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Exercise in cirrhosis: Translating evidence and experience to practice

      Summary

      Physical inactivity, sarcopenia, and frailty are highly prevalent, independent predictors of morbidity and mortality in patients with cirrhosis. Across a range of chronic diseases, exercise training is a key recommendation supported by guidelines and, for some conditions, even by governmental funding of exercise programmes. Consistent with the broader chronic disease literature, the evidence for a benefit of exercise in cirrhosis is promising. Several small trials have reported significant improvements in muscle health (mass, strength, functional capacity), quality of life, fatigue, and reductions in the hepatic venous pressure gradient, without adverse events. With strong emerging evidence surrounding the substantial risks of sarcopenia/frailty and our first-hand experiences with liver pre-transplant exercise programmes, we contend that routine patient care in cirrhosis should include an exercise prescription. Some clinicians may lack the resources and necessary background to translate the existing evidence into a practicable intervention. Our team, comprised of physiotherapists, exercise physiologists, hepatologists, transplant specialists, and knowledge translation experts from six North American centres, has distilled the essential background information, tools, and practices into a set of information ready for immediate implementation into clinics ranging from a family practice setting to specialty cirrhosis clinics. Augmenting the rationale and evidence are supplementary materials including video and downloadable materials for both patients and the physician. Supporting the exercising patient is a section regarding information about nutrition, providing practical tips suitable for all patients with cirrhosis.

      Keywords

      Introduction

      In accordance with the American College of Sports Medicine (ACSM) guidelines for the management of people with chronic diseases and disabilities,
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
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      • Palazzini M.
      Exercise training in pulmonary hypertension: improving performance but waiting for outcome.
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      • Matthews C.
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      • Galvao D.A.
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      • et al.
      American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
      • Wickerson L.
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      • Janaudis-Ferreira T.
      • Deliva R.
      • Lo V.
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      • et al.
      Physical rehabilitation for lung transplant candidates and recipients: an evidence-informed clinical approach.
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      • King M.
      • Lui K.
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      American Association of Cardiovascular and Pulmonary RehabilitationAmerican College of Cardiology FoundationAmerican Heart Association Task Force on Performance Measures (Writing Committee to Develop Clinical Performance Measures for Cardiac Rehabilitation)
      Performance measures on cardiac rehabilitation for referral to cardiac rehabilitation/secondary prevention services.
      exercise training is a key recommendation for all patients with chronic disease. In its online teaching resource, the American Association for the Study of Liver Diseases recommends personalised exercise interventions for patients with cirrhosis.
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      • Dunn M.A.
      Arresting frailty and sarcopenia in cirrhosis: future prospects.
      The American Society for Transplantation has recommended a robust clinical research agenda for exercise interventions in patients in need of solid organ transplantation.
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      • et al.
      Meeting report: consensus recommendations for a research agenda in exercise in solid organ transplantation.
      In certain chronic disease populations, accumulated evidence has led to governmental funding of exercise rehabilitation programmes. Despite recommendations in cirrhosis, the application of exercise training in this population lags well behind that for other chronic diseases.
      • Galie N.
      • Manes A.
      • Palazzini M.
      Exercise training in pulmonary hypertension: improving performance but waiting for outcome.
      • Schmitz K.H.
      • Courneya K.S.
      • Matthews C.
      • Demark-Wahnefried W.
      • Galvao D.A.
      • Pinto B.M.
      • et al.
      American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
      • Wickerson L.
      • Rozenberg D.
      • Janaudis-Ferreira T.
      • Deliva R.
      • Lo V.
      • Beauchamp G.
      • et al.
      Physical rehabilitation for lung transplant candidates and recipients: an evidence-informed clinical approach.
      • Thomas R.J.
      • King M.
      • Lui K.
      • et al.
      American Association of Cardiovascular and Pulmonary RehabilitationAmerican College of Cardiology FoundationAmerican Heart Association Task Force on Performance Measures (Writing Committee to Develop Clinical Performance Measures for Cardiac Rehabilitation)
      Performance measures on cardiac rehabilitation for referral to cardiac rehabilitation/secondary prevention services.
      This may in part be because of initial caution about acute rises in portal pressure with exercise,
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      • Santos C.
      • Barbera J.A.
      • Luca A.
      • Roca J.
      • Rodriguez-Roisin R.
      • et al.
      Physical exercise increases portal pressure in patients with cirrhosis and portal hypertension.
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      • Francois E.
      • Moitinho E.
      • Rodes J.
      • et al.
      Effects of propranolol on the hepatic hemodynamic response to physical exercise in patients with cirrhosis.
      however recent controlled trials have consistently demonstrated safety, improvements in physical fitness, muscle mass and health-related quality of life (HRQoL).
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      • Savier E.
      • Scatton O.
      Physical exercise in cirrhotic patients: towards prehabilitation on waiting list for liver transplantation. A systematic review and meta-analysis.
      • Duarte-Rojo A.
      • Ruiz-Margain A.
      • Montano-Loza A.J.
      • Macias-Rodriguez R.U.
      • Ferrando A.
      • Kim W.R.
      Exercise and physical activity for patients with end-stage liver disease: Improving functional status and sarcopenia while on the transplant waiting list.
      • Jones J.C.
      • Coombes J.S.
      • Macdonald G.A.
      Exercise capacity and muscle strength in patients with cirrhosis.
      Overall physical activity levels in cirrhosis are low, with 76% of waking hours spent in the sedentary state.
      • Wickerson L.
      • Rozenberg D.
      • Janaudis-Ferreira T.
      • Deliva R.
      • Lo V.
      • Beauchamp G.
      • et al.
      Physical rehabilitation for lung transplant candidates and recipients: an evidence-informed clinical approach.
      • Dunn M.A.
      • Josbeno D.A.
      • Schmotzer A.R.
      • Tevar A.D.
      • DiMartini A.F.
      • Landsittel D.P.
      • et al.
      The gap between clinically assessed physical performance and objective physical activity in liver transplant candidates.
      • Wallen M.P.
      • Skinner T.L.
      • Pavey T.G.
      • Hall A.
      • Macdonald G.A.
      • Coombes J.S.
      Safety, adherence and efficacy of exercise training in solid-organ transplant candidates: a systematic review.
      • Ney M.
      • Gramlich L.
      • Mathiesen V.
      • Bailey R.J.
      • Haykowsky M.
      • Ma M.
      • et al.
      Patient-perceived barriers to lifestyle interventions in cirrhosis.
      Multiple barriers to activity exist including the lack of available supervised or home-based exercise programmes, symptoms of fatigue and a lack of practical evidence-based tools for clinicians to translate the literature into a safe, effective exercise assessment and prescription.
      • Ney M.
      • Gramlich L.
      • Mathiesen V.
      • Bailey R.J.
      • Haykowsky M.
      • Ma M.
      • et al.
      Patient-perceived barriers to lifestyle interventions in cirrhosis.
      Ideally, every cirrhosis patient would have ready-access to a certified exercise professional to perform a detailed functional assessment and design a patient-specific exercise regimen that is modified at regular follow-up sessions. Unfortunately, this is not the reality. Even among the most highly resourced patients with cirrhosis (patients on the liver transplant waiting list), as an example, only one in seven Canadian centres offers regularly scheduled exercise programming.
      • Trojetto T.
      • Elliott R.J.
      • Rashid S.
      • Wong S.
      • Dlugosz K.
      • Helm D.
      • et al.
      Availability, characteristics, and barriers of rehabilitation programs in organ transplant populations across Canada.
      Consistent with the ACSM guidelines for chronic disease
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      and our collective experience from six North American centres, we support personalised exercise programming as an essential tool to empower patients to maintain independence in their daily life and optimise their fitness and health, especially while awaiting liver transplantation. The aim of this article is to summarise cirrhosis-specific exercise data and guideline-based exercise recommendations into a practical approach shaped by our clinical experience. The evidence was assimilated using a rapid structured review of the literature. Through the data-gathering and writing process, teleconferences were held to supplement the evidence with consensus-based suggestions of the authors’ guidance on best practices.
      We present a three-step process involving: i) screening to minimise exercise-related adverse events, ii) baseline physical capacity assessment, and iii) exercise programming with subsequent monitoring. Although this process is ideally carried out by a multidisciplinary group led by a CEP (certified exercise professional), if this is not available, clinicians wanting to provide their patients with an exercise prescription can mix and match the options provided in each step of this manuscript, based on consideration of staffing and resources at their clinic. It is essential that all suggestions provided are tailored for each patient and implemented conservatively using caution and common sense. The easy-to-use set of patient handouts included in the supplementary materials support prescribing and promoting cirrhosis-specific exercise by clinicians from all specialties (e.g., family physicians to hepatologists). In patients where exercise safety or efficacy is unclear, or where a CEP, such as a licensed physiotherapist or certified personal trainer (e.g. from the Canadian Society for Exercise Physiology or the American College of Sports Medicine) is readily available, patients should be referred to the CEP as a first-line therapeutic option.

      Rationale for exercise training

      Physical inactivity, sarcopenia, and frailty are highly prevalent, independent predictors of morbidity and mortality in cirrhosis.
      Sedentary time is one of the strongest known predictors of adverse outcomes including all-cause mortality, cardiovascular disease, malignancy, musculoskeletal disease and metabolic disorders.
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      Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis.
      In cirrhosis, a high prevalence of physical inactivity works in combination with multiple other factors including aging, malnutrition, decreased hepatic protein synthesis, hypermetabolism, an increase in inflammatory cytokines, hyperammonemia and low testosterone levels. Cardiac and skeletal muscle deconditioning result in reduced cardiovascular function and reserve, physical frailty, decreased skeletal muscle mass (sarcopenia), strength, and HRQoL.
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      • Asa S.L.
      • Gonzalez-Cadavid N.
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      Myostatin is a skeletal muscle target of growth hormone anabolic action.
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      Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration.
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      MuRF-1 and p-GSK3beta expression in muscle atrophy of cirrhosis.
      • Sinclair M.
      • Gow P.J.
      • Grossmann M.
      • Shannon A.
      • Hoermann R.
      • Angus P.W.
      Low serum testosterone is associated with adverse outcome in men with cirrhosis independent of the model for end-stage liver disease score.
      • Mazurak V.C.
      • Tandon P.
      • Montano-Loza A.J.
      Nutrition and the transplant candidate.

