Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation After Liver Transplantation
Condition: Sarcopenia
MeSH terms: Sarcopenia
Study type: Interventional

Summary: 
      Sarcopenia is an independent predictor of morbidity and mortality in cirrhotic patient before
      and after liver transplantation. Beta-hydroxy-beta-methyl butyrate (HMB) is a leucine
      metabolite with potential efficacy in increasing protein synthesis, muscle mass and its
      functionality.

      The aim of this randomized controlled study is to evaluate the effect of a nutritional
      supplementation with HMB after liver transplantation both on muscle mass and on muscle
      function.
    

Detailed description: 
      Protocol

        1. Introduction:

           Sarcopenia, a condition of skeletal muscle mass depletion and reduction of muscle
           strength, is the most important aspect of malnutrition secondary to liver cirrhosis.
           Sarcopenia is recognized to be an independent factor of morbidity and mortality befor
           and after liver transplantation. The prevalence of sarcopenia in liver transplanted
           patients has been reported to vary between 40% and 76%. Sarcopenia in hepatic cirrhosis
           occurs as a result of an increase in proteolysis or a reduction in protein synthesis, or
           a combination of the two mechanisms. The alterations in the molecular pathways that
           regulate these mechanisms are not entirely known. Recent studies reported an increased
           expression of myostatin, a member of the transforming growth factor ß superfamily , in
           skeletal muscles of animal models with liver cirrhosis and in plasma of cirrhotic
           patients. The authors suggested that the increased expression of myostatin resulted in
           protein synthesis inhibition. In addition, myostatin is able to activate AMPK protein
           kinase, a signaling inhibitor of mTOR (mammalian target of rapamycin), key regulator of
           protein synthesis.

           After Liver transplant, secondary to the recovery of liver function, the progressive
           increase in caloric intakes and the increase in daily physical activity, an improvement
           in the nutritional status of the patient and normalization of body composition is
           expected. However, available data on the modification of nutritional status after liver
           transplantation do not confirm the expected results: worsening of nutritional status was
           reported in the perioperative period with further depletion of lean mass as a result of
           surgical stress, bed rest and postoperative complications. A lack of recovery of muscle
           mass was documented even after one year of transplantation.

           Molecular mechanisms responsible for sarcopenia after liver transplantation are not
           fully clarified. The only study on a small sample of muscle biopsies in post-transplant
           patients described a persistent increase in myostatin expression in these patients. The
           immunosuppressive therapy used in the post transplant involves the use of calcineurin
           inhibitors, a protein involved in differentiation and hypertrophy of muscle fibers, mTOR
           inhibitors and corticosteroids. The use of these drugs is another factor contributing to
           sarcopenia after transplantation.

           o HMB: HMB is a metabolite of leucine with the potential to increase performance and
           muscle trophism. Studies in experimental models of cachexia have resulted in increased
           phosphorylation and activation of secondary mTOR after use of HMB. Experimental studies
           performed on myoblastic cell cultures also revealed an increased expression of IGF-1
           secondary to HMB treatment. Such evidence confirms the anabolic properties of the HMB.
           HMB has also been shown to suppress proteolysis by inhibition of the
           ubiquitin-proteasome pathway in models of neoplastic cachexia and to eb effective in
           reducing muscular atrophy secondary to steroid therapy. The association of
           anti-proteolytic and anabolic properties targeting mTOR make HMB a potentially effective
           supplement for the treatment of sarcopenia after liver transplantation. There are
           currently no data on the use of HMB in this category of patients.

        2. Aims of the study:

           Primary aim of the study: Evaluate the therapeutic efficacy of HMB supplementation for
           three months in patients undergoing liver transplantation on recovery of skeletal muscle
           mass shortly after transplantation (third to fourth month after transplantation).

           Secondary aims of the study:

             -  Evaluate the therapeutic efficacy of HMB supplementation for three months in
                patients undergoing liver transplantation on recovery of skeletal muscular function
                shortly after transplantation (third to fourth month after transplantation).

             -  Evaluate the long-term effects of HMB supplementation in terms of recovery of
                skeletal muscle mass (6 and 12 months after transplantation).

             -  Evaluate the possible effect of HMB supplementation on post-transplant morbidity
                (hospitalization, infectious complications, onset of metabolic complications).

