Does Exercise Training Improve Physical Fitness and Health in Adult Liver Transplant Recipients? A Systematic Review and Meta-analysis : Transplantation

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Original Clinical Science—Liver

Does Exercise Training Improve Physical Fitness and Health in Adult Liver Transplant Recipients? A Systematic Review and Meta-analysis

De Smet, Stefan PT, PhD1,2,3; O’Donoghue, Katriona BSc4; Lormans, Maud MD3; Monbaliu, Diethard MD, PhD3,5; Pengel, Liset PhD6

Author Information
Transplantation 107(1):p e11-e26, January 2023. | DOI: 10.1097/TP.0000000000004313

Abstract

INTRODUCTION

Patients with end-stage liver disease commonly develop sarcopenia1 as a consequence of the multifactorial catabolic state involving increased gluconeogenesis, hypermetabolism, gastrointestinal dysfunction, systemic low-grade inflammation, hypotestosteronemia, muscle hyperammonemia, and physical inactivity.2 In the early posttransplant period, catabolism is aggravated by immobilization, glucocorticosteroid therapy, surgery-induced counter-regulatory hormone production, and impaired insulin secretion or peripheral insulin sensitivity.3-5 Later, although body weight rapidly recovers and exceeds pretransplant levels due to excessive intra-abdominal and subcutaneous fat accretion, at 2 y posttransplant muscle mass typically has not recovered,6,7 and sarcopenia persists.8,9 Whereas hand grip strength recovers within the first year after transplantation, knee extensor muscle strength remains impaired up until 2 y posttransplant.5,10,11 This is problematic because impaired muscle mass and strength are known determinants of (in)dependency in activities of daily living.12 Although sarcopenia is not only associated with impaired quality of life, morbidity, and mortality in liver cirrhosis, it also predicts short- and long-term mortality after liver transplantation (LT).13,14

Along with poor muscle mass and function, patients with end-stage liver disease typically present with impaired cardiorespiratory fitness levels, which may impair their independency in activities of daily living.15,16 Although patients exhibit pronounced physical inactivity,17,18 end-stage liver disease affects peak oxygen consumption (VO2peak) through its extrahepatic manifestations in the cardiovascular, respiratory, cerebral, hematological, and muscular systems. Despite successful transplantation, LT recipients typically remain less physically active than the general population,19,20 and neither muscle mass nor cardiorespiratory fitness recovers to healthy norms,21 placing them at risk for metabolic syndrome19,22 and reduced health-related quality of life (HRQOL).23-25 Furthermore, a sedentary lifestyle, poor physical fitness, sarcopenic obesity, and pharmacological immunosuppression are well-known risk factors for cardiovascular disease. In LT recipients, these coincide with other cardiovascular risk factors, such as metabolic syndrome, diabetes, dyslipidemia, and arterial hypertension, all of which increase in prevalence during the first year(s) posttransplant.26 Cardiovascular disease is a well-established time-dependent risk factor for mortality after LT during both the shorter and longer posttransplantation time periods.27

Overwhelming evidence in the general population and emerging evidence in organ transplant recipients indicate that adequate physical activity or exercise training can maintain and improve physical fitness and cardiometabolic health, with exercise training being more effective than physical activity interventions.18,28-32 Individualized home-based exercise in LT candidates has recently shown to improve frailty and patient survival.33 Exercise-based physical rehabilitation focused on restoration in physical fitness is currently not part of post-LT routine care in most transplant centers.

This systematic review and meta-analysis aims to investigate the existing clinical evidence on the effectiveness and safety of exercise training in LT recipients as a means to improve physical fitness and HRQOL.

MATERIALS AND METHODS

Patient Involvement

As part of the study protocol development, a focus group consisting of 5 LT recipients (aged 38–75; 1 woman, 4 men; LT 5 mo to 9 y prior) was organized to identify the most important study outcome of the present systematic literature review from the perspective of the patients. These patients identified “functional physical fitness,” which they defined as “the capacity to move freely, independently, comfortably, and confidently without instability or restrictions” as the primary outcome of interest for this study.

Protocol Publication and Ethics Statement

This study’s protocol was registered in PROSPERO (CRD42019123883) on February 27, 2019. The review was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.34 Given the nature of this study, using already published data, no ethical approval was sought.

Literature Review Search Strategy

A bibliographic search was conducted from database inception through March 25, 2021, in PubMed, Ovid EMBASE, Web of Science, The Cochrane Library, Transplant Library, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform. Vocabulary terms and keywords were combined for the population, intervention, and outcomes (Table S1, https://links.lww.com/TP/C540). Study titles and abstracts were screened independently by 2 investigators (K.O., M.L.), who then reviewed the full-text versions of potentially eligible manuscripts and convened to agree on the selection of publications. Bibliographies of eligible publications were hand searched for titles not identified via electronic database searches. No language or date limits were applied.

