correspond to 15%-20% of the daily caloric intake, with 50%-60% derived from carbohydrates (primarily complex), and the rest from fat. (52) In terms of supplementation, BCAAs are the most widely studied in ESLD patients. Numerous studies have shown a beneficial effect of oral BCAA supplementation on muscle mass, and the sustained intake has been associated with improvement of health-related quality of life (HRQoL), decreased incidence of cirrhosis-related complications, particularly HE, and improvement of CTP and MELD scores. (53,54) Short-term and longterm studies have established the safety of BCAA, although their main limitation can be the low compliance due to the low palatability of some formulations. (55-57) Apart from BCAA supplements, the addition of a late evening snack containing carbohydrates has also been shown to improve muscle mass and energy metabolism. (58) The calories derived from these snacks can range from 200 to 400 kcal, with a clear effect even with 200 kcal/day. The snack should contain complex carbohydrates to prolong absorption overnight and provide dietary fiber, and patient s preferences should be considered in order to improve compliance. (57-60) The effect of hypercaloric formulations in ESLD patients has also been evaluated. One study showed a significant improvement of nitrogen balance in patients with enteral feeding immediately after LT. Another study used an oral supplement in sarcopenic patients listed for LT that was maintained until transplantation. There was a significant improvement in muscle mass and muscle strength, and a trend toward higher pre-lt survival. (61) Although enteral tube feeding is recommended in practice guidelines for patients not able to maintain adequate oral intake, (52) there is no robust evidence on the usefulness of such intervention in outpatients with ESLD. (52) Moreover, a recent study including inpatients with alcoholic hepatitis failed to demonstrate improved mortality among those receiving intensive enteral nutrition when compared with conventional oral nutrition; whereas, potential risks (eg, aspiration pneumonia) were reported. (62) Until further evidence is available, enteral feedings cannot be recommended for frail or sarcopenic patients with ESLD. TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT TIPS has been shown to exert a direct effect on body composition and other markers of nutritional status. (63) A study evaluated 57 patients undergoing TIPS placement and 32 matched patients with cirrhosis without TIPS. After a mean follow-up of months, total psoas and paraspinal CT muscle area increased significantly only in the TIPS group. Sarcopenia improved in 41 (72%) patients, though failure to reverse it predicted higher mortality compared with successful reversal (43.5% versus 9.8%). (64) Two other studies using bioelectrical impedance have shown progressive improvement in muscle mass after TIPS. (65,66) EXERCISE Exercise, in general, improves skeletal muscle mass, strength, endurance, and cardiopulmonary function. Some of its proven benefits (eg, on atherosclerotic disease, diabetes mellitus, and dyslipidemia) are of particular interest to ESLD patients with multisystemic disease such as nonalcoholic steatohepatitis. In patients with cirrhosis, despite the increasing interest in the effects of exercise, few clinical trials have been performed to date. A summary of these trials is presented on Table 2. It is important to note that a nutritional intervention was included in most exercise studies. We certainly recommend combining exercise with a nutritional intervention based on the notion that nutritional supplementation, when added to exercise, achieves better results than exercise alone. (74) However, for the purposes of this review, we will focus our attention on exercise interventions. REVIEW ARTICLE 129

