This study aims to evaluate the effects of a diet with even protein distribution plus exercise (Group A) versus a diet with skewed protein distribution plus exercise (Group B) versus standard dietary and physical activity advice (Group C) on nutritional status, body composition and functional status in patients awaiting liver transplantation.
Malnutrition and sarcopenia affect many patients awaiting liver transplantation and is associated with reduced quality of life and increased mortality. According to the current European Society for Clinical Nutrition and Metabolism (ESPEN) and European Association for the Study of the Liver (EASL) guidelines, a target of 1.2-1.5 g protein per kg body weight daily is recommended for patients with decompensated liver cirrhosis. While evidence supports that even protein distribution enhances muscle protein synthesis in healthy adults, specific protein timing recommendations are lacking for patients with end-stage liver disease. Therefore, this randomized controlled trial aims to investigate the effects of a 12-week diet with even protein distribution plus exercise (Group A) versus skewed protein distribution plus exercise (Group B) versus standard dietary and physical activity advice (Group C), primarily on nutritional status, body composition and functional status, and secondarily on anthropometric measurements, laboratory parameters, quality of life, disease severity, complications and mortality in liver transplant candidates. Moreover, late postoperative parameters, including length of hospital stay, length of intensive care unit stay, duration of mechanical ventilation, postoperative complications, hospital readmissions, reoperations and mortality will be examined for those who undergo transplantation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
90
Diet of 1.2-1.5 g protein/kg dry body weight/day, equally divided (33.3% at 3 main meals) \| Exercise program: 3 days/week aerobic and 2 days/week resistance \| Duration: 12 weeks
Diet of 1.2-1.5 g protein/kg dry body weight/day, unequally divided (10.0% at breakfast, 60.0% at lunch, 30.0% at dinner) \| Exercise program: 3 days/week aerobic and 2 days/week resistance \| Duration: 12 weeks
Standard dietary and physical activity advice \| Duration: 12 weeks
Laiko General Hospital of Athens
Athens, Attica, Greece
RECRUITINGAgricultural University of Athens
Athens, Attica, Greece
RECRUITINGChanges in Global Leadership Initiative on Malnutrition (GLIM)-defined malnutrition
Malnutrition will be diagnosed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Diagnosis requires at least 1 phenotypic criterion and 1 etiologic criterion. Phenotypic criteria include: a. Non-votional weight loss (%): \> 5% within past 6 months or \> 10% beyond 6 months, b. Low body mass index (BMI, kg/m\^2): \< 20 kg/m\^2 if \< 70 years or \< 22 kg/m\^2 if \> 70 years, c. Reduced muscle mass, assessed by validated body composition measuring techniques \[e.g. Dual-Energy X-ray Absorptiometry (DEXA), Bioelectrical Impedance Analysis (BIA) or Computed Tomography (CT)\]. Etiologic criteria include: a. Reduced food intake or assimillation: ≤ 50% of energy requirements \> 1 week or any reduction for \> 2 weeks or any chronic gastrointestinal condition that adversely impacts food assimilation or absorption, b. Inflammation: acute disease/injury or chronic disease-related.
Time frame: Baseline, 12 weeks
Changes in Computed Tomography (CT)-derived muscle mass
Muscle mass will be assessed using the Skeletal Muscle Index (SMI, cm\^2/m\^2). SMI will be calculated by measuring the total cross-sectional area of skeletal muscles, from a single cross-sectional Computed Tomography (CT) image at L3 vertebral level, using Hounsfield Units of -29 to +150 HU, and normalizing to height squared (m\^2).Thresholds for reduced SMI will be considered \< 50 cm\^2/m\^2 for men and \< 39 cm\^2/m\^2 for women.
Time frame: Baseline, 12 weeks
Changes in handgrip strength (kg)
Handgrip strength (kg) will be assessed using a digital handgrip dynamometer. Thresholds for reduced muscle strength will be considered \< 27 kg for men and \< 16 kg for women.
Time frame: Baseline, 12 weeks
Changes in Short Physical Performance Battery (SPPB) score
The Short Physical Performance Battery (SPPB) includes 3 components: 3-positions balance testing (sec) (0-4 points), 4-meter gait speed test (sec) (0-4 points) and 5-times chair stand test (sec) (0-4 points), with a total score of 0-12. Higher scores indicate a better physical performance: 0-3 points for worst physical performance, 4-9 points for reduced physical performance and 10-12 points for best physical performance.