Inclusion and Exclusion Criteria

Patient Population

The study population included adult (≥18 y) LT recipients, irrespective of gender, time after discharge from the intensive care unit, and etiology of liver disease.

Intervention

All interventions consisting of aerobic (endurance and interval) and peripheral muscle strength training implemented after intensive care unit discharge and lasting at least 2 wk or a total of 8 sessions were considered. Both supervised and home-based training interventions were included.

Comparator

Included was usual care or minimal intervention.

Study Outcomes

The primary outcomes were parameters of physical fitness: cardiorespiratory, muscular, and motor fitness, morphological traits, and metabolic health (Table 1) and HRQOL. Secondary outcomes included adherence to the training program, fatigue, long-term physical activity behavior, graft function, and adverse events.

TABLE 1. - Common terminology used in the present study
Term Definition used in the present article
Physical activity Any bodily movement produced by skeletal muscles that requires energy expenditure 35,36
Physical exercise/physical training/exercise training A subcategory of physical activity that is planned, structured, repetitive, and purposefully focused on improvement or maintenance of 1 or more components of physical fitness 36
Physical fitness Physical fitness refers to a state of well-being characterized by (i) traits and capacities related to present and future health and (ii) the ability to carry out primarily physical-related functions and daily activities with vigor and alertness without undue fatigue and with sufficient energy to enjoy leisure-time pursuits and respond to emergencies 35 We specifically refer to health-related physical fitness, a term encompassing the following 5 components: cardiorespiratory fitness, muscular fitness, motor fitness, morphological traits, and metabolic health 37
Cardiorespiratory fitness The overall capacity of the cardiovascular, respiratory, and muscular system to supply and combust oxygen for execution of physical activity 38,39 ; typically assessed by cardiopulmonary exercise testing and expressed as peak oxygen consumption. Field tests such as a 6-min walk test and an incremental shuttle walk test are expressed in distance and are often used to estimate cardiorespiratory fitness in clinical populations
Muscular fitness The characteristics of a specific muscle or muscle group regarding muscular strength (force generation with a single maximal effort), muscular endurance (capacity to resist repeated contractions over time or a voluntary contraction for a prolonged period of time), and muscular (explosive) power (high-velocity maximal force production in as short a time as possible) 37,38
Motor fitness Physical traits related to speed (ability to perform a movement within a short period of time), agility (ability to rapidly change body position in space with speed and accuracy), and balance (ability to maintain equilibrium while stationary or moving) 35,38
Morphological component of physical fitness Morphological characteristics such as BMI, body composition, subcutaneous fat distribution, abdominal visceral fat, bone density, and flexibility 37
Metabolic health Traits related to glucose tolerance, insulin sensitivity, lipid and lipoprotein metabolism, and substrate oxidation characteristics 37
BMI, body mass index.

Type of Study Designs

Randomized controlled trials (RCTs) were used.

Data Extraction and Analysis

Two investigators (K.O., M.L.) independently extracted relevant study data using a prepiloted data collection form. A third investigator (S.D.S.) identified discrepancies between data sets. Discrepancies were resolved through discussion until consensus was reached.

Risk of Bias Assessment

Eligible publications were assessed for risk of bias using the Cochrane Risk of Bias Tool independently by a minimum of 2 investigators (S.D.S., K.O., M.L.).40 Discrepancies were identified by a third investigator (L.P.) and resolved through discussion. As only 7 full-text RCTs were included in the review, publication bias was not formally assessed.

Statistical Analysis

Meta-analysis was performed if at least 3 studies reported on an outcome. Pooled intervention effects were calculated as mean differences (MDs) or standardized MDs (SMDs) using postintervention means and SD of the intervention and control groups. Analyses were done using RevMan software (version 5.3, The Cochrane Collaboration, 2014). The overall effect was assessed with P < 0.05 being considered as statistically significant. Heterogeneity was assessed by visual inspection of forest plots and by quantitative evaluation using χ² and I² tests. Because eligible studies were expected to have small sample sizes, χ² P < 0.10 was considered indicative of significant heterogeneity; I² test ≥50% was considered indicative of substantial heterogeneity. If moderate or significant heterogeneity was present, a sensitivity analysis was performed whenever possible. Random-effects models were used because training characteristics (mode, volume, intensity, supervision) were expected to differ among studies. Subgroup analyses were planned to evaluate the role of training mode (strength, aerobic, and combined strength and aerobic training), training volume (≤1500 min versus >1500 total training minutes), training intensity (low, moderate, and high-intensity training29), and intervention delivery mode (supervised versus home-based), provided that subgroups included at least 3 studies.

RESULTS

Literature Search Strategy

After elimination of duplicates, literature search yielded 1625 titles, of which 1605 were excluded based on title and abstract (Figure 1). Following full-text screening of the remaining 20 records, 10 records did not meet the inclusion criteria. Eight full-text articles and 2 conference abstracts originating from 8 independent studies (n = 334 patients) were included.41-50

F1
FIGURE 1.:
Flow chart of search process and study selection. RCT, randomized controlled trial.