9 LIVER TRANSPLANTATION, January 2018 TABLE 2. Summary of Studies Investigating an Exercise Intervention in Patients With Cirrhosis Author and Year Design Population Intervention Intensity and Duration Comparator (Adherence) Outcome Results Konishi et al. (67) (2011) Pattullo et al. (68) (2013) Roman et al. (69) (2014) Zenith et al. (70) (2014) Debette-Gratien et al. (71) (2015) Open noncontrolled clinical trial Open noncontrolled clinical trial 17 patients without cirrhosis, 3 patients with cirrhosis, CTP A 100% 10 patients without cirrhosis, 6 patients with cirrhosis, CTP A 83% (BMI 30 kg/m 2 ) RCT 20 patients with cirrhosis MELD 7-13 CTP A 82% RCT 20 patients with cirrhosis MELD 10 CTP A 84% Open noncontrolled clinical trial 13 patients with cirrhosis MELD 7-21 CTP A 63% 8-week exclusive dietary intervention ( g/kg of protein and adjusted calorie intake) followed by pedometer-guided intervention Pedometer-guided intervention 1 behavioral therapy 1 nutritional therapy (1.2 g/kg of protein and adjusted calorie intake) to all Supervised exercise (treadmill or cycle ergometry 1 hour, t.i.w.) L-Leucine to all Supervised exercise (cycle ergometry 40 minutes t.i.w.) 1 nutritional therapy (1.2 g/kg of protein and adjusted calorie intake) (1) to all Supervised exercise (cycle ergometry 20 minutes 1 resistance training 20 minutes, biw) Light (50%) 24 weeks Possibly moderate 24 weeks Moderate (60%-70%) 12 weeks Moderate (60%-80%) 8 weeks Moderate (70%-80%) 12 weeks Exercise (n 5 15) No control Exercise (n 5 16) No control Exercise (n 5 8) Control (n 5 9) Exercise (n 5 9) Control (n 5 10) Exercise (n 5 8) No control CPE 5 Steps/day IR 5 HOMA Body composition 5 BIA HRQoL 5 SF-36 Routine laboratories Adipokines, cytokines IR 5 HOMA and ISI CPE 5 Steps/day Diet 5 3-day food recall Anthropometry HRQoL 5 FIS, MADRS Routine laboratories Adipokines, cytokines CPE 5 6MWT, 2-meter ST SMM 5 thigh circumference Anthropometry HRQoL 5 SF-36 Routine laboratories CPE 5 CPET, 6MWT SMM 5 thigh US HRQoL Routine laboratories CPE 5 CPET, 6MWT SMM 5 quadriceps strength HRQoL 5 SF-36 HOMA-IR, BMI, subcutaneous and visceral fat, IL6, and leptin all improved with exercise (when step target was achieved) Trend for vitality (SF-36) HOMA-IR, hepatic ISI, CPE, weight, % body fat, WC, calorie intake, fatigue, mood, aminotransferases, and leptin improved with exercise. CPE, muscle mass, weight, HRQoL, Cr, and albumin all increased with exercise. No changes in controls CPE, SMM, and HRQoL all improved with exercise. No changes in controls CPE, SMM, mean maximal power, and mean ventilatory threshold power all improved with exercise. 130 REVIEW ARTICLE

10 LIVER TRANSPLANTATION, Vol. 24, No. 1, 2018 TABLE 2. Continued Comparator (Adherence) Outcome Results Intensity and Duration Author and Year Design Population Intervention HVPG, CPE, PhA (BIA), and hyper-nh3 all improved with exercise. HVPG increased in controls. HVPG HRQoL 5 CLDQ CPE 5 CRET Body composition 5 BIA Anthropometry Exercise-induced hyper-nh 3 Safety Exercise (n 5 11) Control (n 5 15) Moderate (60%-80%) 14 weeks Supervised exercise (cycle ergometry 40 minutes 1 kinesiotherapy 30 minutes, t.i.w) 1 nutritional therapy ( g/kg of protein and adjusted calorie intake) to all RCT 29 patients with cirrhosis MELD 7-14 CTP A 64% Macıas-Rodrıguez et al. (72) (2016) HVPG, CPE, heart rate, body weight, WC, fat mass, HOMA, QUICKI, adipokines, and HRQoL all improved with exercise. HVPG CPE 5 CRET Body composition 5 BIA HRQoL 5 CLDQ IR 5 HOMA and QUICKI Adipokines, cytokines Exercise (n 5 50) No control Light-Moderate (50%-60%) 16 weeks Gym-based exercise (60 minutes/week) 1 hypocaloric diet (restriction Kcal/ day, 0.8 g/kg protein) 60 patients with cirrhosis MELD CTP A 92% (BMI 25 kg/m 2 ) Open noncontrolled clinical trial Berzigotti et al. (73) (2017) Two early studies evaluated the effect of exercise in patients with chronic hepatitis C. The first study included 17 patients (3 patients with cirrhosis) who received a dietary plan for 8 weeks, followed by unsupervised walking for a minimum of 8000 steps/day (electronic pedometer) thrice per week for 24 weeks. Body composition including weight, body mass index (BMI), visceral and subcutaneous fat mass, along with homeostasis model assessment for insulin resistance (HOMA-IR) and alanine aminotransferase (ALT) levels, significantly improved by the end of the study. Interleukin 6 (IL6) and leptin decreased. However, no differences were seen in TNF-a or adiponectin levels. HRQoL measured with short-form 36 (SF-36) showed a positive trend in the vitality domain. (67) The second study included 16 patients with obesity (BMI > 30 kg/m 2 ) and insulin resistance (as per HOMA-IR > 2), 6 of