      Sarcopenia

      Sarcopenia is present in 22–62%
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      Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma.
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      • Prado C.M.
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      • Baracos V.E.
      • Bain V.G.
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      Muscle wasting is associated with mortality in patients with cirrhosis.
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      • Harimoto N.
      • Yoshizumi T.
      • Soejima Y.
      • et al.
      Sarcopenia is a prognostic factor in living donor liver transplantation.
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      • Levolger S.
      • de Bruin R.W.
      • van Rosmalen J.
      • Metselaar H.J.
      • Ijzermans J.N.
      Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation.
      of patients with cirrhosis, is most common in those with advanced disease
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      • Levolger S.
      • de Bruin R.W.
      • van Rosmalen J.
      • Metselaar H.J.
      • Ijzermans J.N.
      Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation.
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      • Dasarathy S.
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      • et al.
      A multicenter study to define sarcopenia in patients with end-stage liver disease.
      and is independently associated with both waiting list and post-liver transplant morbidity (infection rates and length of hospital and intensive care unit stay
      • Montano-Loza A.J.
      • Meza-Junco J.
      • Prado C.M.
      • Lieffers J.R.
      • Baracos V.E.
      • Bain V.G.
      • et al.
      Muscle wasting is associated with mortality in patients with cirrhosis.
      • Masuda T.
      • Shirabe K.
      • Ikegami T.
      • Harimoto N.
      • Yoshizumi T.
      • Soejima Y.
      • et al.
      Sarcopenia is a prognostic factor in living donor liver transplantation.
      • van Vugt J.L.
      • Levolger S.
      • de Bruin R.W.
      • van Rosmalen J.
      • Metselaar H.J.
      • Ijzermans J.N.
      Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation.
      • Cruz Jr., R.J.
      • Dew M.A.
      • Myaskovsky L.
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      • Fox K.
      • Fontes P.
      • et al.
      Objective radiologic assessment of body composition in patients with end-stage liver disease: going beyond the BMI.
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      Muscle mass predicts outcomes following liver transplantation.
      • Englesbe M.J.
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      • et al.
      Sarcopenia and mortality after liver transplantation.
      • Tandon P.
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      • Irwin I.
      • Ma M.M.
      • Gramlich L.
      • Bain V.G.
      • et al.
      Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value.
      ) and mortality.
      • van Vugt J.L.
      • Levolger S.
      • de Bruin R.W.
      • van Rosmalen J.
      • Metselaar H.J.
      • Ijzermans J.N.
      Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation.
      The addition of sarcopenia to scoring systems has improved their predictive utility,
      • Durand F.
      • Buyse S.
      • Francoz C.
      • Laouenan C.
      • Bruno O.
      • Belghiti J.
      • et al.
      Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.
      • Montano-Loza A.J.
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      • Baracos V.E.
      • Sawyer M.B.
      • Pang J.X.
      • et al.
      Inclusion of sarcopenia within MELD (MELD-sarcopenia) and the prediction of mortality in patients with cirrhosis.
      • van Vugt J.L.A.
      • Alferink L.J.M.
      • Buettner S.
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      • Bot D.
      • Darwish Murad S.
      • et al.
      A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: a competing risk analysis in a national cohort.
      with the greatest benefit of the combined model for end-stage liver disease (MELD)-sarcopenia score observed in patients with a low MELD score (MELD ≤15), who are traditionally deemed to have a low risk of death.
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      • Meza-Junco J.
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      • Sawyer M.B.
      • Pang J.X.
      • et al.
      Inclusion of sarcopenia within MELD (MELD-sarcopenia) and the prediction of mortality in patients with cirrhosis.
      A recent article put a price tag on sarcopenia, stating that their hospital costs (median estimated) were nearly double those of patients without sarcopenia.
      • van Vugt J.L.A.
      • Buettner S.
      • Alferink L.J.M.
      • Bossche N.
      • de Bruin R.W.F.
      • Darwish Murad S.
      • et al.
      Low skeletal muscle mass is associated with increased hospital costs in patients with cirrhosis listed for liver transplantation-a retrospective study.

      Reduced cardiorespiratory fitness

      Oxygen uptake during peak aerobic exercise is the gold standard measure of aerobic power (peak VO2) while the distance covered during a 6-min walk test (6MWT) is a measure of aerobic endurance. A reduction in each of these measures correlates with increased mortality
      • Dharancy S.
      • Lemyze M.
      • Boleslawski E.
      • Neviere R.
      • Declerck N.
      • Canva V.
      • et al.
      Impact of impaired aerobic capacity on liver transplant candidates.
      • Alameri H.F.
      • Sanai F.M.
      • Al Dukhayil M.
      • Azzam N.A.
      • Al-Swat K.A.
      • Hersi A.S.
      • et al.
      Six Minute Walk Test to assess functional capacity in chronic liver disease patients.
      • Carey E.J.
      • Steidley D.E.
      • Aqel B.A.
      • Byrne T.J.
      • Mekeel K.L.
      • Rakela J.
      • et al.
      Six-minute walk distance predicts mortality in liver transplant candidates.
      • Ney M.
      • Haykowsky M.J.
      • Vandermeer B.
      • Shah A.
      • Ow M.
      • Tandon P.
      Systematic review: pre- and post-operative prognostic value of cardiopulmonary exercise testing in liver transplant candidates.
      and may be a more sensitive predictor of mortality than sarcopenia.
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      • Chang Y.H.
      • Carpenter S.
      • Silva A.C.
      • Rakela J.
      • Aqel B.A.
      • et al.
      Relationship between sarcopenia, six-minute walk distance and health-related quality of life in liver transplant candidates.
      In a systematic review of 1,107 cirrhotic patients who underwent liver transplant (LT) evaluation, the mean VO2peak was 17.4 ml/kg/min, a value falling below the minimum level required for full and independent living (<18 ml/kg/min) and corresponding to the VO2 expected of a sedentary female in the eighth decade of life.
      • Ney M.
      • Haykowsky M.J.
      • Vandermeer B.
      • Shah A.
      • Ow M.
      • Tandon P.
      Systematic review: pre- and post-operative prognostic value of cardiopulmonary exercise testing in liver transplant candidates.
      • Forman D.E.
      • Arena R.
      • Boxer R.
      • Dolansky M.A.
      • Eng J.J.
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      • et al.
      Prioritizing functional capacity as a principal end point for therapies oriented to older adults with cardiovascular disease: a scientific statement for healthcare professionals from the American Heart Association.
      A lower aerobic endurance for activity (as measured by the 6MWT) has also been linked to poor prognosis. Specifically, after adjusting for age and native MELD score, patients with a 6MWT <250 m had a twofold increase in mortality for every 100 m decrease in walking distance.
      • Carey E.J.
      • Steidley D.E.
      • Aqel B.A.
      • Byrne T.J.
      • Mekeel K.L.
      • Rakela J.
      • et al.
      Six-minute walk distance predicts mortality in liver transplant candidates.

      Exercise improves health outcomes in cirrhosis

      Exercise is associated with a wide range of health-related benefits (Fig. 1). Few published clinical trials have been exclusively dedicated to exercise in patients with cirrhosis (Table 1).
      • Brustia R.
      • Savier E.
      • Scatton O.
      Physical exercise in cirrhotic patients: towards prehabilitation on waiting list for liver transplantation. A systematic review and meta-analysis.
      • Duarte-Rojo A.
      • Ruiz-Margain A.
      • Montano-Loza A.J.
      • Macias-Rodriguez R.U.
      • Ferrando A.
      • Kim W.R.
      Exercise and physical activity for patients with end-stage liver disease: Improving functional status and sarcopenia while on the transplant waiting list.
      • Jones J.C.
      • Coombes J.S.
      • Macdonald G.A.
      Exercise capacity and muscle strength in patients with cirrhosis.
      Programmes ranging from 8–14 weeks of supervised aerobic exercise training have been associated with consistent improvements in peak VO2, aerobic endurance, muscle mass and strength, HRQoL and reductions in the hepatic venous pressure gradient (HVPG). It remains unclear whether the reduction in the HVPG seen after 12–16 weeks of exercise is related exclusively to exercise
      • Macias-Rodriguez R.U.
      • Ilarraza-Lomeli H.
      • Ruiz-Margain A.
      • Ponce-de-Leon-Rosales S.
      • Vargas-Vorackova F.
      • Garcia-Flores O.
      • et al.
      Changes in hepatic venous pressure gradient induced by physical exercise in cirrhosis: results of a pilot randomized open clinical trial.
      or to weight loss and concurrent decreases in hepatic steatosis/resistance,
      • Berzigotti A.
      • Albillos A.
      • Villanueva C.
      • Genesca J.
      • Ardevol A.
      • Augustin S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study.
      but it is promising that exercise could reduce the risk of clinical decompensation in cirrhosis. The impact on post-transplant outcomes remains an area requiring evaluation, as does the use of home-based programming, which has been evaluated in two studies.
      • Kruger C.
      • McNeely M.L.
      • Bailey R.J.
      • Yavari M.
      • Abraldes J.G.
      • Carbonneau M.
      • et al.
      Home exercise training improves exercise capacity in cirrhosis patients: role of exercise adherence.
      • Hiraoka A.
      • Michitaka K.
      • Kiguchi D.
      • Izumoto H.
      • Ueki H.
      • Kaneto M.
      • et al.
      Efficacy of branched-chain amino acid supplementation and walking exercise for preventing sarcopenia in patients with liver cirrhosis.
      In cirrhosis, exercise studies have reported improvements in muscle health, quality of life, fatigue, and reductions in the hepatic venous portal gradient, without adverse events.
      Figure thumbnail gr1
      Fig. 1Benefits of exercise for the patient with cirrhosis. Exercise has multiple benefits, resulting from both central (cardiovascular and pulmonary) adaptations and peripheral adaptations. A simplified version of this Figure is provided in the – patient package.
      Table 1Clinical trials of exercise in patients with cirrhosis. *Additional exclusion criteria for studies not detailed here included: varices, alcohol consumption, etc. 6MWT, 6-min walk test; BCAA, branched chain amino acids; BIA, bioelectrical impedance analysis; CHF, chronic heart failure; CP, cardiopulmonary; CPE, cardiopulmonary endurance; CTP, Child-Turcotte-Pugh; Ctrl, control study group; HR, heart rate; HRQoL, health-related quality of life; HVPG, hepatic venous pressure gradient; Int, intervention study group; LVEF, left ventricular ejection fraction; MELD, model for end-stage liver disease; NSD, no significant difference; RCT, randomised controlled trial.
      1st Author, year, study design, durationCharacteristics, CP, exclusion criteria*Study group(s)Outcomes
      Roman 2014
      • Roman E.
      • Torrades M.T.
      • Nadal M.J.
      • Cardenas G.
      • Nieto J.C.
      • Vidal S.
      • et al.
      Randomized pilot study: effects of an exercise programme and leucine supplementation in patients with cirrhosis.
      , RCT, 12 weeks
      MELD 7–13, CP-A 82% n = 17, “Marked symptomatic comorbidities”Int: supervised moderate exercise (n = 8).