Study Characteristics

A summary of the study characteristics and results is presented in Table 2. All except 1 study50 initiated the study intervention within the first year after LT. Interventions lasted 2 to 10 mo and involved supervised43-49 or home-based41-44,50 exercise training. Because Tomás et al44 performed only partial randomization to the subgroups home-based versus supervised training (personal communication), this meta-analysis considered both supervised and home-based programs together. Apart from 1 study that combined strength training with a walking program42 and another study that investigated early postoperative strength training,49 all study interventions comprised moderate- to high-intensity aerobic exercise training with or without muscle strength exercises. Two studies combined exercise intervention with dietary advice.41,50 Most studies failed to accurately describe their comparator of usual care; in 1 study, the control group was assigned a low-intensity intervention consisting of progressive walking.42

TABLE 2. - Summary of study characteristics and results
Author, year, country, publication type Population Intervention and comparator Outcome measures and results
Hickman et al (2021), 50 Australia, full-text article Recruitment and randomization:- n assessed for eligibility: 131- n randomized/completed: 35/27- Time after LT: 4 (IQR: 2–6) y
Control group:- n randomized/completed: 12/11- % male: 83% (including 1 dropout)- Age: 50 ± 15 y (including 1 dropout)
Exercise + diet group:- n randomized/completed: 23/16- % male: 65% (including 7 dropouts)- Age: 51 ± 15 y (including 7 dropouts)
Intervention:- Type: aerobic + strength + diet- Duration: 2 mo- Frequency: aerobic training: accumulation of 150 min of moderate to vigorous aerobic exercise per wk; strength training: 2×/wk- Supervision: home-based, guided through telerehabilitation
Comparator:- Usual care
Primary outcome(s): feasibility and safety
Cardiorespiratory fitness:- 6MWD: no between-group differences
Morphology:- Body weight: trend (P = 0.06) to decrease compared with control- BMI: trend (P = 0.05) to decrease compared with control- Waist circumference: no between-group differences
Metabolic health:- Blood pressure: no between-group differences- Fasting blood glucose: no between-group differences- Total cholesterol, LDL, HDL, and triglycerides: no between-group differences- Metabolic syndrome severity score: no between-group differences
HRQOL:- The mental but not physical component score of the SF-12 improved compared with the control
Adherence:- Participants attended on average in 52% of the 8 intended exercise videoconferences and 71% of the 6 intended diet videoconferences- Greater shift toward the Mediterranean diet than control
Adverse events:- No study-related adverse events- No participant reported feeling unsafe while exercising
Ergene et al (2019), 49 Turkey, abstract Recruitment and randomization:- n assessed for eligibility: NR- n randomized/completed: NR/29- n female/male: n = 9/20- Age: 53 ± 12 y- Time after LT: immediatelyControl group:- n randomized/completed: NR/15Exercise group:- n randomized/completed: NR/14 Intervention:- Type: strength- Duration: 2 mo- Frequency: 2 sessions/d, 5 days/wk- Supervision: combination of supervised and home-based
Comparator:- Routine postoperative care
Primary outcome(s): peripheral muscle strength, “physical performance” (sit-to-stand test), and functional exercise capacity (6MWD)
Cardiorespiratory fitness:- 6MWD: improved compared with controlMuscular fitness:- Knee extensor muscle strength: improved compared with control- 30-s sit-to-stand test: improved compared with controlAdverse events:- There were no adverse events in either group
Moya-Nájera et al (2019), 48 Spain, full-text article Recruitment and randomization:- n assessed for eligibility: 162- n randomized/completed: 54/50- Time after LT: 6 mo
Control group:- n randomized/completed: 28/28- % male: 85%- Age: 55 ± 9 y
Exercise group:- n randomized/completed: 26/22- % male: 82%- Age: 57 ± 7 y
Intervention:- Type: aerobic + strength + flexibility + balance- Duration: 6 mo- Frequency: 2×/wk- Supervision: supervised
Comparator:- Usual care
Primary outcome(s): static and dynamic balance
Muscular fitness:- Hip extensor strength: improved compared with control
Motor fitness:- Static and dynamic postural balance: improved compared with control- Timed up-and-go test: improved compared with control
Morphology:- Sit and reach test: improved compared with control
Adherence:- 94% adherence (45/48 sessions attended)
Adverse events:- Not reported, but the authors did conclude that the intervention was “safe”
Moya-Nájera et al (2017), 47 Spain, full-text article Identical to Moya-Nájera et al (2019) 48 Identical to Moya-Nájera et al (2019) 48 Primary outcome(s): cardiorespiratory fitness (VO2peak), muscle strength, body composition, HRQOL, and liver function
Cardiorespiratory fitness:- VO2peak: improved compared with control
Muscular fitness:- “Global” strength: improved compared with control- Knee extensor muscle strength: no between-group differences
Morphology:- Body weight and fat tissue percentage: no between-group differences
HRQOL:- Physical functioning and vitality scores of SF-36: improved compared with control
Adherence:- Identical to Moya-Nájera et al (2019)
Liver function:- AST, ALT, GGT, ALP, total bilirubin, PT, and INR: no between-group differences
Basha et al (2015), 46 Egypt, full-text article Recruitment and randomization:- n assessed for eligibility: NR- n randomized/completed: NR/30- Time after LT: “since” 6 mo- Only patients with BMI >30 kg/m²
Control group:- n randomized/completed: NR/15- % male: NR- Age: 51 ± 3 yExercise group:- n randomized/completed: NR/15- % male: NR- Age: 50 ± 3 y
Intervention:- Type: aerobic + strength + flexibility- Duration: 3 mo- Frequency: 3×/wk- Supervision: supervised
Comparator:- Usual care
Primary outcome(s): body composition and blood lipid profile
Morphology:- Fat and muscle tissue percentage: respectively, decreased and increased compared with control
Blood cholesterol and triglycerides:- Blood cholesterol and triglycerides: decreased compared with control
Garcia et al (2014), 45 Brazil, full-text article Recruitment and randomization:
- n assessed for eligibility: NR- n randomized/completed: NR/15- Time after LT: 6–12 moControl group:- n randomized/completed: NR/6- % male: 50%- Age: 39 ± 15 yExercise group:- n randomized/completed: NR/9- % male: 67%- Age: 52 ± 15 y
Intervention:
- Type: Aerobic