whom were patients with cirrhosis, to a 24-week dietary and unsupervised physical activity lifestyle intervention. The exercise intervention consisted of an increase of 3000 steps/day (electronic pedometer) from baseline, or aiming for 10,000 total steps/day (whichever represented the largest change). As planned, caloric intake was significantly reduced (due to baseline obesity), and this was accompanied by a significant decrease in body weight and body fat, ALT, aspartate aminotransferase, gamma-glutamyl transpeptidase, fasting glucose, and insulin. Fifty percent of patients were no longer insulin resistant by the end of study (from hepatic insulin sensitivity). Leptin and adiponectin improved, whereas the cytokines showed no change. Fatigue and mood scores also improved. (68) Although these studies were small and focused on adiposity and insulin resistance, they provide proof-of-concept on the feasibility of unsupervised exercise interventions in liver disease. Four studies, including 3 randomized controlled trials (RCTs), have investigated the effects of a supervised exercise intervention. In all cases, patients had to attend specialized cardiac or pulmonary rehabilitation centers to exercise. In a pilot study evaluating the acceptability of a 12-week personalized exercise program in 13 patients with cirrhosis before LT, Debette- Gratien et al. found an improvement in physical fitness and muscular strength. The study design did not include a nutritional intervention, and most patients were CTP A. The main findings were an increase in the VO 2peak from to ml/kg/minute (P ); in the 6MWT, from to meters (P ); and in muscular strength (mean quadriceps isometric strength) from to REVIEW ARTICLE 131

11 LIVER TRANSPLANTATION, January kg/force (P ). There were no significant changes in quality of life. In the 8 patients who finished the protocol, there were no adverse events. (71) Roman et al. evaluated the effects of a 12-week randomized trial with aerobic exercise and leucine supplementation in 20 patients with cirrhosis. Of the 17 patients who finished the study, 9 were allocated to the control group and 8 to the exercise group. Most patients were CTP class A. In the exercise group, there was an improvement in physical fitness following the intervention, as determined both by the 6MWT (median [range], from 365 [ ] to 445 [ ] meters; P ) and the 2-minute step test (from 100 [40-140] to 150 [80-160] steps; P ). The lower thigh circumference, an indirect measure of muscle mass, was also increased (from 41 [34-53] to 46 [36-56] cm; P ). Finally, some domains corresponding to HRQoL were improved (3 of the 8 in SF-36). None of these changes were noted in the control group, and no relevant side effects were evident. (69) With a similar design, Zenith et al. studied 20 patients (most CTP A) with an 8-week combined intervention. Physical fitness improved in the active group after the intervention, with a significant change in VO 2peak of 5 ml/kg/minute from baseline, when compared with the control group (0.5 ml/kg/minute; P ). Although the between-group difference was not significant for 6MWT, it did improve from baseline in the exercise (from to meters; P ) but not in the control group (from to meters; P ). Increase in both thigh circumference and depth of the right quadriceps muscle determined by ultrasound were noted in the exercise group. Finally, activity and fatigue subscores, and self-perceived health status of the chronic liver disease questionnaire (CLDQ) improved as a result of exercise. Attrition rate was 1/10 in the exercise group, and no adverse events were realized during the study. (70) In a randomized trial, Macıas-Rodrıguez et al. evaluated the effects of a 14-week exercise intervention consisting of both aerobic (cycle ergometry) and resistance/stretching training (kinesiotherapy), plus nutritional intervention, in 29 patients with cirrhosis (most CTP A). All patients received beta-blockers during the study in order to prevent acute increases in portal hypertension while exercising. (75) Both active and control groups had 11 patients who completed the intervention. At the end of the study, the hepatic venous pressure gradient (HVPG) significantly decreased in the active group (22.5 [25.2 to 2] mm Hg; P ), but increased in controls (4 [0 to 5] mm Hg; P ), for a between-groups difference. Eliminating 3 patients with an unexplained HVPG increase in the control group did not change the between-group difference. Although no changes were noted in VO 2peak, the ventilatory efficiency (VE/VCO 2 ), another parameter of physical fitness, positively changed in the active group ( 1.9 [ 3.2 to 0.1; P ] versus 0.4 [ 5.7 to 1.4; P 5 0.4] in controls). PhA from bioelectrical impedance (likely reflecting changes in muscle mass), exercise-induced hyperammonemia (final CPET), and the worry domain from CLDQ also improved in the active group. Notably, silent ischemia was found in initial CPET in 3 patients (eliminated from study), and a hypertensive crisis occurred in a patient during final CPET. (72) A recent study evaluated the effect of a 16-week exercise and diet (hypocaloric, reduced protein) program in 60 overweight or obese patients with cirrhosis (almost exclusively CTP A) and portal hypertension (HVPG > 6 mm Hg). Exercise consisted of a personalized 60-minute weekly session at a local gym, aiming for low-to-moderate intensity. Compliance with exercise and diet were 88% and 84%, respectively. At the end of the intervention, a significant decrease in HVPG (21.7 mm Hg [ 10.7%]) and increase in VO 2peak (21 6 7to266 9 ml/kg/minute, P < 0.001) were observed. There was a significant decrease in body weight and fat, whereas no effect in muscle mass was observed. Notably, HVPG had a higher decrease in the subgroups of patients with higher weight loss (10%). Insulin resistance, total cholesterol, and leptin levels improved as well. Because exercise was not intense and frequent enough to improve muscle mass, the demonstrated changes were likely related to weight loss. (73) Exercise Prescription in ESLD Sarcopenia, physical deconditioning, and frailty are all frequent in ESLD and negatively impact clinical outcomes. Remarkably, these conditions can now be objectively evaluated and even quantified, as previously described. The recent interest in frailty assessment by many transplant centers in the United States aims to standardize what transplant physicians have recognized for a few decades, that despite no objective contraindication, some patients just do not pass the eyeball test for LT (ie, global perception of high vulnerability to 132 REVIEW ARTICLE

12 LIVER TRANSPLANTATION, Vol. 24, No. 1, 2018 FIG. 3. Survey results on clinical practice regarding exercise in patients with ESLD. stress). (41) The fact that MELD-sarcopenia and MELD-Na1Frailty are predictive of a higher mortality at lower MELD (<15) or MELD-Na (<18) scores opens the possibility of implementing interventions to improve physical fitness and sarcopenia. Ultimately, these interventions are directed to mitigating morbidity and mortality outcomes. Because exercise benefits multiple dimensions of physiological health and wellness, including improvement in portal hypertension (whether directly or indirectly through weight loss), it is reasonable to suggest that severely sarcopenic or frail LT candidates would benefit as well. However, these patients are at the lower end of physical deconditioning, most belonging to the CTP B/C categories or MELD > 20, and have not been included in clinical trials so far. New data including patients with decompensated liver disease need to emerge before a final conclusion on the benefits of exercise across the different stages of cirrhosis or ESLD can be reached. In order to better understand whether the hepatology community considers exercise an important intervention in ESLD, we performed a survey asking hepatologists about their daily clinical practice (Fig. 3). Survey results indicated that the great majority (87%) of hepatologists recognize the importance of exercise and that most routinely assess whether patients exercise regularly, educate them about its benefits, and provide specific exercise recommendations. Despite this common practice our most prominent professional associations, the American Association for the Study of Liver Diseases and European Association for the Study of the Liver, have yet to provide standardized recommendations on this matter. Our lack of guidance differs from other medical subspecialties where exercise