A Physical Activity Program in End-stage Liver Disease: Pilot Study Assessing Changes in Physical Fitness, Sarcopenia, and the Metabolic Profile
Phase: NA
Conditions: End-stage Liver Disease (ESLD), Liver Transplant, Sarcopenia, Poor Physical Fitness, Cirrhosis, Portal Hypertension
Sponsor: University of Arkansas

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
1 
 
Protocol Title  
   A physical activity program in end-stage liver disease: pilot 
study assessing changes in physical fitness, sarcopenia, and 
the metabolic profile 
 
 
Principal Investigator 
Arny Ferrando, PhD1 
 
 
 
Co-Investigator(s)  
Andres Duarte-Rojo, MD, MSc, DSc2 
 
 
 
 
 
Thaddeus Bartter, MD3 
 
 
 
 
 
Aldo Montano-Loza, MD, MSc, PhD4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Center for Translational Research in Aging and Longevity 
 
 
 
 
 
2Division of Gastroenterology and Hepatology 
 
 
 
 
 
3Division of Pulmonary and Critical Care Medicine 
 
 
 
 
 
 
 
 
 
University of Arkansas Medical Sciences 
 
 
 
 
4300 W. Markham 
 
 
 
 
Little Rock, AR  72032 
 
 
 
 
 
4Division of Gastroenterology 
 
 
 
 
 
 
 
 
 
University of Alberta 
 
 
 
 
1-20A Zeidler Ledcor 
 
 
 
 
Edmonton, Alberta, Canada 
 
 
 
 
 
Location(s) of Study 
University of Arkansas for Medical Sciences  
 
 
 
University of Alberta 
 
Version 
 
 
10 
 
Date  
 
 
10/10/2018 
 
 
 
 
 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
2 
ABSTRACT 
 
Patients with end-stage liver disease (ESLD) have poor physical fitness and muscle wasting 
(sarcopenia). Both conditions have been associated with elevated mortality before and after 
liver transplantation (LT). Limited data have shown that exercise benefits patients with chronic 
liver disease/cirrhosis, however, there are no studies with ESLD patients potentially eligible for 
LT. Effectively improving physical fitness and sarcopenia in ESLD should positively impact 
clinical outcomes before/after LT. The primary aim of this study is to improve both physical 
fitness and sarcopenia in ESLD patients through a 12-week physical training program. 
Secondary aims will focus on changes in anthropometrics, body composition, quality of life, and 
metabolic profile. This is a randomized clinical trial including 50 patients, with half allocated to 
the active group (physical training program) and half to standard of care. Physical training 
program will consist on achieving ≥10,000 steps/day with an increase of ≥4000 above the 
baseline, facilitated by the feedback from daily step counts and behavioral modification therapy 
(favoring change towards a more active lifestyle). All participants will have to wear a pedometer 
bracelet (Fitbit) throughout duration of study (reads blinded to controls), and will receive a daily 
essential amino acid (EAA) supplement containing approximately 2.25 g of L-leucine along with 
nutritional consultation. Cardiorespiratory exercise test (CRET), 6-minute walk test (6MWT), and 
abdominal CT scan will be performed in all participants before and after the period of study to 
assess for physical fitness and sarcopenia. Anthropometrics, bioelectrical impedance, whole-
body DEXA scan, sickness impact profile questionnaire, and the metabolic profile will be 
obtained at baseline and after completion of the study as well. Blood EAA levels, myostatin, and 
insulin-related growth factor-1 will be determined at baseline, and at week 12 of study. Durability 
of changes 6 months post-LT will be assessed as well, when applicable. 
 
 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
3 
INTRODUCTION 
 
End-stage liver disease (ESLD) is the final consequence of cirrhosis and portal hypertension, 
causing great morbidity and mortality, and necessitating liver transplantation (LT) to preserve 
life.(1) Physical fitness is defined as the ability to carry out daily tasks with vigor and alertness, 
without undue fatigue.(2) Compared to healthy peers, patients with ESLD have a poor physical 
fitness, and deterioration progresses along with liver failure. Patients with chronic liver disease 
(with or without cirrhosis) have low to limited activity, with daily pedometer counts between 5000-
7000 steps per day, what is way below a minimum recommended of 10,000 daily steps, for a 
"somewhat active" individual.(3-5) There are several reasons for patients with cirrhosis having 
low to limited physical activity. Some of the most common contributing factors include chronic 
fatigue, muscle wasting, obesity, intentional inactivity (either physician-prescribed or self-imposed 
due to disease misconceptions), poor motor and visuospatial coordination in relation to hepatic 
encephalopathy (HE), covert HE-associated fear of falling, ascites and fluid overload limiting 
mobility, 
and 
concomitant 
cardiopulmonary 
diseases 
(hepatopulmonary 
syndrome, 
portopulmonary hypertension, cirrhotic cardiomyopathy).(6, 7) 
 
Severe skeletal muscle loss or sarcopenia is one of the end results of a limited physical fitness, 
and it is also a major feature of malnutrition. Notably, sarcopenia and HE are closely related and 
they can perpetuate or aggravate each other. Since skeletal muscle represents the major organ 
participating in extrahepatic ammonia metabolism, it is not surprising to find that patients with 
sarcopenia and malnutrition have a higher risk for HE.(8, 9) On the other hand, HE negatively 
impacts muscle mass by affecting motor coordination and physical activity, and experimental data 
have also shown that hyperammonemia has a detrimental impact on skeletal muscle by favoring 
cell autophagy.(10) 
 
Physical fitness and sarcopenia are both common conditions affecting 41-88% of patients with 
ESLD in the LT waitlist,(11, 12) and they have been associated with poor clinical outcomes. Both 
physical fitness and sarcopenia have been independently associated with poor survival before 
and after liver transplantation.(11-16) Sarcopenia has also been linked to a longer hospital stay 
during the LT admission, and with a higher risk for peri-operative infectious complications. A 
recent study has noted that addition of sarcopenia to MELD (model for ESLD) is a better predictor 
of waitlist mortality and dropout than MELD by itself.(17) Due to its paramount importance in 
predicting LT outcomes, two groups have independently proposed the addition of a sarcopenia 
measure to MELD (MELD-psoas and MELD-sarcopenia) in order to have a more accurate 
prognostication of mortality (pre- and posttransplant), and to better prioritize patients for LT.(17, 
18) In spite of all the above evidence, physical fitness and sarcopenia have both been frequently 
overlooked as predictive factors for adverse outcomes in LT.  
 
Cardiorespiratory endurance is a measurement of physical fitness obtained through 
cardiorespiratory stress tests. Two common markers of cardiorespiratory endurance are the 
VO2max obtained by cardiorespiratory exercise testing (CRET), and the distance strolled in the 6-
minute walk test (6MWT). The VO2max is the point at which, during a CRET, the consumption of 
oxygen cannot be augmented in spite of increased exercise intensity (Figure 1a). After the VO2max 
is reached, there is a disproportionate increase in VCO2 production with respect to VO2 
consumption, which is known as the anaerobic threshold (Figure 1b). The anaerobic threshold 
corresponds to the point at which lactic acid rises systemically during incremental exercise, as a 
result of anaerobic glycolysis.  
 