- Duration: 2–3 mo (24 sessions)
- Frequency: 2–3×/wk- Supervision: supervised
Comparator:- Usual care
Primary outcome(s): functional capacity (6MWD) and resting energy expenditure
Cardiorespiratory fitness:- 6MWD: improved over time (within-group effect) in the exercise group but not in the control group (group or interaction effects were not evaluated)
Other:
- Resting energy expenditure: improved over time (within-group effect) in the exercise group but not in the control group (group or interaction effects were not evaluated)Adherence:- All participants of the exercise group completed all 24 training sessions
Tomás et al (2013), 44
Portugal, full-text article
Recruitment and randomization:- n assessed for eligibility: 120- n randomized/completed: 48/39- Time after LT: 2–12 mo- Only patients with FAPControl group:- n randomized/completed: 23/16- % male: 81%- Age: 33 ± 8 ySupervised exercise group:- n randomized/completed: 9/8- % male: 63%- Age: 34 ± 8 yHome-based exercise group:- n randomized/completed: 16/15- % male: 27%- Age: 35 ± 4 y Intervention:- Type: aerobic + strength + balance- Duration: 6 mo- Frequency: 3×/wk- Supervision: either supervised or home-based
Comparator:- Usual care
Primary outcome(s): walking capacity (6MWD), muscle strength, and body composition
Cardiorespiratory fitness:- 6MWD, covered distance: no between-group differences- 6MWD, covered distance multiplied by body weight: increased more in the supervised exercise group than in the home-based exercise group and usual careMuscular fitness:- Knee extensor muscle strength: no between-group differences- Handgrip muscle strength: no between-group differencesMotor fitness:- PND score: 1 patient in the home-based exercise group improved her PND score from IIIA (walking with help of 1 walking aid) to II (impaired walking but without use of any walking aid)Morphology:- Total body skeletal muscle mass: improved in the supervised exercise group compared with the home-based exercise group and control group- Fat mass and percentage: no between-group differences- Proximal femur bone mineral density but not total bone mineral density was higher after the intervention in the control group than in the supervised exercise group
Tomás et al (2011), 43 Portugal, abstract Recruitment and randomization:- n assessed for eligibility: NR- n randomized/completed: NR/37- Time after LT: 2–12 moControl group:- n randomized/completed: NR/14- % male: 79%- Age: 34 ± 10 ySupervised exercise group:- n randomized/completed: NR/8- % male: 63%- Age: 34 ± 7 yHome-based exercise group:- n randomized/completed: NR/15- % male: 27%- Age: 35 ± 5 y Intervention:- Type: aerobic + strength- Duration: 6 mo- Frequency: 3×/wk- Supervision: either supervised or home-based
Comparator:- Usual care
Primary outcome(s): walking capacity (6MWD), fatigue, and HRQOLCardiorespiratory fitness:- 6MWD covered distance multiplied by body weight: improved in the supervised exercise group only (no further details provided)HRQOL:- SF-36: no between-group differencesFatigue:- Multidimensional assessment of fatigue questionnaire: no between-group differences
Mandel (2009), 42 USA, full-text article (PhD dissertation chapter) Recruitment and randomization:- n assessed for eligibility: 74- n randomized/completed: 50/25- Time after LT: 6–12 wkControl group:- n randomized/completed: 25/14- % male: NR- Age: 53 ± 8 yExercise group:- n randomized/completed: 25/11- % male: NR- Age: 54 ± 12 y Intervention:- Type: ambulation program + strength- Duration: 3 mo- Frequency: 3–4×/wk- Supervision: home-based
Comparator:- Usual care: ambulation program
Primary outcome(s): strength and physical function (ability to perform activities)
Note: Whenever post test data at 3 mo were not available, data assessed at 2 mo was used for analysis
Cardiorespiratory fitness:- 6MWD: no between-group differences
Muscular fitness:- 30-s sit-to-stand test: improved compared with control- Number of heel rise repetitions till failure: trend (P = 0.065) for improvement compared with control- Number of bridge repetitions until failure: improved compared with control
HRQOL:- The SF-36 and CLQD: no between-group differences
Adherence:- Execution of the muscle strengthening or the walking program for at least 50% of the time was defined as adherent. Twelve of 14 participants of the control group adhered to the ambulation program. Nine of 11 participants of the exercise group adhered to the training and ambulation program
Liver function:-Albumin, total protein, creatinine, ALP, ALT, AST, and bilirubin: remained within normal post-LT ranges in both the control and exercise group
Adverse events:- No verbal reports of severe muscle/joint pain or other adverse events from participants in either group- A substantial number of participants could not complete the study for medical reasons, primarily because of immunosuppressant medications resulting in hospitalizations
Krasnoff et al (2006), 41 USA, full-text article Recruitment and randomization:- n assessed for eligibility: 292- n randomized/completed: 151/119- Time after LT: 2 mo
Control group:- n randomized/completed: 86/70- % male: 40%- Age: 51 ± 10 y
Exercise + diet group:- n randomized/completed: 65/49- % male: 39%- Age: 50 ± 11 y
Intervention- Type: aerobic + diet- Duration: 10 mo- Frequency: ≥3×/wk- Supervision: home-based
Comparator:- Usual care
Primary outcome(s): cardiorespiratory fitness (VO2peak)
Cardiorespiratory fitness:- VO2peak: improved compared with control
Muscular fitness:- Knee extensor muscle strength: no between-group differences
Morphology:- Fat mass: no between-group differences- Lean body mass: no between-group differences
HRQOL:- SF-36: subscales general health and mental health improved compared with control
Adherence:- Adherence was defined as ≥50% adherence to both the exercise prescription and diet recommendations. 37% (n = 18) adherence in the intervention group
Liver function:- ALP, total bilirubin, AST, and ALT: no between-group differences
6MWD, 6-min walking distance; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CLQD, Chronic Liver Disease Questionnaire; FAP, familial amyloidotic polyneuropathy disease; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein; HRQOL, health-related quality of life; INR, international normalized ratio; IQR, interquartile range; LDL, low-density lipoprotein; LT, liver transplantation; NR, not reported; PND, polyneuropathy disability; PT, prothrombin time; SF-12 or -36, Short-Form Health Survey-12 or -36; VO2peak, peak oxygen uptake.