      Ctrl: (n = 9)

      All pts received leucine (10 g/d)
      Within group comparison relative to baseline measures:

      Int: 6MWT (365 vs. 445 m, p = 0.01) and 2-min step test (p = 0.02); thigh muscle mass (41 vs. 46 cm, p = 0.02); SF-36: general health, vitality & social function significantly improved. Ctrl: NSD
      Zenith 2014
      • Zenith L.
      • Meena N.
      • Ramadi A.
      • Yavari M.
      • Harvey A.
      • Carbonneau M.
      • et al.
      Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis.
      , RCT, 8 weeks
      MELD 10, CP-A 84%, n = 20, LVEF < 60%, history of CAD, positive exercise stress testInt: supervised aerobic exercise + 250–300 kcal on exercise days (n = 9).

      Ctrl: usual care (n = 10)
      Between group comparison, with Int better than Ctrl for:

      Peak V02 being 5.3 ml/kg/min higher (p = 0.01); thigh muscle mass (p = 0.01); thigh circumference (p = 0.001); EQ-VAS self–perceived health (p = 0.01); less fatigue (p = 0.01)
      Debette-Gratien

      2015
      • Debette-Gratien M.
      • Tabouret T.
      • Antonini M.T.
      • Dalmay F.
      • Carrier P.
      • Legros R.
      • et al.
      Personalized adapted physical activity before liver transplantation: acceptability and results.
      , cohort, 12 weeks
      MELD 13–21, CP-A 63%

      n = 13, LVEF <45%, positive stress test; all completed max exercise threshold & pulmonary function testing
      Supervised exercise

      Improvements seen relative to baseline measures:

      Peak V02 being 1.7 ml/kg/min higher (p <0.008); maximum power (p = 0.02); 6MWT (p <0.02); knee extensor muscle (p = 0.008); ventilatory threshold power (p = 0.02) [Study dropouts, n = 6]
      Macias–Rodriguez

      2016
      • Macias-Rodriguez R.U.
      • Ilarraza-Lomeli H.
      • Ruiz-Margain A.
      • Ponce-de-Leon-Rosales S.
      • Vargas-Vorackova F.
      • Garcia-Flores O.
      • et al.
      Changes in hepatic venous pressure gradient induced by physical exercise in cirrhosis: results of a pilot randomized open clinical trial.
      , RCT, 14 weeks
      MELD 7–14, CP-A 64%

      n = 22, “Cardiopulmonary disease”
      Int: Supervised exercise + 30% calories on exercise days (n = 11).

      Ctrl: (n = 11)

      All received nutrition therapy according to HBE
      Between group comparison, with Int better than Ctrl for:

      HVPG being 6.5 mmHg lower (p = 0.009); within group comparison relative to baseline showed Int had significant improvements in ventilatory efficiency (p = 0.033).

      Ctrl: NSD
      Roman 2016
      • Roman E.
      • Garcia-Galceran C.
      • Torrades T.
      • Herrera S.
      • Marin A.
      • Donate M.
      • et al.
      Effects of an exercise programme on functional capacity, body composition and risk of falls in patients with cirrhosis: a randomized clinical trial.
      , RCT, 12 weeks
      MELD 8 ± 0.4, CP-A 5.4 ± 0.2 n = 23, “Contraindication to exercise”Int: supervised exercise (n = 14).

      Ctrl: relaxation programme (n = 9)
      Within group comparison relative to baseline showed Int had:

      Muscle mass increase (p <0.01); fat body mass decrease (p = 0.003); lean body mass increase (p ≤ 0.03); fall risk decrease (p = 0.02)

      Ctrl: NSD
      Berzigotti 2017
      • Berzigotti A.
      • Albillos A.
      • Villanueva C.
      • Genesca J.
      • Ardevol A.
      • Augustin S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study.
      , cohort, 16 weeks
      MELD 9 ± 3, CP-A 92%

      n = 60, BMI 26 kg/m2, “History of CAD”
      Supervised/gym exercise + 500–1,000 kcal/d reduction in dietWithin group comparison relative to baseline showed improvements in:

      Body mass decrease by 5 kg (p <0.0001); HVPG decreased by 1.6 mmHg (p <0.001) [Study dropouts, n = 10]
      Kruger 2018
      • Kruger C.
      • McNeely M.L.
      • Bailey R.J.
      • Yavari M.
      • Abraldes J.G.
      • Carbonneau M.
      • et al.
      Home exercise training improves exercise capacity in cirrhosis patients: role of exercise adherence.
      , RCT,

      8 weeks
      CP-A 70% (n = 40),

      history of LVEF <60% or CAD, or positive outcome on exercise stress test
      Int: home-based exercise + 250–350 kcal on exercise days (n = 20).

      Ctrl: usual care (n = 20)

      All pts received guideline-based nutrition counselling
      Between group comparison, with Int better than Ctrl for:

      6MWT increase by 33.7 m (p = 0.02).

      Between group comparison for Int adherents (≥80% training sessions) better than Ctrls for: 6MWT increase by 46.4 m (p = 0.009); peak VO2 increase by 2.8 ml/kg/min (p = 0.02) [Study dropouts, n = 3]
      Hiraoka, 2017
      • Hiraoka A.
      • Michitaka K.
      • Kiguchi D.
      • Izumoto H.
      • Ueki H.
      • Kaneto M.
      • et al.
      Efficacy of branched-chain amino acid supplementation and walking exercise for preventing sarcopenia in patients with liver cirrhosis.
      , cohort, 12 weeks
      CP-A 91% (n = 33),

      patients with “other organ disease” – CHF, chronic respiratory disease
      Home-based exercise + 210 kcal snack and 13.5 g BCAA at night

      (n = 33)
      Increases seen relative to baseline measures:

      Average daily steps (p = 0.02); muscle volume, leg and handgrip strength (p <0.01 for each); BCAA/tyrosine ratio (p = 0.001) [Study dropouts, n = 2]

      Is my patient safe to start an exercise programme?

      As presented (Table 2), the pre-exercise safety screen can be divided into three major categories: disease-related safety issues, screening for cardiopulmonary safety, and assessing the impact of other comorbidities. As discussed in Exercise training principles and components, as a key safety feature, the programme should be personalised by asking each patient to maintain activity at a rate of perceived exertion (RPE) no more than 5–6/10 on a Borg 0–10 scale,
      • Borg G.
      Physical work and effort.
      an intensity that is “somewhat hard” but still allows them to talk.
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      Table 2Pre-screening to establish exercise safety and intensity. **For all patients, exercise should be guided by the rate of perceived exertion and start at the introductory level unless otherwise specified. CEP, certified exercise professional; MELD, model for end-stage liver disease.
      TopicExercise prescription modification
      Part I Cirrhosis-related screening
        MELD >20?Case-by-case assessment to determine if CEP referral is needed for the patient to progress beyond Introductory exercises
        High-risk varices?Ensure adequate primary or secondary variceal prophylaxis is in place prior to programme
        Hepatic encephalopathy?Medical optimisation of hepatic encephalopathy prior to exercising; programming supervised by caregivers or if not possible, requires CEP supervision
        Ascites?Optimise medical management; progress beyond introductory exercise on days where ascites accumulation is insignificant and/or does not affect balance; caregiver supervision is ideal
        Platelets <20,000/µl or Hb <8.0 g/dlExercise limited to Introductory level to avoid falls and/or injury
        Diabetes mellitus?Blood glucose checks completed before and after exercising (hypoglycaemia unawareness)
      • Colberg S.R.
      • Sigal R.J.
      • Yardley J.E.
      • Riddell M.C.
      • Dunstan D.W.
      • Dempsey P.C.
      • et al.
      Physical activity/exercise and diabetes: a position statement of the american diabetes association.
        Diuretic therapy?At-risk of volume depletion and hypotension with exercise. Prescribe a home blood pressure monitor for use after exercising
      • Sawka M.N.
      • Burke L.M.
      • Eichner E.R.
      • Maughan R.J.
      • Montain S.J.
      • et al.
      American College of Sports Medicine
      American College of Sports Medicine position stand. Exercise and fluid replacement.
      Part II Cardiopulmonary safety concerns
       “Medical clearance” required if any of the following are present
        Signs and SymptomsChest discomfort with exertion; unreasonable breathlessness; dizziness, fainting, blackouts; heart palpitations; lower limb claudication; known heart murmur
        Past or current medical conditionsHeart attack; heart surgery, cardiac catheterisation, or coronary angioplasty; pacemaker/implantable cardiac defibrillator/rhythm disturbance; heart valve disease; heart failure; heart transplantation; congenital heart disease; diabetes; renal disease; ***The method of “Medical Assessment” is left at the discretion of the physician
      • Riebe D.
      • Franklin B.A.
      • Thompson P.D.
      • Garber C.E.
      • Whitfield G.P.
      • Magal M.
      • et al.
      Updating ACSM’s recommendations for exercise preparticipation health screening.
      Part III Overall physiological competence
        Heart rate >100 or <50; systolic blood pressure >160 mmHg or <85; diastolic blood pressure >110 mmHg or <50 mmHg; oxygen saturation <92%Raises concerns about patient’s physiological competence to complete unsupervised exercises
      Patient requires “medical clearance” before receiving an exercise prescription. Will likely require CEP supervised programming
        Specific musculoskeletal (MSK) limitations: history of arthritis, joint swelling, or MSK conditions that limit ambulation or daily activitiesReferral to physiotherapy for pre-exercise counselling and therapy
      May require CEP to perform assessment and specialised programming if MSK issues are unresolved
        Fall risk: history of ≥3 falls within the last year; Hb <8.0 g/dl; hepatic encephalopathy; instability or unsteadiness observed during baseline testingExercise in supported positions to avoid falls/injury (Intro level)
      Progression beyond Introductory exercises requires CEP consultation and supervision
      Exclusion criteria in published cirrhosis exercise trials vary between studies (Table 1). Although the trials universally excluded patients without adequate primary or secondary prophylaxis for varices, others excluded patients with hepatocellular carcinoma, cardiopulmonary disease (identified by various screening techniques – Table 1), alcohol consumption within the past three months, haemoglobin level <110 g/L, mental or physical disabilities preventing exercise, or other significant comorbidities.