In spite of changes in physical fitness and sarcopenia being attributed to a clinical condition (i.e. 
ESLD) evidence points to lifestyle changes as a major player in its causation and perpetuation. A 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
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provocative study has shown that LT by itself is not capable of improving cardiorespiratory 
endurance, as shown in the lack of significant improvement in VO2max in 20 patients who had it 
tested before and more than 1 year after LT. The mild increase in VO2max from 63% to 71% - and 
25% of patients showing decreased VO2max - mostly correlated with the improvement in 
hemoglobin, and stopping of the beta-blocker. Although there was likely some improvement in 
skeletal muscle physiology, as suggested by changes in peak lactate concentration, LT had no 
major impact in aerobic capacity and cardiorespiratory endurance.(19) This suggests that, even 
though poor physical fitness and sarcopenia are primarily driven by ESLD, restoration of normal 
liver function by means of LT is not enough to positively impact physical fitness. Likely in relation 
to the lack of changes in lifestyle favoring healthy habits, patients progressively gain weight after 
liver transplantation,(20) and it is not surprising to find a high prevalence of the metabolic 
syndrome (>50% after the first year post-LT; >50% of what is observed in the general population), 
particularly hypertension and diabetes mellitus (>60% after first year post-LT), and are at great 
risk for cardiovascular complications.(21)  
 
Although there are some conflicting data regarding what benefits physical activity or exercise 
confers to various morbid states, it is in general conceived that improving physical fitness is 
beneficial, both by preventing deterioration of a state of health, and by helping diseased conditions 
through adaptation.(22, 23) In chronic liver disease, and particularly in the setting of ESLD, there 
is a great paucity of data regarding the beneficial effects that exercise or a physical activity 
program can offer to patients. Actually, to date, there is no robust evidence from large randomized 
trials to sustain that the deterioration in physical fitness and sarcopenia that patients with ESLD 
are exposed to, is reversible by any type of intervention.  
 
Pattullo et al included 16 patients with chronic hepatitis C - 6 of whom were cirrhotic - in a 24-
week exercise and dietary program. Exercise consisted on walking and patients were encouraged 
to increase their daily step count using a pedometer to self-monitor their progress. With the aid of 
behavior modification therapy we were able to increase daily step counts from a baseline of 6853 
(2440-9533) to 10967 (7959-13566) steps/day, and there were significant improvements in fasting 
glucose, insulin resistance (HOMA-IR (3.6 [2.8-4.9] to 2.1 [1.8-3.6]), BMI (36 [31-38] to 31 [29-
36]), waist circumference, fatigue and mood scores. These changes were paralleled by significant 
drops in ALT, AST, and GGT levels, and by increased adiponectin, and decreased leptin. Calorie 
restriction had a median of 33% during the intervention.(5) In a total of 8 patients with cirrhosis 
initially included in this study, we could observe an improvement in quality of life as well, reflected 
by the physical component summary of SF36 (specifically on physical function, bodily pain, and 
vitality).(24) With a similar design, Konishi et al, were able to demonstrate that in 16 patients with 
chronic hepatitis C, an increase in daily step counts from around 5500 to over 7000 during a 
period of 6 months had a positive impact in insulin resistance (HOMA-IR), BMI, waist 
circumference, ALT, and leptin levels. Of note, this study provided standardized nutritional 
counseling, but no changes in caloric intake were noted.(4) In a randomized clinical trial, Soriano 
et al showed that a period of 12 weeks of supervised moderate exercise thrice-weekly plus 10 g/d 
of oral leucine (n=8) caused an increase in albumin levels, muscle mass (as reflected by the thigh 
circumference), cardiorespiratory endurance (6MWT increased from 321±36 to 417±33 m), and 
quality of life (according to SF36). None of these changes were noted in the control group 
(n=9).(25) We recently completed a randomized clinical trial consisting of 12 weeks of a 
supervised physical training program in patients with cirrhosis. Out of 23 patients included, 11 
were allocated to moderate exercise/kinesiotherapy for about 70 minutes per session, three times 
per week, at a cardiac rehabilitation center. Remaining patients continued with standard of care. 
Phase angle (PhA) from bioelectrical impedance was used to evaluate muscle mass. We showed 
a trend for improved muscle mass in the exercise group, as PhA improved in 63% of patients 
compared to 25% of the control group (p=0.10).  

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
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Remarkably, branch-chained fatty acids (particularly L-leucine) administration has been recently 
associated with decreased skeletal muscle autophagy and reversal of protein-breakdown 
signaling. Myostatin is one of the mail players driving autophagy and blocking protein synthesis 
through inhibition of the mammalian target of rapamycin, and it has been found to be elevated in 
patients with cirrhosis. It is thought that hyperammonemia increases myostatin, then facilitating 
to impaired proteostasis with the end result of muscle loss or sarcopenia.(26) Finally, insulin-like 
growth factor 1 (IGF-1) is a trophic factor directly affecting muscle growth and repair, and it is 
known to be induced with exercise and L-leucine supplementation (Church. J Am Coll Nutr 
2016;in press).  
 
Although physical fitness is a modifiable risk factor, there are no studies to date assessing whether 
an exercise program aiming to improve cardiorespiratory endurance and physical fitness while on 
the waiting list could potentially improve posttransplant outcomes. One of the concerns with an 
exercise program in patients with cirrhosis and ESLD is its safety. Two of the perils that could 
possibly occur as a consequence of exercise are episodes of gastrointestinal (variceal) bleeding 
and/or HE. Although there are pathophysiologic and anecdotic evidence supporting that an 
increased risk for these complications is plausible, there are no clinical data to substantiate the 
concept. At least 9 published studies(4, 5, 11, 25, 27-30) have subjected patients with cirrhosis 
(± ESLD) to physical activity programs or exercise stress testing - intensity varying from a daily 
low intensity (estimated VO2max of 35-50%) to a single bout of moderate-to-high intensity exercise 
(VO2max 60-100%) - with no documentation of adverse reactions. Particularly no episodes of 
variceal bleeding or HE were observed. However, it is unknown whether such complications were 
intentionally investigated in any of the above-mentioned studies, as none of them was designed 
to identify and correlate such complications of ESLD to physical activity.  
 