as an intervention has been given higher priority, thus providing specific recommendations for daily clinical practice (Table 3). Preparticipation Evaluation Exercise is remotely associated with cardiovascular adverse events, particularly when nonvigorous activities are being performed. The American College of Sports Medicine (ACSM) recommends a medical evaluation prior to sports participation (preparticipation evaluation) for patients with 2 or more traditional risk factors for cardiovascular disease (eg, diabetes, dyslipidemia, ESLD, smoking) if vigorous activities are to be prescribed. An evaluation is warranted in patients with symptomatic or known cardiopulmonary or metabolic TABLE 3. Exercise Recommendations According to Guidelines From Some Professional Associations Exercise Parameter ADA (76) ACC/AHA (77) ACSM (78) DHHS (79) Population Type 1 and 2 diabetes Patients with hypercholesterolemia or hypertension Type Aerobic and resistance Aerobic training training Intensity Moderate-to-vigorous Moderate-to-vigorous activities activities Duration and frequency Other 150 minutes/week: at least 3 days/week and no more than 2 consecutive days without activity Flexibility and balance training for older adults minutes/week: 3-4 sessions per week, each lasting 40 minutes on average Older adults Aerobic, resistance and flexibility training Moderate and vigorous activities minutes/week: daily for minutes Balance exercises in persons with frequent falls or having mobility problems Adults Aerobic training Moderate 150 minutes/week: spread throughout the week (episodes 10 minutes) Resistance training 2 days/week for additional health benefits REVIEW ARTICLE 133

13 LIVER TRANSPLANTATION, January 2018 disease when planning for moderate-to-vigorous exercise. (80) There is no need for clearance for patients performing low-intensity activities, or if none to 1 cardiovascular risk factor are noted. Notably, no mention is made about any risk related to ESLD. Although most transplant candidates bear 2 or more cardiovascular risk factors (64% out of 204 patients evaluated in our transplant center, Al-Shoha et. al, unpublished data), very few have significant cardiopulmonary disease posing a contraindication for exercise. Moreover, patients on the waiting list attain cardiopulmonary clearance after an extensive workup, which includes transthoracic echocardiogram, cardiac stress testing, and pulmonary function tests. Therefore, except for symptomatic patients or those with known heart failure with reduced ejection fraction, portopulmonary hypertension, unexplained syncope, or type 1 diabetes mellitus, no specialized preparticipation evaluation is needed for LT candidates. Moreover, most associations agree that for low-to-moderate intensity activities not exceeding the demand of a brisk walk, there is no need for preparticipation clearance. (76) Under these circumstances, a gradual increase from low-intensity activities is an acceptable strategy. (81) Special consideration, however, should be given to patients with musculoskeletal disorders, as well as to those with frequent falls or problems with balance, for whom specialized consultation may be warranted. Type, Intensity, and Duration of Exercise in ESLD On the basis of randomized clinical trials (Table 2), three 40-to-70 minute sessions per week of supervised moderate intensity exercise (bicycle or treadmill) is a reasonable target goal for ESLD patients. However, apart from the research setting, it is difficult to justify attendance of ESLD patients to cardiopulmonary rehabilitation centers, particularly for a prolonged period of time. Furthermore, even if logistic and financial constraints were overcome, this type of intervention would be too onerous for most patients (ie, due to transportation, waiting time, and expenses for patient and companion). With accumulated evidence on the safety of submaximal physical training in ESLD, consideration of local resources and home-based exercise, commonly recommended for other chronic diseases, is appropriate. In this regard, 30-to-60 minute sessions combining both aerobic and resistance training to achieve 150 minutes/week is a reasonable recommendation for ESLD patients. However, contact and strenuous activities should be forbidden. Aerobic