Assessment of Study Quality

The risk-of-bias assessment is summarized in Figure 2. Only Moya-Nájera et al47,48 and Hickman et al50 reported the use of random sequence generation. Mandel42 and Hickman et al50 were the only studies reporting on the randomization strategy, concealing allocation using envelopes or recruiting a blinded investigator.50 Despite the nature of exercise interventions not allowing adequate blinding of participants, Mandel42 addressed performance bias by ensuring that both exercise and control groups received a similar number of contacts (phone calls or office visits) and by assigning the control group to a low-intensity exercise intervention (progressive ambulation program), which would allow patients to anticipate clinical benefits.

F2
FIGURE 2.:
Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

The study by Hickman et al50 was considered at risk for detection bias because study participants acted as outcome assessors. So was the study by Mandel42 because of investigators being in charge of both coaching and outcome assessment. Basha et al46 was considered not at risk for detection bias because they only investigated objective outcomes (body composition and blood lipid profile) unlikely to be affected. Other studies did not report on blinding of outcome assessors, leaving detection bias risk unclear.

Two studies were at risk of attrition bias because of dropout rates that were either high,42 unequal between control and exercise groups,44 or insufficiently justified44 or because of unclear handling of missing values.42

Most studies were at low risk of reporting bias, with the exception of the study by Tomás et al,43 who reported on the outcome fatigue and HRQOL in a 2011 conference abstract but not in the subsequent 2013 original article.44

Finally, Garcia et al45 was considered at unclear risk for “other potential sources of bias,” because of a low sample size and between-group differences in gender distribution and age.

Overall, study quality was heterogeneous, with many categories of bias considered at unclear risk because of poor reporting.