In an interesting study, Garcia-Pagan et al submitted patients with cirrhosis to a low-to-moderate 
exercise regimen while measuring the hepatic venous pressure gradient (HVPG) and were able 
to find out that exercise increases the HVPG by 21% at a 50% maximum work load. This was 
followed by a return to normal after 5 minutes of stopping physical activity.(31) In a subsequent 
study from the same group, Bandi et al showed that the increase in HVPG during exercise could 
be abolished if the patient was given a beta-blocker before the exercise bout.(32) Since the HVPG 
is the best available marker to determine portal hypertension and the risk for variceal bleeding, 
data above suggest that the risk of variceal bleeding acutely increases during exercise, whenever 
the patient is not receiving a beta-clocker. However, our randomized clinical trial was able to show 
a decrease in the HVPG by the end of the study period in the active group contrasting the 
expected increase observed in controls (HVPG: -2.5 [-5.25 to 2] vs 4 [0.25 to 8], respectively, 
p=0.007).(33) This surprising finding brings to light that there might be some other benefits from 
physical fitness that we are yet unable to see. Moreover, no cases of variceal bleeding were 
observed in this and other clinical trials evaluating the effect of an exercise program in cirrhosis.(5, 
25, 33) 
 
Ammonia, a byproduct of nitrogen metabolism, is the most important factor associated with 
HE.(34) During exercise, and mostly under anaerobic conditions, breaking of ATP will result in 
net production of ammonia, what could expose patients with ESLD to hyperammonemia and 
episodes of HE. In sports medicine, the ammonia threshold, which corresponds to the deflection 
point at which ammonia production increases disproportionately during CRET (Figure 1c), has 
been used as a marker of exercise endurance. Actually, the increase in blood ammonia during 
exercise is directly related to the VO2max such that a more efficient aerobic capacity is associated 
with higher ammonia thresholds (less ammonia production for same VO2max). Although the 
ammonia threshold grossly coincides with the inflection point defining the change from aerobic to 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
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anaerobic metabolism (anaerobic and lactate threshold)(35, 36) there are no data in patients with 
ESLD. Given that ammonia uptake is severely reduced in ESLD, it is possible for patients with 
ESLD to be exposed to hyperammonemia under conditions of aerobic exercise, such that 
exercise could become a hazard even before reaching strenuous levels or exhaustion. Although 
not systematically investigated, there have been no cases of HE reported in clinical trials 
evaluating the effect of exercise in cirrhosis.(5, 25, 33) 
 
Every year about 6000 LT are performed in the US, and currently, there is a growing interest to 
explore the beneficial impact exercise can provide to patients with cirrhosis and ESLD through a 
structured physical training program. As based on data above, such a program may improve 
cardiorespiratory fitness and endurance, obesity and its associated metabolic complications 
(including less insulin resistance), sarcopenia, biomarkers of liver function, quality of life, and even 
portal hypertension. For hepatologists working on liver transplantation this may translate into 
reduced dropout from the transplant list, reduced length of hospitalization after transplant, better 
clinical outcomes including survival, and quality of life,(11, 13, 37) (12, 14) Furthermore, the 
incidence of obesity, metabolic syndrome, and cardiovascular complications after liver 
transplantation could be halted by training patients to change their lifestyle into a more physically 
active one.  
 
We currently spend great resources into avoiding substance abuse relapse and improving 
patient's compliance during the LT evaluation, but have omitted education regarding healthy 
lifestyle habits including physical activity and exercise, what might bring enormous benefits to LT 
worldwide. For patients with cirrhosis and ESLD, the period before liver transplantation is full of 
self-reflection and insight, education, and lifestyle changes. These behavioral tuning has allowed 
keeping the rate of alcohol recidivism at no more than 10% in most transplant centers, and a low 
prevalence for the use of tobacco products after LT. It is expected that any recommendation or 
prescription regarding physical activity would have greater acceptance and a more durable effect 
if properly administered once patients have reached ESLD, or while they are being evaluated for 
LT, as they become very receptive to make changes in their lifestyle as far as it helps to facilitate 
transplant candidacy. However, unlike diabetes mellitus and cardiac diseases, it is unknown for 
ESLD patients what the mode, intensity, and duration of exercise that will provide improved 
outcomes are. More importantly, there is a lack of knowledge regarding the safety of exercise with 
respect to hyperammonemia and occurrence of HE.  
 
 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
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SPECIFIC AIMS 
The primary aims of current study are to: 
 
Improve the physical fitness of patients with ESLD whom are potentially eligible for liver 
transplantation with a 12-week physical training program. 
o The hypothesis is that only patients enrolled in the active arm will improve their 
physical fitness, as determined by cardiorespiratory stress test and 6-minute walk 
test. 
 
Improve sarcopenia in patients with ESLD whom are potentially eligible for liver 
transplantation with a 12-week physical training program 
o The hypothesis is that only patients enrolled in the active arm will show an increase 
in the skeletal muscle area, as determined by CT-scan. 
 
As secondary aims, this 12-week training program will look into: 
 
The changes in the ammonia and anaerobic/lactate thresholds at the end of the study for 
each group.  
o It is expected to find increased ammonia and anaerobic/lactate thresholds in the 
active arm, when compared to the control arm. 
 
The changes in anthropometrics (weight, BMI, waist circumference), and body 
composition at the end of the study for each group. 
o It is expected to find improved anthropometrics, decreased fatty mass, and 
increased fat-free mass in the active arm, when compared to the control arm.  
 
The changes in quality of life at the end of the study for each group. 
o It is expected to find improvements in quality of life in the active arm, when 
compared to the control arm. 
 
Safety of the physical training program, by systematically documenting episodes of 
variceal bleeding, and hepatic encephalopathy. 
o No increased risk for complications such as GI bleeding and encephalopathy is 
expected for the active arm with current research design. 
 
The changes in the metabolic profile (fasting glucose, fasting insulin, lipid profile (total 
cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) at the end of the study for 
each group. 
o It is expected to have an improved metabolic profile in the active arm, when 
compared to the control arm. 
 
The changes in myostatin and insulin-related growth factor 1 (IGF-1) before and after 12 
weeks of study. 
 
In patients undergoing liver transplantation, extension of training program benefits 6 
months after liver transplant (reassessment of physical fitness, sarcopenia, 
anthropometrics, body composition, and metabolic profile). 
o Durability of the beneficial benefits of the training program will be expected across 
all evaluated variables, with no changes in the control arm after transplant.  
 
 
 
 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
8 
RESEARCH STRATEGY 
 
Significance 
 
Unlike other chronic diseases (i.e. diabetes mellitus), there are no recommendations for physical 
training and exercise in patients with cirrhosis. This derives from the fact that there is a paucity of 
data on the physiologic effects of exercise in patients with cirrhosis and portal hypertension, as 
well as on the benefits that such training can bring in the to long term. Moreover, some safety 
concerns have been raised in the past particularly with regards to an increased risk for variceal 
bleeding and HE. Apart from a few pilot studies using supervised exercise as an intervention there 
are no clinical trials addressing the benefits of an exercise program in patients with ESLD. 
Furthermore, no study has looked into how a training program can translate into benefits after LT, 
and since LT patients have a very high risk for metabolic and cardiovascular disease, such a 
study is highly awaited.  
 
