HMB for Denutrition in Patients With Cirrhosis (HEPATIC)
Condition: Sarcopenia; Cirrhosis; Malnutrition
MeSH terms: Liver Cirrhosis; Sarcopenia; Malnutrition; Fibrosis
Study type: Interventional

Summary: 
      Cirrhosis is a late stage of hepatic fibrosis caused by many forms of liver diseases and
      conditions, such as hepatitis and chronic alcoholism. The World Health Organization (WHO) has
      reported that this condition accounts for 1.8% of all deaths in Europe (170,000 deaths/year).

      Patients with cirrhosis are characterized by severe metabolic alterations, which converge in
      a malnutritional state. Malnutrition encompasses glucose intolerance, chronic inflammation,
      altered gut microbiota, reduced muscle mass (sarcopenia), as well as loss and dysregulation
      of adipose tissue (adipopenia). Malnutrition is the most frequent complication that adversely
      affects the outcomes of cirrhotic patients. Yet, despite its clinical repercussions and
      potential reversibility, there are no effective therapies because our limited understanding
      of the mechanisms underlying this altered metabolism.

      β-hydroxy β-methylbutyrate (HMB) is a naturally produced substance regarded as safe and
      effective in preventing muscle loss during chronic diseases. Previous studies have indicated
      some beneficial effects of HMB itself or its parent metabolite, leucine, on adipose tissue,
      glucose intolerance, inflammation, and gut microbiota. This study aims to translate those
      beneficial effects to cirrhotic patients. The investigators hypothesize that HMB can improve
      cirrhosis-related metabolic abnormalities through its pleiotropic effects. The goals of this
      study are: i) to perform a randomized clinical trial to evaluate the efficacy of HMB,
      administered as nutritional supplementation, on clinical symptoms of cirrhosis.

      ii) to uncover the precise metabolic pathways that underlie HMB action, with a special focus
      on muscle, adipose tissue, and gut microbiota.
    

Detailed description: 
      1. Scientific & technical aspects

      State of the art:

      Patients with cirrhosis present a chronic inflammatory state and alterations in protein
      metabolism. These alterations lead to elevated levels of insulin and catecholamines along
      with the development of glucose intolerance and insulin resistance. The reduced availability
      of glucose as energy source translates into an accelerated starvation with reduced body fat
      mass (adipopenia) and loss of skeletal muscle mass (sarcopenia). This catabolic state reduces
      survival and post-liver transplant outcomes in patients with cirrhosis.

      Loss of skeletal muscle mass or sarcopenia is the major component of malnutrition in
      cirrhosis and occurs in the majority of patients. Impaired ureagenesis and portosystemic
      shunting provoke skeletal muscle hyperammonemia which induces up-regulation of myostatin and
      increased autophagy, both of which contribute to sarcopenia.

      The adipose tissue (AT) regulates energy homeostasis in the body regardless of the obesity
      status. Indeed, serum levels of the main adipose-produced cytokines (adipokines) such as
      leptin, adiponectin, and resistin have been found to be increased in cirrhotic patients as
      liver function worsens. Evidence demonstrated that adiponectin interacts with the
      immune/macrophage system and might be of relevance in many liver diseases. Likewise,
      hyperinsulinemia and increased tumor necrosis factor (TNF) α levels upregulated the adipose
      resistin gene in rat models of liver cirrhosis.

      Recently, growing attention has been targeted to the gut microbiota (GM) in the pathogenesis
      of gastrointestinal diseases. GM constitutes a symbiotic ecosystem that keeps homeostatic
      balance within the human body producing a diverse range of compounds that have a major role
      in regulating the activity of distal organs. Recent studies have shown changes in the
      relative abundance of microbiota in the stool, colonic mucosa, and saliva of cirrhotic
      patients. Therefore, modulation of GM arises as a promising tool to prevent and/or to treat
      the development of these liver disorders.

      Clinical guidelines recommend to provide adequate amounts of calories and proteins to
      cirrhotic patients, either by frequent feeding or via diet supplementation. Consequently,
      different high caloric diets have been extensively studied. Yet, few studies have shown
      significant benefit of this type of diets in malnourished cirrhotic patients. Protein
      supplementation may improve the availability of essential amino acids. However, animal
      proteins are enriched in aromatic amino acids that are not metabolized by the skeletal muscle
      and may worsen encephalopathy. Alternatively, modifying the source of nitrogen by using more
      vegetable protein, less animal protein, and/or branched-chain aminoacids (BCAA)
      supplementation may help prevent encephalopathy, sarcopenia and adipopenia. Yet, a recently
      published Cochrane review showed that BCAA did have a beneficial effect on hepatic
      encephalopathy, but found no effect on mortality, quality of life, or nutritional parameters.
      This absence of benefit in nutritional parameters might be counter intuitive, as BCAA provide
      a source of energy to the muscle in addition to being substrates for protein synthesis. The
      investigators hypothesize that beneficial effects associated to BCAA are, at least partially,
      mediated by some product/s of their metabolism, likely formed by hepatic synthesis. The
      cirrhosis-associated liver damage would be hence impeding their synthesis. As consequence, to
      obtain the expected beneficial outcomes of the BCAA ingestion there should be an increase of
      the supplemented BCAA or a direct supplementation of the active metabolite/s.

      b. Objectives HMB is produced from leucine and is one of its most active metabolites. The
      majority of HMB production occurs in the liver. Since the mid-1990s, a large body of studies
      have described that HMB is safe and effective in preventing muscle loss during chronic
      diseases. Moreover, recent studies have also indicated effects of HMB itself or its parent
      metabolite, leucine, on adipose tissue differentiation, glucose intolerance, inflammation,
      gut microbiota, and inflammation reduction. All these beneficial properties make HMB an ideal
      candidate to supplement the diet of individuals with cirrhosis, a hypothesis that will be
      tested in the current study. Thus, the specific aim of this proposal is to perform a
      randomized clinical trial to evaluate the efficacy of HMB, administered as nutritional
      supplementation, on clinical symptoms of cirrhosis. The study will be performed in adult
      individuals with cirrhosis. Power analyses based on previously described variations in muscle
      mass were calculated using R software. The required sample size per group for a power level
      of 0.9 is estimated to be n = 30,
    

Intervention name(s): Ensure Plus Advance; Ensure High Protein
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Supplements, labeled only with the name of the participant and his/her identification number, will be provided to the participants in the Translational Research Unit of the Miguel Servet Hospital. Every 2 weeks, changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA). Likewise they will be asked about compliance and their diets will be controlled by a nutritionist. Fresh stool samples, urine and blood will be collected pre- and post treatment. An extensive bloodwork will be performed at the Clinical Biochemistry Service at the Miguel Servet Hospital (plasma HMB, total cholesterol, triglycerides, LDL&HDL-cholesterol, free fatty acids, glucose, insulin, β-hydroxybutyrate, hs-CRP, and liver transaminases (AST, ALT, GGT).; Supplements, labeled only with the name of the participant and his/her identification number, will be provided to the participants in the Translational Research Unit of the Miguel Servet Hospital. Every 2 weeks, changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA). Likewise they will be asked about compliance and their diets will be controlled by a nutritionist. Fresh stool samples, urine and blood will be collected pre- and post treatment. An extensive bloodwork will be performed at the Clinical Biochemistry Service at the Miguel Servet Hospital (plasma HMB, total cholesterol, triglycerides, LDL&HDL-cholesterol, free fatty acids, glucose, insulin, β-hydroxybutyrate, hs-CRP, and liver transaminases (AST, ALT, GGT).
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: HMB