Time frame: Baseline, 12 weeks
Changes in Liver Frailty Index
The Liver Frailty Index includes 3 components: handgrip strength (kg), 5-times chair stand test (sec) and 3-positions balance testing (sec). Higher scores indicate a greater degree of frailty.
Time frame: Baseline, 12 weeks
Changes in European Working Group on Sarcopenia in Older People 2 (EWGSOP2)-derived sarcopenia
Sarcopenia will be diagnosed using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. Diagnosis requires low muscle strength and low muscle mass. Reduced muscle strength will be diagnozed by: a. Low handgrip strength (kg): \> 27 kg for men and \> 16 kg for women or b. Low chair stand test (sec): \>15 sec for 5-times chair stand test. Reduced muscle mass will be diagnozed by: a. Low Appendicular Skeletal Muscle Mass (ASM, kg): \< 20 kg for men and \< 15 kg for women or b. Low Appendicular Skeletal Muscle Mass Index (ASMI, kg/m\^2): \<7.0 kg/m\^2 for men and \< 5.5 kg/m\^2 for women.
Time frame: Baseline, 12 weeks
Nutritional Risk Screening-2002 (NRS-2002)-derived nutritional risk
Nutritional risk will be assessed using the Nutritional Risk Screening-2002 (NRS-2002) tool. Higher scores indicate greater nutritional risk: \< 3 points indicate good nutritional status and ≥ 3 nutritional risk.
Time frame: Baseline
Malnutrition Screening Tool (MST)-derived nutritional risk
Nutritional risk will be assessed using the Malnutrition Screening Tool (MST) tool. Higher scores indicate greater nutritional risk: \< 2 points indicate good nutritional status and ≥ 2 nutritional risk.
Time frame: Baseline
Malnutrition Universal Screening Tool (MUST)-derived nutritional risk
Nutritional risk will be assessed using the Malnutrition Universal Screening Tool (MUST) tool. Higher scores indicate greater nutritional risk: 0 points indicate low risk, 1 point medium risk and ≥ 2 high risk.
Time frame: Baseline
Short Nutritional Assessment Questionnaire (SNAQ)-derived nutritional risk
Nutritional risk will be assessed using the Short Nutritional Assessment Questionnaire (SNAQ) tool. Higher scores indicate greater nutritional risk: 0-1 points indicate low risk, 2 points medium risk and ≥ 3 points high risk.
Time frame: Baseline
Mini Nutritional Assessment-Short Form (MNA-SF)-derived nutritional status
Nutritional risk will be assessed using the Mini Nutritional Assessment-Short Form (MNA-SF) tool. Lower scores indicate greater nutritional risk: 12-14 points indicate good nutritional status, 8-11 points risk of malnutrition and 0-7 points malnutrition.
Time frame: Baseline
Nutritional Risk Index (NRI)-derived nutritional risk
Nutritional risk will be assessed using the Nutritional Risk Index (NRI) tool. Lower scores indicate greater nutritional risk: \> 100.0 indicate good nutritional status, 97.5-100.0 low risk, 83.5-97.5 medium risk and \< 83.5 high risk.
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Time frame: Baseline
Prognostic Nutritional Index (PNI)-derived nutritional status
Nutritional risk will be assessed using the Prognostic Nutritional Index (PNI) tool. Lower scores indicate greater nutritional risk: ≥ 50 indicate good nutritional status, \< 50 low risk, \< 45 medium risk and \< 40 high risk.
Time frame: Baseline
Controlling Nutritional Status (CONUT)-derived nutritional status
Nutritional risk will be assessed using the Controlling Nutritional Status (CONUT) tool. Higher scores indicate greater nutritional risk: 0-1 points indicate good nutritional status, 2-4 points low risk, 5-8 medium risk and 9-12 high risk.
Time frame: Baseline
Liver Disease Undernutrition Screening Tool (LDUST)-derived nutritional risk
Nutritional risk will be assessed using the Liver Disease Undernutrition Screening Tool (LDUST) tool. ≥ 5 answers "A" indicate good nutritional status and ≥ 2 answers "B" and/or "C" malnutrition.
Time frame: Baseline
Royal Free Hospital-Nutritional Prioritizing Tool (RHT-NPT)-derived nutritional status
Nutritional risk will be assessed using the Royal Free Hospital-Nutritional Prioritizing Tool (RHT-NPT) tool. Higher scores indicate greater nutritional risk: 0 points indicate low risk, 1 point medium risk and 2-7 points high risk.