Innovation 
 
Of the few studies on physical training in cirrhosis there is not a single one balancing the 
intervention to be effective, reproducible, feasible, and widely available. Moreover, safety has not 
been systematically investigated. Although supervised exercise at a physical rehabilitation center 
is effective and reproducible, it is not possible for most patients to join such a program, and these 
are definitively not widely available. Prior studies using a waist pedometer - a feasible and 
available design - might have several flaws: failure of the equipment, incapacity to measure all 
daily activities, lack of knowledge on cardiorespiratory endurance to tailor physical efforts, and no 
objective measure to assess efficacy of the intervention. Thus, both efficacy and reproducibility 
are affected.  
 
Current study has a balanced approach: duration and intensity of physical training have been 
adjusted to provide positive results as based on prior experience (both from supervised and 
pedometer-based studies), there are objective and accurate evaluations of cardiorespiratory 
endurance before and after intervention allowing to safely tailor the intensity of physical activities, 
behavioral modification therapy is included to facilitate changes in lifestyle, relevant safety 
concerns have been addressed and data will be collected to facilitate further safety refinement, 
the equipment to be used (bracelet pedometer) has the highest quality and reliability while 
allowing to correlate effort to changes in heart rate (such as in a supervised exercise program), 
and we are innovating with the use of PhA and bioimpedance vector analysis to reliably assess 
changes in body composition. Moreover, in patients undergoing transplantation, post-LT 
determinations have been considered to investigate duration of the effect in a population that has 
a very high mortality. Results from present study would provide physiological basis and 
preliminary results on efficacy and safety in order to develop a multicenter clinical trial aiming to 
show improved clinical outcomes (survival and dropout from waiting list before LT; survival, quality 
of life, metabolic and cardiovascular complications after LT) in patients with ESLD, as well as a 
future policy for exercise training in patients with ESLD.  
 
 
 
 
 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
9 
APPROACH 
 
All patients referred for an evaluation for liver transplantation, as well as patients with ESLD from 
hepatology clinics at UAMS, will be screened for study and invited to participate, when applicable. 
A total of 50 patients will be included in study. Inclusion and exclusion criteria will be as follows: 
 
Inclusion criteria 
1. Age 40 to 70. 
2. Cirrhosis, any cause, defined as: 
a. Biopsy-proven. 
b. Two or more of the following: albumin <3.5 g/dL, INR >1.3, radiologic or 
endoscopic evidence of portal hypertension. 
3. Creatinine <2.0 mg/dL. 
 
4. Physiologic MELD ≥10. 
5. Decompensated cirrhosis with active or history of variceal bleeding, ascites, hepatic 
encephalopathy, or jaundice. 
6. Potential transplant candidate as per UAMS criteria. 
 
Exclusion criteria 
1. Large gastric or esophageal varices with contraindication to use beta-blockers. 
2. Persistent hepatic encephalopathy grades 2-4. 
3. Prior diagnosis of hepatocellular carcinoma, or hepatic hydrothorax (with prior repeated 
thoracocentesis). 
4. Cirrhotic cardiomyopathy or congestive heart failure, pulmonary vascular complications, 
known active coronary artery disease, syncope, and cardiac dysrhythmias.  
5. Physical impediment to perform a cardiorespiratory fitness test. 
6. Use of implantable defibrillator or a pacemaker. 
 
Note: all inclusion / exclusion criteria will be obtained from routine investigations available during 
transplant evaluation, as part of the standard of care. 
 
Description of Study Interventions 
Physical Activity  
After signing of informed consent patients will be given a Fitbit to measure all physical activity 
throughout the day. The Fitbit is a digital pedometer inside of a bracelet capable of continuously 
measuring all physical activities (24/7) and heart rate. Each subject should wear her/his bracelet 
during the whole duration of the study, for a total of 14 weeks. There will be a 1-week delay 
between enrollment into the study and the initial study's appointment, in order to obtain the 
baseline physical activity from each subject (corresponds to week -2, see Study Calendar). 
Physical activity and heart rate logs will be electronically downloaded to the investigator's 
computer during each follow up visit. 
 
Physical activity prescription will target ≥10,000 steps/day, taking into account all activities 
performed throughout the day, although the increment in activity should be no less than 4000 
steps/day above the baseline. Apart from walking, there will be no physical activity that would be 
favored in particular to all participants, but each one will be able to choose and perform the type 
of exercise of their preference. The VO2max, ammonia, lactate and anaerobic thresholds observed 
on each subject will help better determine the intensity of exercise each patient should be able to 
tolerate safely.  
 
Nutritional Intervention 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
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Dietary advice will be provided at the beginning of the study and individually tailored to the 
participant’s usual eating habits, with the following modifications: 
 
High in low glycemic-index foods and fiber 
 
Low in fat and cholesterol 
 
500 kcal/d calorie restriction if obese 
 
A light snack at night. 
 
Protein amount at 1.2-1.5 g/kg/d 
 
Low sodium (<2000 mg/d) and water restriction to be defined as per standard of care. 
 
Moreover, patients will receive a 10 g bid essential amino acid (EAA) supplement containing 
approximately 2.25 g/d of L-leucine and 5.2 g of branch-chained amino acids (Reginator, Prinova, 
Carol Stream, Illinois). This supplement should not affect the total daily caloric intake, or sodium 
restriction. The intention is to favor healthy food eating habits, along with enough protein to 
support muscle repair and building. Compliance to the dietary behavior changes will be assessed 
every 2 to 4 weeks by the LT nutritionist.  
 
Behavioral Modification 
The behavior modification theory will be applied in the form of a structured set of cues and 
questions between investigator and participant at each visit in order to provide individually tailored 
counseling to enhance internal motivation and facilitate behavior change toward physical activity 
and dietary improvement that are adaptable to each participant’s usual habits.  
 
Follow Up 
The study will occur over a total of 14 weeks, although duration of the intervention will consist of 
12 weeks. The first two weeks will serve the purpose of identifying the baseline physical activity 
of each participant. During the second week all baseline studies/determinations will be completed, 
with randomization occurring by the end of week 2. Allocation will be stratified by presence or 
absence of refractory ascites. 
 
Follow up visits for behavioral therapy will occur every 2 weeks for the first 8 weeks, and then on 
a 4-weekly basis (only active group). Nutritional consultation will occur every 2 to 4 weeks 
throughout the study (both active and control group). During each visit, the EAA supplement jar 
will be inspected for percent emptiness (in analogy to a pill count) in order to quantify adherence. 
Bi-weekly phone calls will be made to all subjects to enhance adherence to recommendations. 
Standard of care investigations (blood chemistries, hematology and coagulation, liver function 
tests, etc.) will be ordered according to the needs of the patient and the criteria of the investigator 
or responsible clinician. Clinical status and complications from portal hypertension, particularly 
variceal bleeding and HE, will be systematically investigated on each visit. 
 
