Effect of Molecular Hydrogen in Patients With NAFLD
Condition: Non-Alcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      Molecular hydrogen H2 acts as antioxidant which selectively reduces cytotoxic harmful
      reactive oxygen species ROS and concomitantly acts as biological messenger, which mediates
      several signaling pathways that play cytoprotective role in many human diseases. Due to their
      small size and high permeability, H2 is easily transportable into subcellular structures as
      mitochondria.
    

Detailed description: 
      Non-alcoholic fatty liver disease, NAFLD, is the most common cause of liver disease.
      According to the forecasts, the non-alcoholic steatohepatitis will be the most common cause
      of liver transplantation and hepatic mortality in 2030. NAFLD is also a significant risk
      factor for the development of hepatocellular carcinoma, even in the non-cirrhotic stage of
      liver disease. The prevention of the progression of NAFLD to NASH (nonalcoholic
      steatohepatitis) is therefore a key factor in preventing this unfavorable prognosis.

      Obesity and its associated comorbidities are among the most widespread and challenging
      conditions in the confrontation of the medical profession in the 21st century. The main
      metabolic consequence of obesity is insulin resistance, which is strongly associated with the
      storage of triacylglycerols in the liver. Hepatic steatosis may be associated with
      steatohepatitis, a condition that can lead to liver cirrhosis and, in the final stage, liver
      transplantation.

      According to various sources, the incidence of NAFLD in the population is 20-30%, in obese up
      to 60%, which makes it the most common liver disease. In the USA, it is even 3 times more
      common than type 2 diabetes mellitus and 5-10 times more common than chronic hepatitis C. The
      incidence of non-alcoholic steatohepatitis NASH is 2-3% and is now thought to be the cause of
      up to 80% cryptogenic liver cirrhosis. The risk of developing cirrhosis in patients with
      simple hepatic steatosis is 1-2% over 8 years.

      Insulin resistance, which is defined as an elevated HOMA (homeostasis model assessment) index
      above 1,4, is found in 70% of patients with NAFLD and plays a major role in the accumulation
      of triacylglycerols TAG (triacylglyceride) in the liver. Through the rise of
      hormone-sensitive lipase, hyperinsulinemia leads to the hydrolysis of free fatty acids FFA
      from visceral adipocytes to the portal vein, through which they enter directly into the
      liver, where they are esterified to TAG. Reducing the production of apolipoprotein B-100,
      which is an important part of their secretion from the liver into the circulation in the form
      of VLDL-lipoproteins, is also a potentiating factor in TAG deposition in the liver. Free
      oxygen radicals ROS (reactive oxygen species), which are formed due to the oxidative stress,
      are formed directly in the hepatocyte. However, their formation in visceral adipocytes has
      also been shown to be involved in liver damage. The main site of ROS are mitochondria. In
      NAFLD, known mitochondrial dysfunction leads to pathological oxidation of FFA (free fatty
      acid) in peroxisomes and microsomes, making them another source of ROS. ROS, through damage
      of the mitochondrial membrane by lipoperoxidation and induction of Fas-ligand expression on
      the hepatocyte, leads to cell apoptosis.

      By activating stellate cells, a larger amount of extracellular matrix is formed - Mallory's
      hyaline, which is associated with the formation of balloon degeneration of hepatocytes, that
      is a typical histological feature of NASH.

      From the cytokines, TNF-alpha is mainly used. It is formed by hepatocytes due to the
      increased supply of FFA. The diagnostic process is often random. One of the options for
      non-invasive measurement of liver fibrosis is transient elastography FibroScan, which is used
      for direct measurement of liver elasticity or use of noninvasive fibrosis indexes (NFS,
      Fib-4, APRI etc) as nondirect tools. Initial studies have confirmed that H2 penetrates cell
      membranes and protects mitochondria and cell nuclei from acute oxidative stress. Several
      studies have reported the effect of H2 on mitochondrial function. With H2, the investigators
      protect the potential of the mitochondrial membrane, increase ATP production and reduce
      organelle swelling. There are at least four possible mechanisms for H2 through which gene
      expression can be altered through mitochondrial bioenergetics, of which ghrelin is probably
      the most important. Ghrelin is the hormone responsible for appetite.

      It reaches its maximum level during hunger. Obestatin has the opposite effect, which in turn
      suppresses the feeling of hunger. The role of ghrelin as an energy modulator in H2
      intervention may be promoted by interaction with expressed glucose transporters, which
      increase glucose consumption and modulate oxidative phosphorylation in mitochondria. Exercise
      led to a significant change in ghrelin levels but had no effect on plasma levels of
      obestatin.

      Molecular hydrogen has been shown to relieve oxidative stress, have an anti-inflammatory
      effect and improve lipid, glucose and energy production in patients as well as in animal
      models of hepatic steatosis and atherosclerosis. The basic molecular mechanisms remain
      largely unknown.

      Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen
      radicals, especially the hydroxyl radical. In several previous experiments, the use of
      hydrogen-enriched water, HRW, has been shown to have antioxidant effects. The effects of
      hydrogen on the prevention of hepatocarcinogenesis in STAM mice were also investigated. The
      number of tumors was significantly lower in the HRW groups and the tumors were smaller than
      in the other groups. The results clearly demonstrated that HRW can be an effective treatment
      for apoptosis, inflammation and hepatocarcinogenesis in NAFLD.

      The aim of the study is to verify effectiveness and safety of molecular hydrogen on a group
      of patients with NAFLD.
    

Intervention name(s): HRW drink, HRW Natural Health Products Inc., Made in Vancouver, Canada; placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): The cohort will consist of 17 patients with NAFLD. Name of the product that will be the source of molecular hydrogen: HRW drink, HRW Natural Health Products Inc., Made in Vancouver, Canada. It is a nutritional supplement that is a source of molecular hydrogen.
All study participants will drink one tablet dissolved in 0.33 l of tap water every 8 hours.
They did this for 8 weeks. Blood analysis at study entry and after 8 weeks (end of study).; 13 probands in the control group who will receive placebo. All study participants will drink one placebo tablet dissolved in 0.33 l of tap water every 8 hours.
They did this for 8 weeks. Blood analysis at study entry and after 8 weeks (end of study)
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Molecular hydrogen; effective antioxidant; oxygen radicals; NAFLD; mitochondria