Time frame: Baseline
Dual-Energy X-ray Absorptiometry (DEXA)-derived muscle mass
Muscle mass will be assessed using the Appendicular Skeletal Muscle Mass Index (ASMI, kg/m\^2) using Dual-Energy X-ray Absorptiometry (DEXA). Thresholds for reduced muscle mass will be considered \< 7.0 for men and \< 5.4 for women.
Time frame: Baseline
Food Frequency Questionnaire (FFQ)-derived dietary habits
Long-term dietary habits will be assessed using a semi-quantitative Food Frequency Questionnaire (FFQ).
Time frame: Baseline
International Physical Activity Questionnaire (IPAQ)-derived physical activity levels
Physical activity levels will be assessed using the International Physical Activity Questionnaire (IPAQ)-Short Form. IPAQ includes 7 open-ended questions. Higher scores (MET-min/week) indicate higher physical activity levels.
Time frame: Baseline
Changes in Bioelectrical Impedance Analysis (BIA)-derived muscle mass
Muscle mass will be assessed using the Appendicular Skeletal Muscle Mass Index (ASMI, kg/m\^2) by Bioelectrical Impedance Analysis (BIA). Thresholds for reduced ASMI will be considered \< 7.0 for men and \< 5.7 for women.
Time frame: Baseline, 12 weeks
Changes in body weight (kg)
Body weight (kg) will be measured using a calibrated weight scale.
Time frame: Baseline, 12 weeks
Changes in Body Mass Index (BMI, kg/m^2)
Body Mass Index (BMI, kg, m\^2) will be calculated by dividing body weight (kg) by height squared (m\^2), which will be measured using a calibrated stadiometer.
Time frame: Baseline, 12 weeks
Changes in Mid-Arm Muscle Circumference (MAMC, cm)
Mid-Arm Muscle Circumference (MAMC, cm) will be calculated using the following formula: MAMC (cm) = Mid-Arm Circumference (MAC, cm) - \[0.314\*Triceps Skinfold Thickness (TSF, mm)\]. MAC will be measured using a non-stretchable measuring tape and TSF using a calibrated skinfold caliper. Thresholds for reduced MAMC will be considered \< 25 cm for men and \< 22 cm for women.
Time frame: Baseline, 12 weeks
Changes in Bristol Stool Chart
Bowel habits will be assessed using the Bristol Stool Chart. Bristol Stool Chart classifies stool forms in 7 types: types 1-2 indicate constipation, types 3-4 normal stool form, and types 5-7 looser stools tending toward diarrhea
Time frame: Baseline, 12 weeks
Changes in Chronic Liver Disease Questionnaire (CLDQ)
Quality of life will be assessed using the Chronic Liver Disease Questionnaire (CLDQ). CLDQ includes 29 items in 6 domains: fatigue, activity, emotional function, abdominal symptoms, systemic symptoms, and worry. Each is scored on a 7-point scale, with higher domain and total scores indicating a better quality of life.
Time frame: Baseline, 12 weeks
Changes in aspartate aminotransferase (AST, U/L)
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in alanine aminotransferase (ALT, U/L)
Data will be collected through medical chart review
Time frame: Baseline, 12 weeks
Changes in alkaline phosphatase (ALP, U/L)
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in gamma-glutamyltransferase (GGT, U/L)
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in total bilirubin (mg/dL)
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in direct bilirubin (mg/dL)
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in International Normalized Ratio (INR)
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in MELD-Na score
Data will be collected through medical chart review. Higher MELD-Na scores indicate greater severity of chronic liver disease and higher predictive risk of mortality (\< 17 points: \<2%, 17-20 points: 3-4%, 21-22 points: 7-10%, 23-26 points: 14-15%, 27-31 points: 27-32%, ≥ 32 points: 65-66%)
Time frame: Baseline, 12 weeks
Changes in Child-Pugh score
Data will be collected through medical chart review. Higher Child-Pugh scores indicate greater severity of liver cirrhosis \[class A (5-6 points): mild, class B: (7-9 points): moderate, class C (10-15) points: severe\]
Time frame: Baseline, 12 weeks
Changes in presence of oedema and/or ascites
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in presence of jaundice
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in presence of variceal bleeding
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in presence of infections
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Changes in presence of hepatic encephalopathy
Data will be collected through medical chart review.
Time frame: Baseline, 12 weeks
Mortality
Data will be collected through medical chart review.
Time frame: From baseline to 12 weeks