End-stage Liver Disease, Frailty, Liver Cirrhosis, Liver Transplantation, Malnutrition, Sarcopenia
Conditions
Keywords
liver disease, end-stage liver disease, liver cirrhosis, liver transplantation, malnutrition, sarcopenia, frailty, diet, nutrition, nutrition therapy, protein, protein distribution, exercise, prehabilitation, nutritional status, body composition, functional status, physical performance, quality of life
Brief summary
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.
Detailed description
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.
Interventions
BEHAVIORALDiet with even protein distribution plus exercise program
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
BEHAVIORALDiet with skewed protein distribution plus exercise program
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
BEHAVIORALStandard dietary and physical activity advice
Standard dietary and physical activity advice \| Duration: 12 weeks
Sponsors
Kalliopi Anna Poulia
Laikο General Hospital, Athens
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* End-stage liver disease, diagnosed by transient elastography (FibroScan) or imaging-based evaluation with compatible clinical picture * Referred for liver transplantation and evaluated to have a high likelihood of being listed, according to primary hepatologist assessment, or already listed for liver transplantation * No prior formal dietary advice
Exclusion criteria
* Age \< 18 years old * Estimated waiting time for liver transplantation \< 3 months * Estimated life expectancy \< 3 months * Chronic kidney disease requiring protein restriction * Exercise contraindicated (e.g., active or recent variceal bleeding, severe grade of hepatic encephalopathy, refractory ascites, etc.) * Unstable or severe psychiatric disorder * Pregnancy or lactation * Inability to provide written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Global Leadership Initiative on Malnutrition (GLIM)-defined malnutrition | Baseline, 12 weeks | 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. |
| Changes in Computed Tomography (CT)-derived muscle mass | Baseline, 12 weeks | 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. |
| Changes in handgrip strength (kg) | Baseline, 12 weeks | 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. |
| Changes in Short Physical Performance Battery (SPPB) score | Baseline, 12 weeks | 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. |
| Changes in Liver Frailty Index | Baseline, 12 weeks | 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. |
| Changes in European Working Group on Sarcopenia in Older People 2 (EWGSOP2)-derived sarcopenia | Baseline, 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nutritional Risk Screening-2002 (NRS-2002)-derived nutritional risk | Baseline | 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. |
| Malnutrition Screening Tool (MST)-derived nutritional risk | Baseline | 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. |
| Malnutrition Universal Screening Tool (MUST)-derived nutritional risk | Baseline | 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. |
| Short Nutritional Assessment Questionnaire (SNAQ)-derived nutritional risk | Baseline | 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. |
| Mini Nutritional Assessment-Short Form (MNA-SF)-derived nutritional status | Baseline | 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. |
| Nutritional Risk Index (NRI)-derived nutritional risk | Baseline | 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. |
| Prognostic Nutritional Index (PNI)-derived nutritional status | Baseline | 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. |
| Controlling Nutritional Status (CONUT)-derived nutritional status | Baseline | 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. |
| Liver Disease Undernutrition Screening Tool (LDUST)-derived nutritional risk | Baseline | 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. |
| Royal Free Hospital-Nutritional Prioritizing Tool (RHT-NPT)-derived nutritional status | Baseline | 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. |
| Dual-Energy X-ray Absorptiometry (DEXA)-derived muscle mass | Baseline | 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. |
| Food Frequency Questionnaire (FFQ)-derived dietary habits | Baseline | Long-term dietary habits will be assessed using a semi-quantitative Food Frequency Questionnaire (FFQ). |
| International Physical Activity Questionnaire (IPAQ)-derived physical activity levels | Baseline | 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. |
| Changes in Bioelectrical Impedance Analysis (BIA)-derived muscle mass | Baseline, 12 weeks | 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. |
| Changes in body weight (kg) | Baseline, 12 weeks | Body weight (kg) will be measured using a calibrated weight scale. |
| Changes in Body Mass Index (BMI, kg/m^2) | Baseline, 12 weeks | 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. |
| Changes in Mid-Arm Muscle Circumference (MAMC, cm) | Baseline, 12 weeks | 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. |
| Changes in Bristol Stool Chart | Baseline, 12 weeks | 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 |
| Changes in Chronic Liver Disease Questionnaire (CLDQ) | Baseline, 12 weeks | 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. |
| Changes in aspartate aminotransferase (AST, U/L) | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in alanine aminotransferase (ALT, U/L) | Baseline, 12 weeks | Data will be collected through medical chart review |
| Changes in alkaline phosphatase (ALP, U/L) | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in gamma-glutamyltransferase (GGT, U/L) | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in total bilirubin (mg/dL) | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in direct bilirubin (mg/dL) | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in International Normalized Ratio (INR) | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in MELD-Na score | Baseline, 12 weeks | 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%) |
| Changes in Child-Pugh score | Baseline, 12 weeks | Data will be collected through medical chart review. Higher Child-Pugh scores indicate greater severity of liver cirrhosis \[class A (5-6 points): mild, class B: (7-9 points): moderate, class C (10-15) points: severe\] |
| Changes in presence of oedema and/or ascites | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in presence of jaundice | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in presence of variceal bleeding | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in presence of infections | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Changes in presence of hepatic encephalopathy | Baseline, 12 weeks | Data will be collected through medical chart review. |
| Mortality | From baseline to 12 weeks | Data will be collected through medical chart review. |
Countries
Greece
Contacts
CONTACTKalliopi Anna Poulia
CONTACTEvangelos Cholongitas
Outcome results
None listed