Research Tests - Variables to Measure 
Prior to randomization each subject will be scheduled to undergo all baseline investigations, as 
follows (see Research Calendar below): 
 
Cardiorespiratory stress test (CRET) and anaerobic threshold (Week -1, Day 1) 
CRET will be performed early in the morning on a fasting state, following the maximal incremental 
cycle ergometry protocol from our Pulmonary Physiology Laboratory, and in agreement with the 
American Thoracic Society.(38) Briefly, test consists on having the patient on a cycle ergometer 
performing a progressively increasing work rate until reaching: volitional exhaustion, or 
termination by the medical monitor. The Borg Rating of Perceived Exertion Scale will be used to 
help titrate intensity of work rate (aiming for a level of 13 to 17). Gas exchange measurement for 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
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Date: 10/10/2018 
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oxygen uptake and carbon dioxide outflow will be performed during the test, in order to determine 
VO2 (oxygen consumption) and VCO2 (carbon dioxide consumption) in real time. The VO2max will 
be identified as a clear plateau in the VO2 curve. In cases where no plateau can be observed due 
to exhaustion, the VO2peak at the time of test termination will be used as an equivalent. The 
anaerobic threshold will be identified by means of the V-slope method on the VO2 to VCO2 plot 
(respiratory exchange ratio).(38) Thirty minutes after completion of the test, each patient will be 
clinically evaluated for clinical signs of HE according to standard criteria (Table 1 and Figure 2). 
This test will be repeated after completion of the study period (12 weeks), and 6 months after LT. 
 
Ammonia and lactate thresholds (Week -1, Day 1) 
In order to obtain frequent venous samples, an 18-20 Ga IV catheter with a saline lock will be 
placed in the forearm before the test. Ammonia levels will be determined on venous samples with 
an automated point-of-care device (PocketChem Ammonia Checker II, Arkray Inc., Kyoto, Japan), 
prior to the start of the test, and then repeated every 3 minutes until termination of test, with a 
final sample 20 minutes after termination of the test. This will allow identification of the ammonia 
threshold when results are plotted against % VO2max. After a baseline determination of lactate, 
repeated samples will be obtained every 2 minutes, immediately after the test is finished, and 20 
min after termination. This will allow correlating the anaerobic threshold obtained from the 
respiratory exchange ratio with the lactate threshold. For both the ammonia and lactate thresholds 
is it estimated that 6-7 blood draws will be performed per patient (4 mL per sample) corresponding 
to 24-28 mL in total. These two tests will be repeated after completion of the study period (12 
weeks). 
 
Six-minute walk test (6MWT) (Week -1, Day 3) 
The 6MWT will be performed in agreement with the recommendations of the American Thoracic 
Society.(39) In brief, the test will be done indoors, along a long and flat enclosed corridor, aiming 
for as many laps (100 ft per half-lap) as possible, while patient is wearing a pulse oxymeter. The 
investigator applying the test will use a stopwatch and write down heart rate and oxygenation, at 
baseline, and every minute until reaching a total of six minutes. The Modified Borg Scale will be 
used to rate shortness of breath and fatigue before and after the test. This test will be repeated 
after completion of the study period (12 weeks), and 6 months after LT. 
 
Sarcopenia (abdomen CT-scan) (Week -1, Day 3) 
A noncontrasted abdominal CT-scan will be used to measure the cross-sectional area of skeletal 
muscle at the level of the third lumbar vertebrae (L3). Images will be analyzed with SliceOmatic 
4.3 (Tomovision, Montreal, Canada) measuring the cross-sectional area of skeletal muscle at this 
level (i.e. psoas, paraspinals, quadratus lumborum, transversus abdominis, rectus abdominis, 
and internal and external obliques). Muscle areas will be analyzed by an operator trained in 
musculoskeletal anatomy with tissue-specific Hounsfield unit thresholds (-29 to +150).(16) The 
L3 skeletal muscle area will be normalized to stature by the division of the muscle area by the 
height squared. Sarcopenia will be defined as a reduction in the L3 area of muscle mass ≤52.4 
cm2/m2 in males and ≤38.5 cm2/m2 in females. This test will be repeated after completion of the 
study period (12 weeks), and 6 months after LT. 
 
Nutritional consultation, anthropometrics, and body composition (Week -2, Day 3) 
A dietitian or designated investigator will evaluate anthropometrics (weight, height, waist 
circumference), bioelectrical impedance, and whole-body dual energy X-ray absorptiometry scan 
(DXA). Bioelectrical impedance will be performed according to the manufacturer's 
recommendations: after overnight fasting, with subject in supine position with arms and legs 
abducted from the body, and source and sensor electrodes placed on the dorsum of both hand 
and foot on the right side of the body, respectively. After obtaining resistance (R), reactance (Xc) 

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and phase angle (PhA), two analyses will be performed: PhA and bioelectrical impedance vector 
analysis (BIVA). PhA will be evaluated as a nutritional marker reflecting muscle mass. Sarcopenia 
will be defined as a PhA < 5.4°. Following normalization of R and Xc to patient´s height (R/H, and 
Xc/H, respectively), R/H and Xc/H will be plotted as bivariate vectors on the R-Xc graph 
(expressed in Ohm/m) in order to obtain BIVA. Individual vectors for each patient will be calculated 
and analyzed to determine nutritional status, muscle mass, and hydration status. For DXA a 
standard protocol and quality assurance procedure will be followed.  DXA will be used to estimate 
body composition.  Briefly, before each DXA scan, the subjects’ height, weight, gender, and race 
will be entered into the computer program. The subjects will be in a supine position on the DXA 
table with hands pronated and flat on the table. Total body mode will be selected for each scan, 
and scanning thickness will be determined by the DXA software. Anthropometrics, PhA, BIVA, 
and DXA will be repeated after completion of the study period (12 weeks), and 6 months after LT. 
 
Blood Biomarkers 
Myostatin and IGF-1 levels will be determined in blood (R&D Systems, Minneapolis, MN) at 
baseline and during week 12 visit to clinic. Also, at baseline and during week 12 visit blood EAA 
(high-performance liquid chromatography; vendor, City, State) will be quantified. The latter will be 
performed at Dr. Arny Ferrando's laboratory at no cost. Dr. Ferrando will be blinded to the source 
of serum samples. In order to facilitate blinding, blood samples will be processed by clinical 
coordinator into aliquots, de-identified, and stored at Dr. Ferrando's laboratory for future assay 
running. Only the clinical coordinator and the PI will have access to the code that identifies the 
serum samples provided for EAA quantification.  
 