      Cirrhosis-related safety considerations

      The 2015 Baveno VI Consensus recommends screening for varices in all cirrhosis patients with a Fibroscan score ≥20 kPa or platelet count ≤150,000/µl.
      • de Franchis R.
      • Baveno V.I.
      Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      If high-risk varices are seen or if the patient has had a previous variceal bleed, primary or secondary variceal prophylaxis must be in place before exercise is prescribed.
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      For other cirrhosis-related considerations, none are absolute contraindications to low-intensity activity, however large volume ascites, pedal oedema, and hepatic encephalopathy (HE) can impact the efficacy of the exercise prescription as well as adherence and tolerability,
      • Jones J.C.
      • Coombes J.S.
      • Macdonald G.A.
      Exercise capacity and muscle strength in patients with cirrhosis.
      thereby necessitating some exercise programme modifications (Table 2). In patients with transient or overt HE, readiness to engage, understand, and safely follow-through with exercise directions should be considered, however we do not routinely carry out testing for covert HE before prescribing exercise. The one caveat in these patients is that a caregiver must be present during exercise sessions. Studies in patients with acute brain injury, dementia, and serious mental illness support the efficacy and feasibility of exercise despite cognitive issues.
      • Browne J.
      • Mihas P.
      • Penn D.L.
      Focus on exercise: client and clinician perspectives on exercise in individuals with serious mental illness.
      • Jones T.M.
      • Dear B.F.
      • Hush J.M.
      • Titov N.
      • Dean C.M.
      MyMoves program: feasibility and acceptability study of a remotely delivered self-management program for increasing physical activity among adults with acquired brain injury living in the community.
      • van der Wardt V.
      • Hancox J.
      • Gondek D.
      • Logan P.
      • Nair R.D.
      • Pollock K.
      • et al.
      Adherence support strategies for exercise interventions in people with mild cognitive impairment and dementia: a systematic review.
      Although thrombocytopenia is not considered a contraindication to exercise, in keeping with data in stem cell transplant patients,
      • Ibanez K.
      • Espiritu N.
      • Souverain R.L.
      • Stimler L.
      • Ward L.
      • Riedel E.R.
      • et al.
      Safety and feasibility of rehabilitation interventions in children undergoing hematopoietic stem cell transplant with thrombocytopenia.
      exercises with high risk of injury or falling should be avoided, especially if platelets are <20,000/µl.

      Cardiopulmonary safety screening

      Recognising the high prevalence of cardiovascular risk factors in the population and their low correlation with events, guidelines have shifted to no longer require mandatory cardiac testing for individuals with ≥2 traditional cardiac risk factors (e.g., male age >45 y, female age >55 y, hyperlipidemia, hypertension, tobacco use, family history of early coronary artery disease [first-degree relative male <55 y, female <65 y]).
      • Pescatello L.S.
      • Devaney J.M.
      • Hubal M.J.
      • Thompson P.D.
      • Hoffman E.P.
      Highlights from the functional single nucleotide polymorphisms associated with human muscle size and strength or FAMuSS study.
      • Riebe D.
      • Franklin B.A.
      • Thompson P.D.
      • Garber C.E.
      • Whitfield G.P.
      • Magal M.
      • et al.
      Updating ACSM’s recommendations for exercise preparticipation health screening.
      More recent recommendations like the ACSM guidelines,
      • Riebe D.
      • Franklin B.A.
      • Thompson P.D.
      • Garber C.E.
      • Whitfield G.P.
      • Magal M.
      • et al.
      Updating ACSM’s recommendations for exercise preparticipation health screening.
      recommend “medical clearance” for those who are starting a moderate intensity programme AND have signs, symptoms, or a history of cardiovascular (i.e., cardiac, peripheral artery, cerebrovascular), metabolic (i.e., type 1 or 2 diabetes mellitus) or renal disease. The exact procedure for medical clearance is left at the discretion of the clinician. Notably, the ACSM defines moderate intensity as 40–59% heart rate reserve, a VO2 reserve of 3.0–5.9 metabolic equivalents (METs), or an RPE of 12–13 on a 6–20 Borg scale (or 5–6 on a 0–10 scale), an intensity that causes noticeable increases in HR and breathing. How can we practically apply this information? As summarised by another recent review in the area, asymptomatic patients wanting to pursue low-moderate activity should adhere to the tenant to “start low and go slow”11. Most associations agree that non-vigorous physical activity (not exceeding the demand of a brisk walk) does not require pre-participation cardiac clearance.
      • Colberg S.R.
      • Sigal R.J.
      • Yardley J.E.
      • Riddell M.C.
      • Dunstan D.W.
      • Dempsey P.C.
      • et al.
      Physical activity/exercise and diabetes: a position statement of the american diabetes association.

      Selected comorbidities

      All patients should be asked whether they get exertional symptoms that limit their activities of daily living (ADL). This question may help to identify additional diagnoses (e.g., muscle cramping, claudication, joint pain/limited range of motion) that may require programme modification or physiotherapy intervention prior to the initiation of an exercise programme.
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      Fall risk should be specifically assessed, although no screening tool has been validated in patients with cirrhosis. Falls in cirrhotic patients are strongly associated with especially high risk of morbidity and death.
      • Ezaz G.
      • Murphy S.L.
      • Mellinger J.
      • Tapper E.B.
      Increased morbidity and mortality associated with falls among patients with cirrhosis.
      Knowing that many factors can increase the risk of falls (e.g., covert HE, psychoactive drugs, and muscle weakness),
      • Urios A.
      • Mangas-Losada A.
      • Gimenez-Garzo C.
      • Gonzalez-Lopez O.
      • Giner-Duran R.
      • Serra M.A.
      • et al.
      Altered postural control and stability in cirrhotic patients with minimal hepatic encephalopathy correlate with cognitive deficits.
      observations made during baseline patient assessment (e.g., unsteadiness, tremors, use of chair or wall for support) are indicators of fall risk. So too is a history of three or more falls in the past year, routine use of a cane or walker, and self-reported fear of falling.
      • Nevitt M.C.
      • Cummings S.R.
      • Kidd S.
      • Black D.
      Risk factors for recurrent nonsyncopal falls. A prospective study.
      • Speechley M.
      • Tinetti M.
      Falls and injuries in frail and vigorous community elderly persons.
      • Lusardi M.M.
      • Fritz S.
      • Middleton A.
      • Allison L.
      • Wingood M.
      • Phillips E.
      • et al.
      Determining risk of falls in community dwelling older adults: a systematic review and meta-analysis using posttest probability.
      Patients suspected to be at high risk for falls require supported activity (i.e., exercises performed while seated; or if standing, using a support such as a grab bar or handrail to hold on to) and, ideally, should be supervised by a caregiver. Multimodal exercise programmes have reduced fall risk in the elderly
      • El-Khoury F.
      • Cassou B.
      • Charles M.A.
      • Dargent-Molina P.
      The effect of fall prevention exercise programmes on fall induced injuries in community dwelling older adults: systematic review and meta-analysis of randomised controlled trials.
      • Gillespie L.D.
      • Robertson M.C.
      • Gillespie W.J.
      • Sherrington C.
      • Gates S.
      • Clemson L.M.
      • et al.
      Interventions for preventing falls in older people living in the community.
      • Weerdesteyn V.
      • Rijken H.
      • Geurts A.C.
      • Smits-Engelsman B.C.
      • Mulder T.
      • Duysens J.
      A five-week exercise program can reduce falls and improve obstacle avoidance in the elderly.
      and in patients with cirrhosis.
      • Roman E.
      • Garcia-Galceran C.
      • Torrades T.
      • Herrera S.
      • Marin A.
      • Donate M.
      • et al.
      Effects of an exercise programme on functional capacity, body composition and risk of falls in patients with cirrhosis: a randomized clinical trial.
      The safety implications of additional comorbidities, including concurrent end-stage renal disease and pulmonary disease requiring oxygen, are beyond the scope of this review, but have been covered in detail in disease specific guidelines and in the recent ACSM guidelines.
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      For patients at risk of falling, programming beyond the introductory level of supported activity provided in this guide is best advanced after consultation with a CEP.