             -  Evaluate tolerance for HMB intake in liver transplant patients

           This controlled trial is not sponsored by a drug company.

        3. Patients:

           The protocol of the study needs to be approved by the local ethic committee. Patients
           are enrolled in the study after been informed of the purpose and protocol of treatment
           and need to sign a written informed consent.

        4. Statistical analysis, sample size and randomization:

           For categorical variables, the Person-Chi-square test or the Fischer test will be used.
           For continuous variables, the Mann-Whitney Test will be used. The ANOVA variance
           analysis will be applied followed by the "t-test" when significant differences will be
           highlighted. Values of p <0.05 will be considered statistically significant.

           For the sample size calculation, the increase in muscle mass, evaluated by DEXA and
           expressed as Fat Free Mass Index-FFMI (core indexed for height), 12 weeks after the
           beginning of supplementation was considered as the primary endpoint. On the basis of
           literature data, the investigators expect unchanged lean mass in the control group with
           a DS of ± 1 kg / m2 at 3-4 months after supplementation. In the HMB-treated group the
           investigators expect to increase the FFMI of 1.2 kg / m2 with the same DS. A total of 12
           patients per group will need to have a statistical power of at least 80% with an alpha
           error of 5%.Block randomization, consisting of 4 individuals per block, was executed in
           a 1:1ratio using random numbers generated by an independent statistician (SPSS version
           16.0). Knowledge of the randomization code was limited to the physician.

        5. Protocol of the study:

      Basal Evaluation:

      The registration will include the main clinical and biochemical data prior to transplantation
      (including nutritional evaluation if present) and after transplantation.

      Nutritional counseling will be provided to all patients to ensure similar caloric and daily
      protein intake in the two groups, according to the current guidelines (caloric intake of
      20-25 kcal / kg / die ± 10%, protein intake of 1.2 g / kg / day).

      At the time of the enrollment and during the subsequent controls the following data will be
      recorded :

        1. calorie intake in the week preceding the visit by a three days non-consecutive food
           diary;

        2. anthropometric parameters (height, weight, body mass index, brachial circumference,
           triceps)

        3. body composition by dual-energy-xray-absorptiometry (DEXA) using dedicated software to
           estimated fat free mass index (FFMI) (Fat free mass in kg/ height in cm)

        4. muscular function evaluated by 6 minute walk test-6MWT, Timed Up and Go test-TUGT), e
           l'Hand grip Test (HG).

        5. biochemical and metabolic parameters

        6. pharmacological therapy

      During the study, clinical complications (hospital admissions, infectious events, onset of
      comorbidity) will be recorded.

      During the study, the tolerability of the supplement (analogue-visual scale), adherence to
      absorption and any intolerance or secondary adverse effects will be detected.

      Randomization: Patient are randomized to Group 1 - placebo (or control group) and Group 2 -
      supplementation (or treatment group)

      Randomization: Patient are randomized to Group 1 - placebo (or control group) and Group 2 -
      supplementation (or treatment group)

      The placebo will be 200 ml of fruit juice given twice daily. Supplementation will be HMB 1.5
      g dissolved in 200 ml of fruit juice and taken twice daily. Supplementation/placebo will be
      provided for 12 weeks.

      End-points of the study:

        -  Recovery of FFMI ( 3°-4° after liver transplantation)

        -  Recovery of muscle function (amelioration of 6-MWT, TUGT test and HG test) (3-4°, 6° and
           12th month after liver transplantation )

        -  Reduction of morbidity after liver transplantation (Hospital admission, infections,
           onset of metabolic disease) 3-4°, 6° and 12th month after liver transplantation )

        -  Tolerably of HMB supplementation ( 3°-4° after liver transplantation) Collateral effects
           of HMB are recorded.
    

Intervention name(s): BETA-HYDROXY-BETA-METHYLBUTYRATE (HMB); Placebo
Intervention type(s): Dietary Supplement; Other
Intervention description(s): 1.5 g of HMB dissolved in 200 ml of fruit juice will be provided for 12 weeks twice daily; The placebo will be 200 ml of fruit juice given twice daily
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: cirrhosis; liver transplantation; HMB