Meta-analysis of Primary Outcomes

Cardiorespiratory Fitness

Meta-analysis of 6 studies (n = 275)41,42,44,45,47,50 showed a trend for favorable effects of exercise training on cardiorespiratory fitness as evaluated by VO2peak and 6-min walking distance (SMD: 0.23, 95% confidence interval [CI], −0.01 to 0.48, P = 0.06; χ² = 2.57, P = 0.77; I² = 0%; Figure 3). Insufficient studies were available for meta-analysis of VO2peak in isolation. Pooled analysis of 4 studies (n = 106)42,44,45,50 showed no favorable effects of exercise training on 6MWD in isolation (MD: 26 m, 95% CI, −12 to 65 m, P = 0.18; χ² = 3.92, P = 0.27; I² = 23%).

F3
FIGURE 3.:
Forest plot of pooled effect of exercise training on cardiorespiratory fitness assessed by VO2peak and 6MWD. 6MWD, 6-min walking distance; CI, confidence interval; SD, standard deviation; VO2peak, peak oxygen uptake.

Mandel42 investigated the effects of strength training in de novo LT recipients. Aside from a progressive ambulation program delivered to both the exercise and control group, the study intervention did not include an aerobic exercise intervention. Exclusion of Mandel42 was performed to assess whether the anticipated lack of strength training effects on cardiorespiratory fitness may have affected previous meta-analyses. However, exclusion of Mandel42 did not change the outcome in either of both aforementioned meta-analyses (data not shown).

Muscular Fitness

Three studies assessed knee extensor muscle strength by dynamometry.41,44,47 One study assessed lower body muscle (strength) endurance by means of a 30-s sit-to-stand test.42 Pooled analysis on data from the 4 full-text articles (n = 233)41,42,44,47 showed no favorable effect of exercise training on lower body muscular fitness (SMD: 0.18, 95% CI, −0.13 to 0.49, P = 0.27; χ² = 3.82, P = 0.28; I² = 22%; Figure 4).

F4
FIGURE 4.:
Forest plot of pooled effect of exercise training on lower body muscular fitness assessed by dynamometry or 30-s sit-to-stand test. CI, confidence interval; df, degrees of freedom.

To explore the effect of strength training in particular, either performed or not performed in conjunction with aerobic exercise, a subgroup analysis of 3 studies (n = 114)42,44,47 was conducted and showed a trend toward improved lower body muscular fitness (SMD: 0.34, 95% CI, −0.03 to 0.72, P = 0.07; χ² = 1.77, P = 0.41; I² = 0%; Figure 5).

F5
FIGURE 5.:
Forest plot of pooled effect of exercise training on lower body muscular fitness assessed by dynamometry or 30-s sit-to-stand test in a subanalysis restricted to studies implementing muscle strengthening exercises. CI, confidence interval; df, degrees of freedom.

Motor Fitness

Only Moya-Nájera et al48 evaluated changes in postural balance and global motor fitness (timed up-and-go test), both improving after a 6-mo exercise training program. Tomás et al44 reported on a cohort of 39 de novo LT recipients with familial amyloidotic polyneuropathy (FAP) and documented an improvement in the polyneuropathy disability score of 1 patient who participated in home-based training.

Morphology

Fat percentage was reported by 4 studies41,44,46,47; however, the Krasnoff et al41 study showed apparent errors in data reporting. Meta-analysis of the 3 remaining studies (n = 119) showed no significant effect of exercise training, while showing significant heterogeneity (MD: −1.5%, 95% CI, −5.1% to 2.1%, P = 0.42; χ² = 11.77, P = 0.003; I² = 83%). The small number of studies did not allow a sensitivity analysis.

Four studies evaluated body composition, either by DXA scan41,44 or bioelectrical impedance analysis,46,47 and reported variable findings. Krasnoff et al41 documented that both exercise and usual care groups experienced a significant increase in body weight, lean body mass, fat mass, and fat percentage. However, similar to Moya-Nájera et al,47 they did not find a significant difference in body composition between these groups. In the FAP patient study, Tomás et al44 found an increase in total body skeletal muscle mass that was greater in those allocated to supervised training than in those allocated to home-based training or usual care; no differences were found for fat mass or percentage, and proximal femur bone mineral density was found to be higher in usual care than in those undertaking supervised training. Basha et al46 reported a significant reduction in fat percentage and increase in muscle percentage in the exercise group relative to the usual care group.

Moya-Nájera et al48 reported that lower back and hamstring flexibility assessed by the sit and reach test was improved in the exercise group relative to the usual care group.

Metabolic Health

Only 2 studies reported on metabolic health parameters. Basha et al46 reported that de novo LT recipients after a 3-mo supervised strength and aerobic training program showed significantly lower cholesterol and triglyceride levels than usual care. Conversely, Hickman et al50 found that a 2-mo aerobic and strength program along with a Mediterranean diet failed to improve metabolic syndrome severity score or laboratory markers of metabolic health.