Quality of life and metabolic profile (Week -2, Day 3) 
The questionnaire Sickness Impact Profile (SIP) will be used to assess changes in the quality of 
life. Recent evidence suggests SIP to be superior to SF-36 in detecting health-related quality of 
life changes occurring in patients with ESLD.  Metabolic profile will include determinations of 
fasting glucose, insulin (in subjects without diabetes mellitus), lipid profile (triglycerides, total-
cholesterol, HDL-cholesterol, LDL-cholesterol), and HbA1c. Both SIP and the metabolic profile 
will be repeated after completion of the study period (12 weeks). The metabolic profile will be 
repeated 6 months after LT as well. 
 
Randomization 
Each participant will be randomly assigned to the active (physical activity + behavioral therapy + 
nutritional intervention) or control (nutritional intervention) group. The random allocation sequence 
will be generated using computer-generated random numbers. There will be no stratification in 
the randomization process, and allocation will be concealed.  
 
Statistical analysis 
Subjects sample has been defined by convenience, as there is no precedent for sample 
estimation. Descriptive statistics will include mean ± SD and/or median (range), according to 
distribution of data. Shapiro-Wilk test will be used to assess normal distribution. Results on VCO2 
will be plotted against VO2, whereas lactate, and ammonia will be plotted against VO2max, for all 
patients as an aggregate. The lines determining the anaerobic, lactate, and ammonia thresholds 
will be calculated by linear regression. Continuous variables comparisons within groups will be 
done with paired t-test or Wilcoxon, whereas between groups will be done with t-test or Mann-
Whitney. Categoric variables will be compared with chi-square or Fisher's exact test, as 
appropriate. Agreement between methods used to address body composition, bioelectrical 
impedance and DXA, will be investigated with Bland-Altman test.  
 
Data collection and handling 

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Apart from the data generated by the study demographics and clinical information to properly 
classify the hepatic functional and cardiorespiratory status of each participant will be retrieved 
from the electronic medical record (EMR). Such information will include results from standard of 
care laboratories, imaging, and other special studies (EGD, pulmonary function tests, 
echocardiogram), to calculate MELD score, and Child-Turcotte-Pugh scores.  
 
A database will be created to accumulate all of the clinical information generated during this study. 
No identifiers, apart from name and DOB, will be collected. All data will be stored in databases 
kept in a study folder created at PI's computer (password-protected). Main database will include 
aforementioned identifiers, however, each subject will have a unique study ID assigned, and once 
an analytic table is created, all PHI will be removed from the table (after approval by the PI). Only 
this de-identified dataset with unique study ID's will be used for statistical analyses. Therefore, 
the risk to the privacy of the individuals will be minimized.  
 
The access to the research folder and its contents will be restricted to the research staffs listed in 
this submission form. The PHI will be kept in the main database until completion of the study. The 
main database containing PHI will be kept in the study folder and will be never transferred out 
without de-identification of the data. No hard copy research data will be generated in this project. 
 
In order to quantify the muscle mass at the level of L3, electronic copies of abdomen CT-scans 
with no identifiers will be shared with Aldo Montano-Loza from the University of Alberta, in 
Canada. After proper quantification an analytic table including unique study ID's will be sent back 
to UAMS for integration into the main database.  
  
Risks and Benefits 
CRET is a safe procedure and the risk for having a complication, such as an acute coronary 
syndrome is mostly related to underlying chronic disease. The risk of death varies as well, from 1 
death in 20,000 - 70,000 tests, depending mostly on the presence of underlying heart disease. In 
cohorts including healthy subjects, no deaths or major complications have been observed. Since 
LT candidates have to undergo a thorough cardiopulmonary evaluation and patients with any 
moderate to severe cardiopulmonary condition are not considered transplant candidates the risks 
for any major complication or death in this study should equal zero. Moreover, the personnel 
taking care of CRET constantly monitors physiologic responses to exercise (including 
electrocardiogram monitoring), and are trained to stop the test whenever there are signs for an 
impending complications, and can immediately and effectively perform cardiac resuscitation.  
 
Unlike CRET, in the 6MWT each patient determines the intensity of their exercise according to 
symptoms and cardiorespiratory fitness. The 6MWT is thus considered a very safe procedure, 
and it has been performed (without electrocardiogram monitoring) in thousands of older persons 
and thousands of patients with heart failure or cardiomyopathy without serious adverse events.  
Although patients with cardiopulmonary disease may be at increased risk for arrhythmias or 
cardiovascular collapse during testing, it is very unlikely for a complication to be witnessed given 
the selection criteria followed during LT evaluation (as above).  
 
The risks associated with placement of an IV catheter and blood collection from a vein are minor 
bleeding, bruising, infection (a small risk any time the skin is broken), or needing more than one 
attempt to locate veins.  
 
Both CT and DXA scans are associated with exposure to small amounts of ionizing radiation. The 
abdominal CT-scan will be restricted to a simple phase (non-contrasted) in order to limit radiation 
exposure, and thus it should not exceed 10 mSv. Since the initial CT-scan is performed as part 

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of the LT evaluation (standard of care), the study will derive in radiation exposure of approximately 
20 mSv. This is a very low radiation exposure that might be associated with a low additional 
increase in lifetime risk for cancer (1 in 1000 to 10,000). In the case of DXA, exposure per whole-
body scan is similar to daily background natural radiation exposure (0.01 mSv). 
 
The electrical current used in bioelectrical impedance is very small and thus unlikely to stimulate 
electrically excitable tissues, particularly cardiac and nervous tissues. Moreover, there are no 
reports of untoward effects among thousands of individuals in whom bioelectrical impedance 
analysis has been performed. Actually, the currents employed are very small and below the 
threshold of perception.    
 
No complication is properly expected from the exercise program since each patient will tailor 
her/his own intensity of exercise according to individual fitness and symptoms that might occur 
while exercising (i.e. fatigue, or shortness of breath). Although there is a theoretical increased risk 
for variceal bleeding and HE, these complications have not been observed in prior studies. 
Moreover, the CRET and ammonia and lactic acid determinations (obtained with ammonia/lactate 
thresholds) would provide the investigator with some sense of risk for complications during 
intense exercise and could adequately advise patients at a higher risk for complications to avoid 
moderate to intense exercise. 
 
The database containing PHI will remain within UAMS firewall and only used for specific research 
purposes in this project. Aggregated data will be analyzed and published, but specific data 
elements will not be made available.  Further, subjects will not forfeit any rights by participating - 
their health care and eligibility for health benefits will not be affected in any way. Although a breach 
in confidentiality is always a risk when collecting personal information from patients, we believe 
this is small given the system that has been developed to obtain and handle data.  
 
All participants might benefit from study by increasing their physical fitness and dietary habits 
during and after the study, and they will be able to keep their Fitbit to continue monitoring physical 
activity.  
 