      Assessing baseline physical performance

      Studies have confirmed the robust prognostic value of a range of performance tools in cirrhosis, including composite measures such as the short physical performance battery (SPPB) and single components, such as gait speed.
      • Lai J.C.
      • Covinsky K.E.
      • Dodge J.L.
      • Boscardin W.J.
      • Segev D.L.
      • Roberts J.P.
      • et al.
      Development of a novel frailty index to predict mortality in patients with end-stage liver disease.
      • Lai J.C.
      • Covinsky K.E.
      • McCulloch C.E.
      • Feng S.
      The liver frailty index improves mortality prediction of the subjective clinician assessment in patients with cirrhosis.
      • Tandon P.
      • Tangri N.
      • Thomas L.
      • Zenith L.
      • Shaikh T.
      • Carbonneau M.
      • et al.
      A rapid bedside screen to predict unplanned hospitalization and death in outpatients with cirrhosis: a prospective evaluation of the clinical frailty scale.
      • Sinclair M.
      • Poltavskiy E.
      • Dodge J.L.
      • Lai J.C.
      Frailty is independently associated with increased hospitalisation days in patients on the liver transplant waitlist.
      The evaluation of baseline physical performance serves two important purposes. It overlaps with the safety pre-screen as an evaluation of cardiopulmonary endurance and capacity to exercise. It also establishes an objective baseline against which progress can be measured. We present a toolkit of our selected measures for use in clinical practice. The specific details for performing each measure are available in the supplementary materials – Physician Resource Package. If only one test can be done, we suggest the 4 m gait speed, with the SPPB or liver frailty index (LFI) of three tests (<3 min) as more comprehensive second choices. Further information on the tools available, including those described below, is available at Can-Restore (https://www.cntrp.ca/cr---healthcare-professionals), while rehabmeasures.org provides information regarding psychometric properties, normative data, instrument description and equipment, and minimally important differences.
      Both composite measures of physical performance and single components have been shown to have robust prognostic value in cirrhosis.

      Activities of daily living – duration ∼1 min

      The Katz Activities of Daily Living Scale assesses a patient’s self-reported independence, a low score was associated with an almost twofold risk of 90-day mortality.
      • Tapper E.B.
      • Finkelstein D.
      • Mittleman M.A.
      • Piatkowski G.
      • Lai M.
      Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis.
      Screening for ADLs identifies very deconditioned patients. Under caregiver supervision, and at the discretion of the practitioner, even this group may be able to carry out supported introductory level activities.

      Duke Activity Status Index – duration ∼2 min

      The Duke Activity Status Index (DASI) is a 12-item questionnaire that measures perceived functional capacity, has been validated against the VO2peak, is an accepted component in the pre-cardiac surgery risk stratification algorithm,
      • Fleisher L.A.
      • Fleischmann K.E.
      • Auerbach A.D.
      • Barnason S.A.
      • Beckman J.A.
      • Bozkurt B.
      • et al.
      2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      and has been used successfully in multiple chronic disease populations.
      • Alonso J.
      • Permanyer-Miralda G.
      • Cascant P.
      • Brotons C.
      • Prieto L.
      • Soler-Soler J.
      Measuring functional status of chronic coronary patients. Reliability, validity and responsiveness to clinical change of the reduced version of the Duke Activity Status Index (DASI).
      • Arena R.
      • Humphrey R.
      • Peberdy M.A.
      Using the Duke Activity Status Index in heart failure.
      • Carter R.
      • Holiday D.B.
      • Grothues C.
      • Nwasuruba C.
      • Stocks J.
      • Tiep B.
      Criterion validity of the Duke Activity Status Index for assessing functional capacity in patients with chronic obstructive pulmonary disease.
      • Ravani P.
      • Kilb B.
      • Bedi H.
      • Groeneveld S.
      • Yilmaz S.
      • Mustata S.
      The Duke Activity Status Index in patients with chronic kidney disease: a reliability study.
      Moreover, it is sensitive to change with an intervention, two or more units considered to be clinically meaningful.
      • Gary R.A.
      • Cress M.E.
      • Higgins M.K.
      • Smith A.L.
      • Dunbar S.B.
      Combined aerobic and resistance exercise program improves task performance in patients with heart failure.
      The score (www.mdcalc.com) can be converted into an approximate daily MET and an estimate of VO2 peak (in ml/kg = 0.43 × DASI + 9.6). The ranges for interpretation of functional capacity include excellent (>10 METs), good (7 to 10 METs), moderate (4 to 6 METs) and poor (<4 METs). Despite the potential for over-reporting of activities
      • Dunn M.A.
      • Josbeno D.A.
      • Schmotzer A.R.
      • Tevar A.D.
      • DiMartini A.F.
      • Landsittel D.P.
      • et al.
      The gap between clinically assessed physical performance and objective physical activity in liver transplant candidates.
      and the lack of cirrhosis-specific research in this area, in our experience the DASI is quick to administer, can help determine if a patient requires a lower training level, and is useful for monitoring progression over time.

      Composite batteries – short physical performance battery
      • Tandon P.
      • Tangri N.
      • Thomas L.
      • Zenith L.
      • Shaikh T.
      • Carbonneau M.
      • et al.
      A rapid bedside screen to predict unplanned hospitalization and death in outpatients with cirrhosis: a prospective evaluation of the clinical frailty scale.
      • Volpato S.
      • Cavalieri M.
      • Sioulis F.
      • Guerra G.
      • Maraldi C.
      • Zuliani G.
      • et al.
      Predictive value of the Short Physical Performance Battery following hospitalization in older patients.
      OR liver frailty index
      • Gillespie L.D.
      • Robertson M.C.
      • Gillespie W.J.
      • Sherrington C.
      • Gates S.
      • Clemson L.M.
      • et al.
      Interventions for preventing falls in older people living in the community.
      • Arena R.
      • Humphrey R.
      • Peberdy M.A.
      Using the Duke Activity Status Index in heart failure.
      • Carter R.
      • Holiday D.B.
      • Grothues C.
      • Nwasuruba C.
      • Stocks J.
      • Tiep B.
      Criterion validity of the Duke Activity Status Index for assessing functional capacity in patients with chronic obstructive pulmonary disease.
      – duration ∼3–5 min

      Both composite batteries share two of three tests: i) time to do five unassisted chair stands (arms folded across chest), and ii) seconds holding balance in three positions. The third test in each of the batteries is: gender-adjusted grip strength for the LFI and gait speed for the SPPB. Both composite tools predict transplant waiting list mortality and hospitalisation risk, and are supported by online calculators https://liverfrailtyindex.ucsf.edu/ and http://www.geriatricmobility.com/sppb-calculator/ respectively. Notably, specific to exercise testing, some concern has been raised in the ACSM guidelines regarding the lack of correlation between grip strength and overall physical performance or the performance of ADLs.
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.

      4-m gait speed – duration <1 min

      Included in the SPPB, this test is one of the best predictors of disability, morbidity, mortality, and fall risk across a range of chronic diseases and in the elderly.
      • Verghese J.
      • Holtzer R.
      • Lipton R.B.
      • Wang C.
      Quantitative gait markers and incident fall risk in older adults.
      • Viccaro L.J.
      • Perera S.
      • Studenski S.A.
      Is timed up and go better than gait speed in predicting health, function, and falls in older adults?.
      It is recommended by the ACSM guidelines as a basic test of function prior to exercise initiation.
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      In 373 patients with cirrhosis, gait speed was independently associated with the rate of hospitalisation after adjusting for covariates such as MELD and Child-Pugh score.
      • Dunn M.A.
      • Josbeno D.A.
      • Tevar A.D.
      • Rachakonda V.
      • Ganesh S.R.
      • Schmotzer A.R.
      • et al.
      Frailty as tested by gait speed is an independent risk factor for cirrhosis complications that require hospitalization.
      Mean gait speed was 0.95 m/s with every 0.1 m/s decrease in gait speed associated with a 22% increase of hospital day stay with significant projected cost implications. Gait speeds of <0.6 to <0.8 m/s have been associated with poor outcomes in older adults.
      • Abellan van Kan G.
      • Rolland Y.
      • Andrieu S.
      • Bauer J.
      • Beauchet O.
      • Bonnefoy M.
      • et al.
      Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force.

      The 6 Minute Walk Test (6MWT) – duration ∼15 min

      The lengthiest of the suggested performance measures, the 6MWT is highly recommended but left optional for the clinician to judge whether it can be practically incorporated into the pre-exercise screen. Beyond mortality prediction,
      • van Vugt J.L.A.
      • Alferink L.J.M.
      • Buettner S.
      • Gaspersz M.P.
      • Bot D.
      • Darwish Murad S.
      • et al.
      A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: a competing risk analysis in a national cohort.
      • van Vugt J.L.A.
      • Buettner S.
      • Alferink L.J.M.
      • Bossche N.
      • de Bruin R.W.F.
      • Darwish Murad S.
      • et al.
      Low skeletal muscle mass is associated with increased hospital costs in patients with cirrhosis listed for liver transplantation-a retrospective study.
      the 6MWT is an excellent opportunity to observe the patient’s aerobic capacity, risk of adverse events (e.g., does the patient have any symptom limitations, chest pain, dyspnoea as they walk, fall risk), readiness and motivation to exercise, muscle function, mobility, and balance. Repeated measures over time demonstrate responsiveness to change with an exercise intervention. Moreover, it offers a long enough period of activity to be an opportunity for the health care practitioner to educate the patient about how to measure their exercise intensity based on the RPE Borg 0–10 scale
      • Borg G.
      Physical work and effort.
      (Exercise training principles and components).

      Cardiopulmonary exercise testing

      Cardiopulmonary exercise testing (CPET) is routinely utilised at some European centres for pre-transplant evaluation. A recent systematic literature review including patients awaiting liver transplantation confirmed the use of CPET testing as independent predictors of pre-transplant and post-transplant mortality.
      • Ney M.
      • Haykowsky M.J.
      • Vandermeer B.
      • Shah A.
      • Ow M.
      • Tandon P.
      Systematic review: pre- and post-operative prognostic value of cardiopulmonary exercise testing in liver transplant candidates.
      As this technique takes at least 30 min and requires dedicated equipment and trained personnel, although extremely objective and very helpful for exercise prescription, it is not routinely carried out at many centres.