Health-related Quality of Life

Because literature is scarce and a large variability exists in outcome measures used to quantify HRQOL, the meta-analysis was limited to the “physical function” measure of Short-Form Health Survey-36 in 3 studies (n = 194; Figure 6).41,42,47 A significant effect was found in favor of exercise training (MD: 9.1, 95% CI, 0.3-17.8, P = 0.04; χ² = 3.75, P = 0.15; I² = 47%).

F6
FIGURE 6.:
Forest plot of pooled effect of exercise training on physical function subcomponent of the SF-36 questionnaire. CI, confidence interval; df, degrees of freedom; SF-36, Short-Form Health Survey-36.

Secondary Outcomes

Adherence

Five studies reported on adherence rates to the allocated exercise program, and found them to be high for supervised programs but variable for home-based programs.41,42,45,47,50 The definitions of adherence varied according to study set up and are detailed in Table 1. Actual dropout rates in exercise versus control groups are discussed later. Moya-Nájera et al47 and Garcia et al45 reported an adherence rate of 94% and 100%, respectively, to the allocated supervised programs of strength or aerobic training. In contrast, Krasnoff et al41 found a 37% adherence rate to a home-based aerobic exercise and dietary intervention, whereas Mandel42 reported an 82% adherence rate to a home-based strength training program with written exercise instructions, daily exercise logs, and biweekly telephone calls. Last, Hickman et al50 reported 52% and 71% attendance rates to virtually delivered exercise and diet videoconferences, respectively.

Fatigue

In an abstract, Tomás et al43 reported that fatigue did not improve in transplanted FAP patients allocated to home-based or supervised strength and aerobic training.

Liver Function

Three studies reported on laboratory values of liver and kidney function.41,42,47 Although group-specific data from baseline to the follow-up were not provided, all 3 studies reported that laboratory values of liver and kidney function remained in normal post-LT ranges in both exercise training and usual care groups.

Adverse Events and Dropouts

Few studies reported on safety other than clarifying reasons for dropout.42,49,50 Hickman et al,50 Ergene et al,49 and Mandel42 specifically reported that no exercise-related adverse events were documented.

Five studies reported on dropout rates,41,42,44,47,48,50 which varied from 8%44 to 56%42 in the exercise groups, and from 0%47,48 to 44%42 in the usual care groups (Table 1). Pooled dropout rates in the exercise and usual care groups were 45% (n = 74/164) and 46% (n = 80/174), respectively.

Health-related dropouts may be worth noting in the light of safety evaluation. Moya-Nájera et al47,48 reported that n = 4 of 26 dropped out from exercise training, compared with n = 0/28 participants in usual care. Two of these 4 dropouts were related to loss of vitality associated with hepatitis C virus recurrence. Mandel42 reported a dropout rate of n = 14 of 25 patients in the exercise group versus n = 11 of 25 in usual care. In the exercise group, health-related dropouts were due to death (n = 1), hospitalizations related to immunosuppression (n = 7), knee pain (n = 1), groin abscess formation (n = 2), and renal failure (n = 1). In usual care, health-related dropouts were due to death (n = 1), hospitalizations related to immunosuppression (n = 5), and fall injury unrelated to the study intervention (n = 1). Krasnoff et al41 reported a dropout rate of n = 11 of 60 and n = 11 of 81 in the intervention and usual care group, respectively. Health-related dropouts in the intervention and control group included death (n = 4 versus 2, respectively) and illness (n = 4 versus 3, respectively).

DISCUSSION

RCTs into the effects of aerobic and strength training after LT are scarce. Only 8 RCTs were identified, which moreover presented with challenges of small sample sizes, a risk of bias due to the difficulty of applying blinded research in this setting, and poor methodological reporting. Despite these limitations and significant heterogeneity in study design, meta-analysis showed a statistically significant benefit of exercise training on the physical function subcomponent of the Short-Form Health Survey-36 HRQOL, as well as a trend for statistical significance for a favorable effect of exercise training on cardiorespiratory fitness and of strength training on muscular fitness. The evidence from this systematic review and meta-analysis is encouraging. It indicates the need for well-designed RCTs in larger cohorts of patients, and this review highlights specific challenges that will need to be addressed when designing and interpreting these studies.

Although few studies reported on prospectively collected adverse events, across the selected RCTs, both aerobic and strength training interventions were found to be safe.42,49,50 This review was restricted to RCTs because, after LT, patients will experience changes in physical fitness that occur naturally and are independent of exercise. Although a broader selection of studies may have allowed for wider insight in the safety aspect of exercise training, any future clinical trials should include prospective safety evaluations.

As per this study’s design, the selected RCTs focused on strength training,42,49 others on aerobic training,41,45 but the majority43,44,46–48,50 included both components. The duration of exercise programs was variable, though all lasted for at least 2 mo and were therefore of sufficient duration to expect detectable training adaptations.51 Although the objective was to identify optimal training mode, volume, intensity, and delivery method, a larger number of studies would be required to enable such investigation.