Ethics 
This study will be conducted according to US and international standards of Good Clinical Practice 
(FDA regulations) for all studies.  Applicable government regulations, University of Arkansas for 
Medical Sciences research policies and procedures will also be followed.  This protocol and any 
amendments will be submitted and approved by the University of Arkansas for Medical Sciences 
Institutional Review Board (IRB) to conduct the study.  All subjects for this study will be provided 
a consent form describing this study and providing sufficient information in language suitable for 
subjects to make an informed decision about their participation in this study.  The formal consent 
of a subject, using the IRB-approved consent form, will be obtained before that subject is 
submitted to any study procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the 
consent.   
 
 

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Figure 1. Plots showing VO2max, anaerobic, and lactate/ammonia thresholds. 
1a 
 
 
           1b 
 
 
 
    1c 
 
 
 
 
 
 
 
 
 
 
 

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Figure 2. Relationship between SONIC and West Haven (WH) criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overt HE 
Covert HE 
Unimpaired 
WH 0 
WH 1 
WH 2 
WH 3 
WH 4 
Progression of Hepatic Encephalopathy 

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Table 1. West Haven criteria for diagnosis and classification of overt hepatic 
encephalopathy. 
 
 
 
   
 
 
 
 
 
 
West Haven 
Features 
Grade 0 
No abnormalities detected 
 
Grade 1 
Trivial lack of awareness 
Euphoria or anxiety 
Shortened attention span  
Impairment of addition or subtraction 
Grade 2 
Lethargy or apathy 
Disorientation for time 
Obvious personality change 
Inappropriate behavior 
Grade 3 
Somnolence to semi-stupor 
Response to stimuli 
Confused  
Gross disorientation 
Bizarre behavior 
Grade 4 
Coma, unable to test mental state 

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BIBLIOGRAPHY 
 
1. 
D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in 
cirrhosis: a systematic review of 118 studies. Journal of hepatology. 2006;44(1):217-31. 
2. 
Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: 
definitions and distinctions for health-related research. Public Health Rep. 1985;100(2):126-31. 
3. 
Tudor-Locke C, Hatano Y, Pangrazi RP, Kang M. Revisiting "how many steps are enough?". 
Medicine and science in sports and exercise. 2008;40(7 Suppl):S537-43. 
4. 
Konishi I, Hiasa Y, Tokumoto Y, Abe M, Furukawa S, Toshimitsu K, et al. Aerobic exercise improves 
insulin resistance and decreases body fat and serum levels of leptin in patients with hepatitis C virus. 
Hepatology research : the official journal of the Japan Society of Hepatology. 2011;41(10):928-35. 
5. 
Pattullo V, Duarte-Rojo A, Soliman W, Vargas-Vorackova F, Sockalingam S, Fantus IG, et al. A 24-
week dietary and physical activity lifestyle intervention reduces hepatic insulin resistance in the obese 
with chronic hepatitis C. Liver international : official journal of the International Association for the Study 
of the Liver. 2013;33(3):410-9. 
6. 
Soriano G, Roman E, Cordoba J, Torrens M, Poca M, Torras X, et al. Cognitive dysfunction in 
cirrhosis is associated with falls: a prospective study. Hepatology. 2012;55(6):1922-30. 
7. 
Lemyze M, Dharancy S, Wallaert B. Response to exercise in patients with liver cirrhosis: 
implications for liver transplantation. Digestive and liver disease : official journal of the Italian Society of 
Gastroenterology and the Italian Association for the Study of the Liver. 2013;45(5):362-6. 
8. 
Montano-Loza AJ, Duarte-Rojo A, Rose C. Sarcopenia and myosteatosis increase the risk of hepatic 
encephalopathy in cirrhotic patients. Hepatology. 2014;60(4):384-5A. 
9. 
Ruiz-Margain A, Macias-Rodriguez RU, Duarte-Rojo A, Espinosa-Cuevas A, Torre A. Association 
between malnutrition in patients with liver cirrhosis and the presence of hepatic encephalopathy. 
Hepatology. 2014;60(4):380A. 
10. 
Qiu J, Tsien C, Thapalaya S, Narayanan A, Weihl CC, Ching JK, et al. Hyperammonemia-mediated 
autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. American journal of physiology 
Endocrinology and metabolism. 2012;303(8):E983-93. 
11. 
Dharancy S, Lemyze M, Boleslawski E, Neviere R, Declerck N, Canva V, et al. Impact of impaired 
aerobic capacity on liver transplant candidates. Transplantation. 2008;86(8):1077-83. 
12. 
Tandon P, Ney M, Irwin I, Ma MM, Gramlich L, Bain VG, et al. Severe muscle depletion in patients 
on the liver transplant wait list: Its prevalence and independent prognostic value. Liver transplantation : 
official publication of the American Association for the Study of Liver Diseases and the International Liver 
Transplantation Society. 2012;18(10):1209-16. 
13. 
Carey EJ, Steidley DE, Aqel BA, Byrne TJ, Mekeel KL, Rakela J, et al. Six-minute walk distance 
predicts mortality in liver transplant candidates. Liver transplantation : official publication of the American 
Association for the Study of Liver Diseases and the International Liver Transplantation Society. 
2010;16(12):1373-8. 
14. 
Englesbe MJ, Patel SP, He K, Lynch RJ, Schaubel DE, Harbaugh C, et al. Sarcopenia and mortality 
after liver transplantation. Journal of the American College of Surgeons. 2010;211(2):271-8. 
15. 
Neviere R, Edme JL, Montaigne D, Boleslawski E, Pruvot FR, Dharancy S. Prognostic implications 
of preoperative aerobic capacity and exercise oscillatory ventilation after liver transplantation. American 
journal of transplantation : official journal of the American Society of Transplantation and the American 
Society of Transplant Surgeons. 2014;14(1):88-95. 
16. 
Montano-Loza AJ, Meza-Junco J, Prado CM, Lieffers JR, Baracos VE, Bain VG, et al. Muscle wasting 
is associated with mortality in patients with cirrhosis. Clinical gastroenterology and hepatology : the 
official clinical practice journal of the American Gastroenterological Association. 2012;10(2):166-73, 73 
e1. 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
19
17. 
Montano-Loza AJ, Duarte-Rojo A, Meza-Junco J, Baracos VE, Sawyer MB, Pang JX, et al. Inclusion 
of Sarcopenia Within MELD (MELD-Sarcopenia) and the Prediction of Mortality in Patients With Cirrhosis. 
Clin Transl Gastroenterol. 2015;6:e102. 
18. 
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. Journal of hepatology. 
2014;60(6):1151-7. 
19. 
Lemyze M, Dharancy S, Neviere R, Pruvot FR, Declerck N, Wallaert B. Aerobic capacity in patients 
with chronic liver disease: Very modest effect of liver transplantation. Presse Med. 2010;39(7-8):e174-81. 
20. 
Kouz J, Vincent C, Leong A, Dorais M, Rakel A. Weight gain after orthotopic liver transplantation: 
Is nonalcoholic fatty liver disease cirrhosis a risk factor for greater weight gain? Liver transplantation : 
official publication of the American Association for the Study of Liver Diseases and the International Liver 
Transplantation Society. 2014;20(10):1266-74. 
21. 
Pagadala M, Dasarathy S, Eghtesad B, McCullough AJ. Posttransplant metabolic syndrome: an 
epidemic waiting to happen. Liver transplantation : official publication of the American Association for the 
Study of Liver Diseases and the International Liver Transplantation Society. 2009;15(12):1662-70. 
22. 
Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al. Cardiovascular effects of intensive 
lifestyle intervention in type 2 diabetes. The New England journal of medicine. 2013;369(2):145-54. 
23. 
Goldberg RB, Mather K. Targeting the consequences of the metabolic syndrome in the Diabetes 
Prevention Program. Arteriosclerosis, thrombosis, and vascular biology. 2012;32(9):2077-90. 
24. 
Agarwal A, Pattullo V, Garcia-Saenz-de-Sicilia M, Sockalingam S, Fantus IG, Allard J, et al. Can a 
lifestyle intervention improve risk factors for a negative response to peginterferon treatment in patients 
with chronic hepatitis c, cirrhosis, and obesity? Journal of hepatology. 2014;60:S478. 
25. 
Soriano GR, E.; Torrades, M.T.; Cardenas, G.; Cordoba.; Vidal, S. Impact of an exercise programme 
on quality of life, effort tolerance and muscle mass in patients with cirrhosis. Journal of hepatology. 
2011;54:S61. 
26. 
Dasarathy S. Cause and management of muscle wasting in chronic liver disease. Curr Opin 
Gastroenterol. 2016;32(3):159-65. 
27. 
Lemyze M, Dharancy S, Neviere R, Wallaert B. Cardiopulmonary response to exercise in patients 
with liver cirrhosis and impaired pulmonary gas exchange. Respiratory medicine. 2011;105(10):1550-6. 
28. 
Pieber K, Crevenna R, Nuhr MJ, Quittan M, Peck-Radosavljevic M, Fialka-Moser V, et al. Aerobic 
capacity, muscle strength and health-related quality of life before and after orthotopic liver 
transplantation: preliminary data of an Austrian transplantation centre. Journal of rehabilitation medicine 
: official journal of the UEMS European Board of Physical and Rehabilitation Medicine. 2006;38(5):322-8. 
29. 
Wiesinger GF, Quittan M, Zimmermann K, Nuhr M, Wichlas M, Bodingbauer M, et al. Physical 
performance and health-related quality of life in men on a liver transplantation waiting list. Journal of 
rehabilitation medicine : official journal of the UEMS European Board of Physical and Rehabilitation 
Medicine. 2001;33(6):260-5. 
30. 
Wong F, Girgrah N, Graba J, Allidina Y, Liu P, Blendis L. The cardiac response to exercise in cirrhosis. 
Gut. 2001;49(2):268-75. 
31. 
Garcia-Pagan JC, Santos C, Barbera JA, Luca A, Roca J, Rodriguez-Roisin R, et al. Physical exercise 
increases portal pressure in patients with cirrhosis and portal hypertension. Gastroenterology. 
1996;111(5):1300-6. 
32. 
Bandi JC, Garcia-Pagan JC, Escorsell A, Francois E, Moitinho E, Rodes J, et al. Effects of propranolol 
on the hepatic hemodynamic response to physical exercise in patients with cirrhosis. Hepatology. 
1998;28(3):677-82. 
33. 
Macias-Rodriguez RU, Torre A, Ilarraza-Lomeli H, Ruiz-Margain A, Garcia-Flores O, Duarte-Rojo A. 
Changes in hepatic venous pressure gradient induced by a phsyical exercise program in cirrhotic patients: 
a randomized open clinical trial. Hepatology. 2014;60(4):246-7A. 