      Sarcopenia assessment as defined by low muscle mass

      There are a range of muscle mass measures that are robust predictors of adverse clinical outcomes in the cirrhosis population.
      • Tandon P.
      • Raman M.
      • Mourtzakis M.
      • Merli M.
      A practical approach to nutritional screening and assessment in cirrhosis.
      Given that muscle strength/performance measures likely have a higher sensitivity than muscle mass,
      • Yadav A.
      • Chang Y.H.
      • Carpenter S.
      • Silva A.C.
      • Rakela J.
      • Aqel B.A.
      • et al.
      Relationship between sarcopenia, six-minute walk distance and health-related quality of life in liver transplant candidates.
      • Goodpaster B.H.
      • Park S.W.
      • Harris T.B.
      • Kritchevsky S.B.
      • Nevitt M.
      • Schwartz A.V.
      • et al.
      The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study.
      • Wang C.W.
      • Feng S.
      • Covinsky K.E.
      • Hayssen H.
      • Zhou L.Q.
      • Yeh B.M.
      • et al.
      A comparison of muscle function, mass, and quality in liver transplant candidates: results from the functional assessment in liver transplantation study.
      our team variably performs muscle mass measurements before prescribing exercise. From the literature, it is clear that cross-sectional imaging offers the most accurate assessment of body composition,
      • van Vugt J.L.
      • Levolger S.
      • de Bruin R.W.
      • van Rosmalen J.
      • Metselaar H.J.
      • Ijzermans J.N.
      Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation.
      particularly relevant in the setting of sarcopenic obesity.
      • Montano-Loza A.J.
      • Angulo P.
      • Meza-Junco J.
      • Prado C.M.
      • Sawyer M.B.
      • Beaumont C.
      • et al.
      Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis.
      If this modality can overcome the practical limitations of repeatability, cost, and safety and is incorporated into standard of care radiology reporting, it would be a very valuable metric to follow alongside an exercise intervention.

      Malnutrition assessment

      Assessment of malnutrition involves evaluation of dietary intake and the factors that may compromise intake, including taste fatigue, poor palatability of sodium restricted diets, ascites, early satiety, and socioeconomic factors.
      • Tandon P.
      • Raman M.
      • Mourtzakis M.
      • Merli M.
      A practical approach to nutritional screening and assessment in cirrhosis.
      Ideally, the malnutrition assessment should be performed by a registered dietitian. Even in the absence of an assessment, basic nutrition education should be provided to all patients, highlighting the patient’s daily protein and calorie targets (the nutrition prescription for exercising patients section and supplementary materials – Patient Resource Package).

      Identify and treat muscle-specific metabolic issues

      Patients should have baseline testing and aggressive management of muscle-wasting metabolic disorders, such as diabetes, thyroid disorders, vitamin D deficiency, and especially ammonia excess, the primary metabolic driver of cirrhotic sarcopenia.
      • Dasarathy S.
      • Merli M.
      Sarcopenia from mechanism to diagnosis and treatment in liver disease.

      Assessing exercise readiness and overcoming barriers to exercise

      Fatigue and sedentary behaviour are ubiquitous in cirrhosis. Additional barriers to exercise include: i) a paucity of multidisciplinary teams or pre-habilitation programmes despite improvements in clinical outcomes and cost-savings;
      • Dunn M.A.
      • Josbeno D.A.
      • Schmotzer A.R.
      • Tevar A.D.
      • DiMartini A.F.
      • Landsittel D.P.
      • et al.
      The gap between clinically assessed physical performance and objective physical activity in liver transplant candidates.
      • Lai J.C.
      • Covinsky K.E.
      • Dodge J.L.
      • Boscardin W.J.
      • Segev D.L.
      • Roberts J.P.
      • et al.
      Development of a novel frailty index to predict mortality in patients with end-stage liver disease.
      ii) inactivity due to unplanned hospital stays (average of six days each year
      • Dunn M.A.
      • Josbeno D.A.
      • Schmotzer A.R.
      • Tevar A.D.
      • DiMartini A.F.
      • Landsittel D.P.
      • et al.
      The gap between clinically assessed physical performance and objective physical activity in liver transplant candidates.
      • Tandon P.
      • Tangri N.
      • Thomas L.
      • Zenith L.
      • Shaikh T.
      • Carbonneau M.
      • et al.
      A rapid bedside screen to predict unplanned hospitalization and death in outpatients with cirrhosis: a prospective evaluation of the clinical frailty scale.
      ) which may trigger or accelerate physical decline; iii) cost and accessibility issues associated with supervised nutrition/exercise programming;
      • Berzigotti A.
      • Albillos A.
      • Villanueva C.
      • Genesca J.
      • Ardevol A.
      • Augustin S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study.
      iv) mental health issues counter-active to exercise, such as depression, anxiety, and fear of falling due to kinesiophobia – the psychological inhibition of activity;
      • Malini F.M.
      • Lourenco R.A.
      • Lopes C.S.
      Prevalence of fear of falling in older adults, and its associations with clinical, functional and psychosocial factors: the Frailty in Brazilian Older People-Rio de Janeiro study.
      • Rochat S.
      • Bula C.J.
      • Martin E.
      • Seematter-Bagnoud L.
      • Karmaniola A.
      • Aminian K.
      • et al.
      What is the relationship between fear of falling and gait in well-functioning older persons aged 65 to 70 years?.
      and, v) lack of awareness of the benefits of exercise regarding morbidity and mortality, transplant de-listing, quality of life and symptom management.
      Recognising that this article is a stepping stone on the path to universal exercise prescription in cirrhosis, well-known barriers can be addressed with the information herein and changes to the way we practice. i) Each patient can be provided with customised exercise and nutrition instructions and supporting information. ii) Although hospitalisation is a period of high risk for physical decline
      • Puthucheary Z.A.
      • Rawal J.
      • McPhail M.
      • Connolly B.
      • Ratnayake G.
      • Chan P.
      • et al.
      Acute skeletal muscle wasting in critical illness.
      it can be utilised as a valuable opportunity to connect the patient with an exercise professional and dietitian. Patients should ideally be followed by these practitioners in hospital and educated about a home exercise regimen at the time of discharge. iii) Patients can be encouraged to access our online supplementary videos to support their home-based activities and to co-exercise with family or friends, thereby converting exercise into a social activity.
      • Berzigotti A.
      • Albillos A.
      • Villanueva C.
      • Genesca J.
      • Ardevol A.
      • Augustin S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study.
      • Zenith L.
      • Meena N.
      • Ramadi A.
      • Yavari M.
      • Harvey A.
      • Carbonneau M.
      • et al.
      Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis.
      iv) Mental health issues, such as depression and anxiety, should be identified and treated. v) Educational material provided with the clinician’s endorsement will help to highlight the importance of exercise and nutrition in the medical care of cirrhosis.
      Knowing that patients and clinicians underestimate the sedentary lifestyle of LT candidates,
      • Dunn M.A.
      • Josbeno D.A.
      • Schmotzer A.R.
      • Tevar A.D.
      • DiMartini A.F.
      • Landsittel D.P.
      • et al.
      The gap between clinically assessed physical performance and objective physical activity in liver transplant candidates.
      if available to them, we encourage patients to access wearable activity monitors offering real-time awareness of steps per day, calories expended per day, and percent sedentary-moderate physical activity. This is an objective approach to assessing activity and provides a benchmark for improvement.
      Motivational interviewing can also be incorporated into clinical interactions. This is an empathetic, non-confrontational approach to changing behaviour where the patient is an equal partner. This effective technique uses open-ended questions to collaboratively explore a patient’s readiness, motivation, and confidence to change and to resolve ambivalence, emphasise autonomy, and provide patient self-efficacy.
      • Bean M.K.
      • Powell P.
      • Quinoy A.
      • Ingersoll K.
      • Wickham 3rd, E.P.
      • Mazzeo S.E.
      Motivational interviewing targeting diet and physical activity improves adherence to pediatric obesity treatment: results from the MI Values randomized controlled trial.
      We provide sample questions that are used in our practices and have been well received (Table 3).
      Table 3Motivational interviewing questions to elicit behaviour change in cirrhosis. Adapted from.
      • DiLillo V.
      • Siegfried N.J.
      • Smith West D.
      Incorporating motivational interviewing into behavioral obesity treatment.
      Assessing ambivalence/motivation for exercise & nutritional changes
       How is your loss of muscle strength and sedentary lifestyle affecting you right now?
       What have you done in the past to increase muscle strength or mobility?
       What are your hopes for the future if you can become stronger and improve your symptoms?
      Assessing exercise readiness
       How would you like your health to be different?
       How ready are you to change your activity and eating patterns to improve your strength and mobility?
       Some people do not wish to discuss their weakness, tiredness, or challenges with doing things they were previously able to do, while others do not mind talking about these things. How do you feel about this?
      The importance of change
       What do you think would happen if you continue to become weaker?
       If you were to regain strength and mobility, what would that be like?
      Building confidence
       What would make you more confident about making these changes?
       If you decided to change, what are your options to achieve this?
      Identifying possible barriers
       What may interfere with you from being more physically active or eating better?
       Do you have any concerns or fears about your ability to participate in exercise?

      Exercise training principles and components

      Exercise training principles

      The most important advice for any exercise programme in a patient with chronic disease is to “start low, progress slowly, and be alert for symptoms”1. Exercise is differentiated from physical activity as it is planned and performed on a repeated basis over an extended period of time for the purpose of improving fitness, performance, and health.
      • Bouchard C.
      • Tremblay A.
      • Despres J.P.
      • Theriault G.
      • Nadeau A.
      • Lupien P.J.
      • et al.
      The response to exercise with constant energy intake in identical twins.
      The exercise training prescription provided to each patient follows the FITT principles: Frequency, Intensity, Time, Type of exercise. The FITT table for exercise principles in cirrhosis is presented in Table 4 and in the supplementary materials – Patient Resource Package, modified to be printed as a set of instructions that can be personalised for each patient.
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      The benefits of exercise lead us to recommend that all patients with cirrhosis should be encouraged and supported to engage in exercise appropriate for their physical abilities.
      Table 4FITT (Frequency, Intensity, Type, Time) recommendations for exercise in cirrhosis (adapted from reference
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      ).
      CharacteristicAerobicResistanceFlexibility & Balance
      FrequencyStart with 4 days/week; aim to do every day2 or more days/week on non-consecutive days if using external resistance2 or more days/week
      IntensityModerate intensity 5–6 on a 10-point Borg Scale. The exerciser should pass the talk test = be able to speak comfortably during exercise to ensure they are not overexerting themselvesEnsure good form for the exercises to work the correct muscles and have the desired effect. Perform with a weight or exercise resistance band that a rest is needed after 10–15 repetitions (a “set”). When 3 sets of 10–15 repetitions can be completed easily, increase the stiffness of the resistance band or the weight to make the 10–15 repetitions difficult againStretch until there is a feeling of tightness or slight discomfort
      TimeThe very deconditioned may need to start with walk 1-min, rest 1-min then repeat for a total time of 5 min. Gradually increase walking time and decrease resting time.