training would be particularly relevant to improve overall fitness and CPE, while resistance training would help reverse sarcopenia, improve strength and balance, and bone mineral density. Whether the use of weights is appropriate for patients with esophageal/gastric varices is unclear, and thus weight-bearing exercises or repetitions with small weights (1-2 lbs) are advised, as well as the use of beta-blockade when applicable. In frail patients with severe sarcopenia, balance and stretch training designed to strengthen postural muscles and improve range of motion is recommended prior to attempting aerobic and resistance training. Physical therapists, particularly with geriatric specialty, are a great resource for this initial phase. Duration of an exercise program should entail a minimum of 3 months in order to facilitate physiological adaptation. (78) Depending on the intensity of exercise and the degree of malnutrition, dietary interventions favoring protein or supplemental amino acid intake would be concomitantly warranted. Until proven useful in clinical trials, a pharmacologic intervention is not recommended (Fig. 4). Potential Benefits of Exercise in LT Candidates Despite the lack of evidence in reversing severe sarcopenia and frailty with exercise, cardiovascular rehabilitation and exercise literature clearly substantiate that, independently of the degree of physical deconditioning, all patients benefit from exercise training. Thus, it is conceivable for exercise to improve physical fitness (cardiovascular endurance), glucose control, and other features of the metabolic syndrome, adiposity, skeletal muscle strength and endurance, and sarcopenia. Effects at the musculoskeletal level should translate into improved balance (reducing propensity to falls), ambulation, sense of well-being, and caregiver independency. The latter is a particularly important goal, as caregiver burnout is an unaccountable cause for further ESLD deterioration in LT candidates. HVPG and NH 3 metabolism should improve as well, although no study has looked into the effects of exercise on HE or other complications derived from portal 134 REVIEW ARTICLE

14 LIVER TRANSPLANTATION, Vol. 24, No. 1, 2018 FIG. 4. Exercise model for patients with ESLD considering the type of exercise and its impact on physical fitness, sarcopenia/malnutrition, and frailty, as well as potential benefits on clinical outcomes. A nutritional intervention is always recommended along with physical training. hypertension. Larger and better-designed clinical trials investigating the role of exercise on clinical outcomes in LT candidates are needed. With approximately 1 in 5 wait-list patients dying or becoming too sick to transplant every year, (82) transplant providers are in need of new interventions to successfully bridge our patients to LT. Until more evidence is available, exercise provides an effective, safe, and affordable intervention to help our patients remain healthier and become less vulnerable while on the waiting list. Future Directions Lifestyle modification programs have been successful in improving health and well-being in multiple areas of medicine. Apart from tailored recommendations regarding exercise and diet, these programs focus on lifestyle changes favoring increased activities of daily living and nonexercise activity thermogenesis (NEAT). Examples of NEAT and corresponding energetic costs are shown in Table 4. NEAT is the main component of energy expenditure (thermogenesis), even in people who regularly exercise. (83) As such, targeting NEAT with exercise routines complements physical training and creates a more durable intervention. In order to improve patient s independency, activities of daily living should be emphasized as part of NEAT. In a previous study including 9 patients with hepatitis C related TABLE 4. Examples of NEAT and Corresponding Energetic Cost Activity Calories/hour Sitting or riding in an automobile 0-50 Standing Cooking dinner Cleaning Grocery shopping Sweeping or vacuuming Fishing Walking or pushing a stroller Climbing stairs Gardening or mowing lawn Dancing NOTE: Actual calories burned per hour (calories/hour) will vary depending on age, sex, weight, and activity intensity, among other factors. REVIEW ARTICLE 135