A small focus group with LT recipients held in preparation of the present review protocol suggested that, from a patient perspective, motor fitness should be considered an important training goal because it may contribute to "functional physical fitness." Few of the selected RCTs investigated postural balance and motor fitness other than by 6MWD. Moya-Nájera et al48 reported that postural balance and the timed up-and-go test (coordination, agility, and dynamic balance) were highly responsive to a 6-mo intervention of concurrent aerobic, strength, balance, and flexibility exercise. Future studies should likewise address these outcomes.

The currently available data fall short in the evaluation of the impact of exercise training on metabolic and cardiovascular health. Two studies evaluated markers of metabolic health but reported contrasting findings.46,50 The 2 largest studies did not indicate an important role for exercise training in the attenuation of fat mass accretion.41,47 Long-term effects on cardiovascular events remain to be investigated. This is surprising, as metabolic and cardiovascular comorbidities after LT are abundant and exercise training is likely to positively impact metabolic and cardiovascular health.26,32,46

Risk-of-bias analysis of the selected RCTs revealed inadequate methodological reporting, in particular regarding selection and detection bias. The study quality was also compromised because of performance bias, which seems inherent to research involving physical exercise interventions. In an attempt to address this, Mandel42 allocated a low-intensity progressive ambulation program to the control group, along with a follow-up schedule similar to that of the intervention group. Despite the lack of blinding, such an approach leads to participants in both groups experiencing subjective anticipatory benefits. Last, the average sample size was small (n = 42), and most studies did not report whether an a priori power calculation was performed.

The nature of both the study patient population and study intervention warrants caution when translating the conclusions of this review to clinical practice. Most studies used strict inclusion and exclusion criteria related to age, etiology of liver failure, single versus multiorgan transplantation, and medical contraindications to exercise. In addition, willingness to participate in a physical exercise program requires a certain attitude, belief, and commitment from the patient. In the 2 largest studies, 11% (n = 19/170) and 45% (n = 45/99) of eligible study subjects declined to participate.41,47,48 Moreover, adherence rates were variable across supervised and home-based programs, and in some studies, dropout rates were substantial.42 As a result, across the 5 studies that provided numbers of contacted study subjects, only 43% (n = 338/779) were randomized, and only 33% (n = 260/779) were eventually included in the final analyses.41,42,44,47,48,50 The study population of this review thus represents a medically preselected (sub)group of LT patients who were willing and able to complete a physical exercise training program. Last, 1 study in particular investigated exercise training in patients suffering from FAP, a progressive neurodegenerative disease for which LT is currently considered the best treatment option to halt disease progression.44 For FAP patients who typically exhibit malabsorption and malnutrition, a certain extent of weight gain, preferably driven by muscle mass, is considered beneficial. In other studies, LT was performed primarily as a treatment for advanced liver cirrhosis from various etiologies, where rapid posttransplant weight gain is generally considered problematic, as it is primarily driven by fat accretion and often leads to sarcopenic obesity.5–8,10

Two meta-analyses within the scope of the present study have recently been published.52,53 Choo et al52 evaluated the effects of supervised exercise training in both chronic liver disease and LT patients. The authors included only 1 RCT in LT patients. Janaudis-Ferreira et al53 evaluated the effects of exercise training versus control across all solid organ transplant recipient types and included only 2 RCTs in LT patients. The present review includes 8 unique RCTs in LT patients. Therefore, based on a stronger body of evidence and in line with the aforementioned meta-analyses, our findings may provide further support for the favorable effects of exercise training on cardiorespiratory and muscular fitness, and HRQOL after LT.

The present study holds several clinical implications. First, exercise training at moderate intensity is safe and benefits both mental and physical well-being after LT. Training programs should include both aerobic and muscle strengthening exercises to improve both cardiorespiratory and muscular fitness. Furthermore, postural stability exercises are advised to improve motor fitness and hence support activities of daily living.12,48 Finally, both researchers and clinicians should beware of selection bias and training adherence. Home-based programs require thoughtful implementation strategies to ensure adequate adherence to the training program.

Further well-designed and adequately powered RCTs are warranted to identify the most effective training and implementation strategies and to evaluate a standardized set of clinical (eg, survival, cardiovascular health, graft function, physical fitness), patient-reported (eg, HRQOL, depression, anxiety, social roles), and health-economic outcomes during the short- and longer-term follow-up.

CONCLUSION

This study indicates that exercise training in LT recipients is safe, benefits the physical function aspect of HRQOL, and may lead to improved cardiorespiratory and muscular fitness. Although clinical recommendations highlight the importance of physical activity and exercise in all types of solid organ transplantation, robust evidence to support this in LT recipients is still lacking. Well-designed and adequately powered RCTs are warranted.

ACKNOWLEDGMENTS

The authors would like to thank the liver transplant patients for their enthusiastic participation in the focus group.

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