      Build to 40 min in each session.

      Aim: 150 min each week
      Videos are divided into 7 major muscle groups. Start with 3–4 exercises per session, doing 1 set of 10–15 repetitions.

      Aim: Increase to all 7 exercises per day, doing 3 sets of 10–15 repetitions
      1 set of 3 repetitions.

      Stretches can be held for 30–60 s.

      Aim: 1 set of 3 repetitions (5–10 min)
      TypeWalking (indoors or outdoors) to improve overall functionality.

      Other activities can be selected by the patient (e.g., cycling, elliptical)
      Progressive weight training activities or functional strengthening exercises, such as stair climbingStretches and balance exercises targeting the large muscles of the upper and lower body

      Exercise programming details

      Encourage non-exercise activity thermogenesis

      Non-exercise activity thermogenesis (NEAT) involves continuous and vital low-intensity movements. It encourages patients to take advantage of opportunities for physical activity within their day-to-day routine and thereby can complement exercise, resulting in a more sustainable increase in activity levels.
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      • Duarte-Rojo A.
      • Ruiz-Margain A.
      • Montano-Loza A.J.
      • Macias-Rodriguez R.U.
      • Ferrando A.
      • Kim W.R.
      Exercise and physical activity for patients with end-stage liver disease: Improving functional status and sarcopenia while on the transplant waiting list.
      Examples of NEAT activities may include choices such as parking 10 min away from a store when shopping, stepping in place while watching TV, washing dishes instead of putting them in the dishwasher, and climbing stairs instead of taking the elevator.
      • Villablanca P.A.
      • Alegria J.R.
      • Mookadam F.
      • Holmes Jr., D.R.
      • Wright R.S.
      • Levine J.A.
      Nonexercise activity thermogenesis in obesity management.
      A detailed list of calories burned using NEAT activities is found in a recent review on the topic.
      • Villablanca P.A.
      • Alegria J.R.
      • Mookadam F.
      • Holmes Jr., D.R.
      • Wright R.S.
      • Levine J.A.
      Nonexercise activity thermogenesis in obesity management.
      The capacity of a cirrhosis patient to partake in these additional activity opportunities will depend upon their baseline level of function.

      Scheduled exercise programming

      For individuals living with chronic disease, scheduled exercise programmes are generally structured to include a warm-up (5–10 min), an exercise phase with aerobic and resistance exercise components (20–60 min; for severely deconditioned patients, this can be performed with rest breaks, as their fitness improves, it can become continuous), and a cool-down phase including flexibility and balance training (5–10 min).
      • Moore G.
      • Durstine J.L.
      • Painter P.
      American College of Sports Medicine
      ACSMs exercise management for persons with chronic diseases and disabilities.
      • Butler R.N.
      • Davis R.
      • Lewis C.B.
      • Nelson M.E.
      • Strauss E.
      Physical fitness: benefits of exercise for the older patient.
      We have developed instructional exercise videos for the resistance, flexibility, and balance training components. The descriptions are provided (Table 5) and are available at www.wellnesstoolbox.ca. We have provided a detailed set of steps to formulate an exercise prescription and included this in the supplementary materials – Physician Resource Package. This includes details on baseline exercise instructions and the how to’s of prescribing exercise programme progression and reassessment.
      Table 5Programming levels and link to associated videos (www.wellnesstoolbox.ca).
      Muscle strengthening & resistance activities – start with 1 set of 10–15 repetitions
      Shoulders:IntroLateral arm raises
      P1Lateral arm raises with banding
      P2Lateral arm raises with free weights
      P3Lateral arm raises with free weights and single leg
      Biceps:IntroArm curls with light or no weights
      P1Arm curls with banding
      P2Arm curls with free weights
      P3Arm curls/single leg
      Triceps:IntroSeated triceps extension with banding
      P1Over-head triceps extension with banding
      P2Over-head triceps extension with free weights
      P3Triceps dip
      Quadriceps:IntroSeated leg extensions
      P1Seated leg extension held for a longer time
      P2Seated leg extensions with banding
      P3Seated leg extensions with banding (higher resistances)
      Hamstring:IntroStanding leg curls
      P1Standing hamstring curl with towel on wall
      P2Standing leg curls with banding
      P3Standing leg curls with banding (higher resistances)
      Lower Leg:IntroSeated calf raises
      P1Standing calf raises
      P2Standing calf raises with banding
      P3Single leg calf raises with or without banding
      Multi-joint:IntroChair sit to stand
      P1Wall squat
      P2Squat with banding or hand held free weights
      P3Increase resistances or weights
      Flexibility – 1 set of 3 repetitions
      IntroSimple range of motions for shoulders, elbows, lower back, and knees to Static stretches that can be performed seated in a chair (e.g., chair sit and reach, lateral side bends, chest stretch)
      P1Standing static stretches (e.g., toe touch, calf stretch, shoulder stretch, triceps stretch, chest stretch)
      P2Floor and standing stretches (e.g., hurdler’s stretch, calf stretch, wrist stretch, shoulder and chest stretch)
      P3Floor and standing stretches (e.g., hurdler’s stretch, calf stretch, wrist stretch, shoulder and chest stretch)
      Balance – 1 set of 3 repetitions
      IntroSingle leg raises with assistance of a chair
      P1Single leg raises with assistance of a chair and eyes are closed
      P2Dynamic balance: walking in a straight line with a narrow gait
      P3Dynamic balance: walk heel to toe

      The nutrition prescription for exercising patients

      We include an excerpt of “The Nutrition in Cirrhosis Guide”, the full version available at www.wellnesstoolbox.ca and the Canadian Liver Foundation’s website
      • Tandon P.
      • DenHeyer V.
      • Ismond K.P.
      • Kowalczewski J.
      • Raman M.
      • Eslamparast T.
      • et al.
      The nutrition in cirrhosis guide.
      (supplementary materials – Patient Resource Package). Patients should ideally be assessed by a dietitian and given four main targets for their routine daily intake.

      Target caloric intake

      Patients are informed of their caloric intake target (ranging from 20–40 kcal/kg/day) stratified by their dry weight body mass index.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      Barriers to intake are explored and solutions provided, including: when and which liquid food supplements to consume; eat a meal or snack every 3 to 4 h; avoid low calorie liquids (e.g., tea, coffee) before meal-times as they may reduce appetite.
      • Tandon P.
      • DenHeyer V.
      • Ismond K.P.
      • Kowalczewski J.
      • Raman M.
      • Eslamparast T.
      • et al.
      The nutrition in cirrhosis guide.

      Target protein intake

      Dietary protein is an essential macronutrient in exercising adults, providing both the required amino acids and the anabolic stimulus necessary for muscle protein synthesis.
      • Robinson S.M.
      • Reginster J.Y.
      • Rizzoli R.
      • Shaw S.C.
      • Kanis J.A.
      • Bautmans I.
      • et al.
      Does nutrition play a role in the prevention and management of sarcopenia?.
      There is retrospective evidence linking low protein intake with mortality in cirrhosis
      • Ney M.
      • Abraldes J.G.
      • Ma M.
      • Belland D.
      • Harvey A.
      • Robbins S.
      • et al.
      Insufficient protein intake is associated with increased mortality in 630 patients with cirrhosis awaiting liver transplantation.
      and observational evidence linking low protein intake to muscle mass and strength loss in the elderly.
      • Houston D.K.
      • Nicklas B.J.
      • Ding J.
      • Harris T.B.
      • Tylavsky F.A.
      • Newman A.B.
      • et al.
      Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study.
      • McLean R.R.
      • Mangano K.M.
      • Hannan M.T.
      • Kiel D.P.
      • Sahni S.
      Dietary protein intake is protective against loss of grip strength among older adults in the Framingham offspring cohort.
      Branched chain amino acid (BCAA) supplementation has been associated with improvements in liver function, HRQoL, muscle mass, and reductions in HE, but their expense and poor taste minimises frequent use.
      • Marchesini G.
      • Bianchi G.
      • Merli M.
      • Amodio P.
      • Panella C.
      • Loguercio C.
      • et al.
      Nutritional supplementation with branched-chain amino acids in advanced cirrhosis.
      • Muto Y.
      • Sato S.
      • Watanabe A.
      • Moriwaki H.
      • Suzuki K.
      • Kato A.
      • et al.
      Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis.
      • Kawaguchi T.
      • Izumi N.
      • Charlton M.R.
      • Sata M.
      Branched-chain amino acids as pharmacological nutrients in chronic liver disease.
      Patients are provided with their guideline-based daily protein intake target (1.2–1.5 g/kg/day) in g/day
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • Assis-Camilo M.
      • Pirlich M.
      • Kondrup J.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      and information about high protein and BCAA-rich foods. It remains unclear whether animal- or vegetable-based protein is of greater benefit in patients with cirrhosis.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.