Title: A physical activity program in end-stage liver disease 
PI: Arny Ferrando 
Version 10 
Date: 10/10/2018 
20
34. 
Rose CF. Ammonia-lowering strategies for the treatment of hepatic encephalopathy. Clinical 
pharmacology and therapeutics. 2012;92(3):321-31. 
35. 
Yuan Y, So R, Wong S, Chan KM. Ammonia threshold--comparison to lactate threshold, correlation 
to other physiological parameters and response to training. Scandinavian journal of medicine & science in 
sports. 2002;12(6):358-64. 
36. 
Yuan Y, Chan KM. A longitudinal study on the ammonia threshold in junior cyclists. British journal 
of sports medicine. 2004;38(2):115-9. 
37. 
Totti V, Zancanaro M, Trerotola M, Nanni Costa A, Antonetti T, Anedda A, et al. Quality of life and 
energy 
expenditure 
in 
transplant 
recipient football 
players. 
Transplantation 
proceedings. 
2013;45(7):2758-60. 
38. 
ATS/ACCP Statement on cardiopulmonary exercise testing. American journal of respiratory and 
critical care medicine. 2003;167(2):211-77. 
39. 
ATS statement: guidelines for the six-minute walk test. American journal of respiratory and critical 
care medicine. 2002;166(1):111-7. 
 

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STUDY CALENDAR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive therapy will be provided only to the active group. 
IGF-1: insulin-related growth factor 1 
 
Basal 
Wk -2  
Wk -1 
Wk 0 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk 12 
Post-LT 
Sign consent 
✔ 
 
 
 
 
 
 
 
 
 
CRET 
 
 
✔ 
 
 
 
 
 
✔ 
✔ 
Anaerobic 
threshold 
 
 
✔ 
 
 
 
 
 
✔ 
✔ 
6MWT 
 
 
✔ 
 
 
 
 
 
✔ 
✔ 
NH3 & Lactate 
thresholds 
 
 
✔ 
 
 
 
 
 
✔ 
 
CT scan 
 
 
✔ 
 
 
 
 
 
✔ 
✔ 
SIP 
 
✔ 
 
 
 
 
 
 
✔ 
 
Bioimpedance  
& DXA 
 
✔ 
 
 
 
 
 
 
✔ 
✔ 
Nutritional 
consultation 
 
 
 
✔ 
✔ 
✔ 
✔ 
✔ 
  
 
Pill count 
 
 
 
 
✔ 
✔ 
✔ 
✔ 
✔ 
 
Anthropometry 
 
✔ 
 
 
 
 
 
✔ 
✔ 
✔ 
Pedometer 
count 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
 
Heart rate 
count 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
 
Cognitive 
Therapy 
 
 
 
 
✔ 
✔ 
✔ 
✔ 
  
 
Metabolic 
profile 
✔ 
 
 
 
 
 
 
 
✔ 
✔ 
Myostatin & 
IGF-1 
 
 
✔ 
 
 
 
 
 
✔ 
 
Essential 
amino acids 
 
 
✔ 
 
 
 
 
 
✔