      Late evening snack

      Patients are advised that cirrhosis impairs glycogen storage. This creates an accelerated state of starvation leading to a rapid breakdown of fat and muscle after just a 10-h fast.
      • Owen O.E.
      • Reichle F.A.
      • Mozzoli M.A.
      • Kreulen T.
      • Patel M.S.
      • Elfenbein I.B.
      • et al.
      Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis.
      They are advised to eat a snack containing 20–40 g of protein and 50 g of complex carbohydrates either shortly before bedtime or during night-time hours, an intervention proven to increase muscle mass.
      • Plank L.D.
      • Gane E.J.
      • Peng S.
      • Muthu C.
      • Mathur S.
      • Gillanders L.
      • et al.
      Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial.
      • Tsien C.D.
      • McCullough A.J.
      • Dasarathy S.
      Late evening snack: exploiting a period of anabolic opportunity in cirrhosis.

      Adjusting intake for exercise

      Evidence-based recommendations are available guiding nutrient intake in healthy, exercising adults
      • Kerksick C.M.
      • Arent S.
      • Schoenfeld B.J.
      • Stout J.R.
      • Campbell B.
      • Wilborn C.D.
      • et al.
      International society of sports nutrition position stand: nutrient timing.
      • Jager R.
      • Kerksick C.M.
      • Campbell B.I.
      • Cribb P.J.
      • Wells S.D.
      • Skwiat T.M.
      • et al.
      International Society of Sports Nutrition Position Stand: protein and exercise.
      with protein intake every 3–4 hours resulting in improved tissue repair and augmented muscle protein synthesis. Although not directly transferable, these basic principles can be applied to patients with cirrhosis. Glycogen stores are easily depleted by high volume exercise. As in two of our published trials, on exercise days, it is our practice to recommend an additional 250–300 kcal of carbohydrate-based caloric intake pre- or post-exercise.
      • Kruger C.
      • McNeely M.L.
      • Bailey R.J.
      • Yavari M.
      • Abraldes J.G.
      • Carbonneau M.
      • et al.
      Home exercise training improves exercise capacity in cirrhosis patients: role of exercise adherence.
      • Zenith L.
      • Meena N.
      • Ramadi A.
      • Yavari M.
      • Harvey A.
      • Carbonneau M.
      • et al.
      Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis.
      The only other exercise trial in cirrhosis which provided additional calories for exercising patients did so by increasing the daily caloric intake, estimated by the Harris-Benedict equation, by 30%.
      • Macias-Rodriguez R.U.
      • Ilarraza-Lomeli H.
      • Ruiz-Margain A.
      • Ponce-de-Leon-Rosales S.
      • Vargas-Vorackova F.
      • Garcia-Flores O.
      • et al.
      Changes in hepatic venous pressure gradient induced by physical exercise in cirrhosis: results of a pilot randomized open clinical trial.

      Future directions

      To make exercise widely available in cirrhosis, we need to generate new models of delivery, by overcoming barriers of affordability and availability. Home-based exercise is the most attractive intervention, as it eliminates transportation needs, and emphasises ADLs. A recent trial of home-based therapy showed benefit in patients with compensated cirrhosis who adhered to the treatment regimen.
      • Kruger C.
      • McNeely M.L.
      • Bailey R.J.
      • Yavari M.
      • Abraldes J.G.
      • Carbonneau M.
      • et al.
      Home exercise training improves exercise capacity in cirrhosis patients: role of exercise adherence.
      Technology, such as wearable activity monitors, video streaming, smartphones, and virtual reality should be exploited to create home-based telehealth or virtual interventions that can be remotely monitored by a specialised team. Objective activity monitoring is especially important to guide therapy for cirrhotic patients because of their strong tendency to grossly overestimate their self-assessed activity levels.
      • Dunn M.A.
      • Josbeno D.A.
      • Schmotzer A.R.
      • Tevar A.D.
      • DiMartini A.F.
      • Landsittel D.P.
      • et al.
      The gap between clinically assessed physical performance and objective physical activity in liver transplant candidates.
      The main aim of cognitive behavioural therapy sessions is to motivate and empower patients to be their own instrument of change, facilitating adherence and allowing more permanent lifestyle modifications.
      • Dalle Grave R.
      • Calugi S.
      • Centis E.
      • El Ghoch M.
      • Marchesini G.
      Cognitive-behavioral strategies to increase the adherence to exercise in the management of obesity.
      • Shaw K.
      • O'Rourke P.
      • Del Mar C.
      • Kenardy J.
      Psychological interventions for overweight or obesity.
      Socialisation and gamification of exercise activities with the use of social media could further enhance interventions by providing peer support, modelling, and incentivising participation. Motivational interviewing (Table 3) is an efficient and effective method
      • Bean M.K.
      • Powell P.
      • Quinoy A.
      • Ingersoll K.
      • Wickham 3rd, E.P.
      • Mazzeo S.E.
      Motivational interviewing targeting diet and physical activity improves adherence to pediatric obesity treatment: results from the MI Values randomized controlled trial.
      that requires further exploration in cirrhosis.
      Among nutritional interventions, BCAA are known for their beneficial effect on HE and lowering of circulating ammonia levels.
      • Gluud L.L.
      • Dam G.
      • Les I.
      • Marchesini G.
      • Borre M.
      • Aagaard N.K.
      • et al.
      Branched-chain amino acids for people with hepatic encephalopathy.
      As shown (Fig. 2), hyperammonemia has a pivotal role in the aetiology and perpetuation of sarcopenia in cirrhosis, and evidence from both experimental and human studies shows BCAA, especially l-leucine supplementation, can support skeletal muscle anabolism. However, one of the side effects of BCAA is that, by depleting the Krebs (tricarboxylic) acid cycle, it can be detrimental to energy generation, and therefore, combining BCAA with an alpha-ketoacid donor (e.g., l-ornithine-l-aspartate) has been proposed as a solution.
      • Holecek M.
      Branched-chain amino acid supplementation in treatment of liver cirrhosis: updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation.
      This requires further evaluation in cirrhosis.
      Figure thumbnail gr2
      Fig. 2Elevated ammonia as a cause for sarcopenia in cirrhosis. Hyperammonemia from impaired hepatic detoxification affects skeletal muscle by 1) causing intracellular amino acid depletion in association with production and export of glutamine (what is metabolised back to ammonia in extra-muscular tissues, thus perpetuating damage); 2) blocking of mammalian target of rapamycin complex 1 and affecting protein anabolism; and 3) increasing myostatin expression and favoring skeletal muscle catabolism. Experimental data also substantiates a role for hyperammonemia in promoting skeletal muscle autophagy. BCAA, branch-chain amino acids; GCN2, general control non-depressible 2 (amino acid deficiency sensor); GLN, glutamine; GLU, glutamate; GLS1, glutaminase; GS, glutamine synthetase; mTORC1, mammalian target of rapamycin complex 1; NH3, ammonia.
      The drug discovery pipeline for sarcopenia and disorders of physical function has been rather slow to produce therapeutics. Follistatin is a negative regulator of the muscle growth inhibitor myostatin (Fig. 2). It is secreted by hepatocytes in response to exercise, but secretion is impaired in cirrhosis.
      • Rinnov A.R.
      • Plomgaard P.
      • Pedersen B.K.
      • Gluud L.L.
      Impaired follistatin secretion in cirrhosis.
      Experimental data show that follistatin can reverse the impairment in skeletal muscle protein synthesis in animals with portosystemic shunting,
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      • McCullough A.J.
      • Muc S.
      • Schneyer A.
      • Bennett C.D.
      • Dodig M.
      • et al.
      Sarcopenia associated with portosystemic shunting is reversed by follistatin.
      and patients with inclusion cell myositis treated with follistatin show increased performance in the 6MWT.
      • Mendell J.R.
      • Sahenk Z.
      • Al-Zaidy S.
      • Rodino-Klapac L.R.
      • Lowes L.P.
      • Alfano L.N.
      • et al.
      Follistatin gene therapy for sporadic inclusion body myositis improves functional outcomes.
      There is data from a randomised controlled trial supporting the effects of testosterone treatment on muscle mass in hypogonadal males with cirrhosis,
      • Sinclair M.
      • Grossmann M.
      • Hoermann R.
      • Angus P.W.
      • Gow P.J.
      Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial.
      but theoretical safety concerns have precluded its widespread acceptance. Larger trials with longer follow-up times are required. Future studies evaluating the impact of HE therapies on muscle mass and function are awaited. With exciting advances in gut microbiota, there may be strategies to modify the microbiome to benefit skeletal muscle function in patients with cirrhosis.
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      • Milani C.
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      Aging gut microbiota at the cross-road between nutrition, physical frailty, and sarcopenia: is there a gut-muscle axis?.
      Lastly, as has been done in other chronic disease populations, there is a justifiable need for educational initiatives and formal exercise guidelines through national hepatology and transplantation organisations. It is essential that health practitioners feel supported to make exercise and nutrition prescriptions a routine part of every clinic visit.
      As has been demonstrated across a range of chronic diseases, including frailty management
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      • Guimaraes-Pinheiro C.
      • Maseda A.
      • Lorenzo T.
      • Millan-Calenti J.C.
      Effects of physical exercise interventions in frail older adults: a systematic review of randomized controlled trials.
      • Dent E.
      • Lien C.
      • Lim W.S.
      • Wong W.C.
      • Wong C.H.
      • Ng T.P.
      • et al.
      The Asia-Pacific clinical practice guidelines for the management of frailty.
      and prevention,
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      • Guralnik J.M.
      • Ambrosius W.T.
      • Blair S.
      • Bonds D.E.
      • Church T.S.
      • et al.
      Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial.
      lung disease,
      • Hoffman M.
      • Chaves G.
      • Ribeiro-Samora G.A.
      • Britto R.R.
      • Parreira V.F.
      Effects of pulmonary rehabilitation in lung transplant candidates: a systematic review.
      and colorectal cancer,
      • Minnella E.M.
      • Bousquet-Dion G.
      • Awasthi R.
      • Scheede-Bergdahl C.
      • Carli F.
      Multimodal prehabilitation improves functional capacity before and after colorectal surgery for cancer: a five-year research experience.
      we believe that the routine integration of exercise and nutrition regimens will reduce health care costs/utilisation while improving muscle health, functionality, and HRQoL for our patients with cirrhosis.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      All authors contributed to the concept, design, recommendations, and manuscript preparation.

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