Clinical trial NCT05325398: Effect of Molecular Hydrogen in Patients With NAFLD
Official title: Effect of Molecular Hydrogen in Patients With Non Alcoholic Faty Liver Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Non-Alcoholic Fatty Liver Disease
Keywords: Molecular hydrogen
effective antioxidant
oxygen radicals
NAFLD
mitochondria
Lead sponsor: Comenius University
Sponsor class: OTHER
Collaborators: name: NWN & Drink HRW
First posted: 2022-04-13
Enrollment: 30
Sex: ALL
Minimum age (years): 33
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* People with age 33-69 years
* BMI ≥ 25
* Confirmation of fatty liver by ultrasonographic examination
* Signed informed consent
* Alcohol intake according to the AUDIT questionnaire 5 or less points for men or 4 or less points for women

Exclusion Criteria:

* Unsigned informed consent
* BMI \< 25
* Presence of severe inflammatory disease with activity (Crohn's disease, ulcerative colitis, active tuberculosis, rheumatoid arthritis, etc.)
* Presence of acute infectious disease (acute hepatitis, peritonitis, cholecystitis, pancreatitis, etc.)
* Presence of active neoplastic disease
* Alcohol intake according to the AUDIT questionnaire more as 5 points for men or more as 4 points for women

Primary outcomes:
measure: Changes in body parameters: Weight in kilograms, height in meters, waist circumference in centimeters
timeFrame: 8 weeks
measure: Changes in blood parameters ALT
timeFrame: 8 weeks
measure: Changes in blood parameters AST
timeFrame: 8 weeks
measure: Changes in blood parameters ALP
timeFrame: 8 weeks
measure: Changes in blood parameters GMT
timeFrame: 8 weeks
measure: Changes in blood parameters Albumin
timeFrame: 8 weeks
measure: Changes in blood parameters Cholinesterase
timeFrame: 8 weeks
measure: Changes in blood parameters Bilirubin
timeFrame: 8 weeks
measure: Changes in blood parameters Glucose
timeFrame: 8 weeks
measure: Changes in blood parameters Cholesterol
timeFrame: 8 weeks
measure: Changes in blood parameters Triacylglycerol
timeFrame: 8 weeks
measure: Changes in blood parameters Insulin
timeFrame: 8 weeks
measure: Changes in blood parameters HOMA index
timeFrame: 8 weeks
measure: Changes in blood parameters Leucocytes
timeFrame: 8 weeks
measure: Changes in blood parameters Hemoglobin
timeFrame: 8 weeks
measure: Changes in blood parameters Platelets
timeFrame: 8 weeks
measure: Changes in blood parameters TBARS
timeFrame: 8 weeks
measure: Changes in blood parameters MDA
timeFrame: 8 weeks
measure: Changes in blood parameters LDH
timeFrame: 8 weeks
measure: Changes in blood parameters MMP-2
timeFrame: 8 weeks
measure: Changes in blood parameters MMP-9
timeFrame: 8 weeks
measure: Changes in blood parameters 8-OHdG
timeFrame: 8 weeks
measure: Changes in blood parameters SOD
timeFrame: 8 weeks
measure: Changes in blood parameters NFkB
timeFrame: 8 weeks
measure: Changes in blood parameters TNF alfa
timeFrame: 8 weeks
measure: Changes in blood parameters HSP 60
timeFrame: 8 weeks
measure: Changes in blood parameters HSP 70
timeFrame: 8 weeks
measure: Changes in blood parameters Alpha tocopherol
timeFrame: 8 weeks
measure: Changes in blood parameters Gama tocopherol
timeFrame: 8 weeks
measure: Changes in blood parameters Beta carotene
timeFrame: 8 weeks
measure: Changes in blood parameters Coenzyme Q 10 in platelets
timeFrame: 8 weeks
measure: Changes in blood parameters Coenzyme Q 10 in plasma
timeFrame: 8 weeks
measure: Changes in blood parameters Coenzyme Q 10 in whole blood
timeFrame: 8 weeks
Secondary outcomes:
Other outcomes:
measure: Entry check of patients health status- clinical examination SPG and SPL
timeFrame: 2 hours
measure: Entry check of patients health status- urinary sediment
timeFrame: 2 hours
measure: Entry check of patients health status- USG
timeFrame: 2 hours
measure: Entry check of patients health status- Life style risk factors questionnaire
timeFrame: 1 hours
measure: Entry check of patients health status- AUDIT questionnaire of alcohol intake
timeFrame: 30 minutes
measure: Entry check of patients health status- Fast Depression screening by Patient Health Questionnaire
timeFrame: 10 minutes
measure: Entry check of patients health status- Generalized Anxiety Disorder
timeFrame: 10 minutes
Locations:
city: Bratislava
country: Slovakia
facility: 3rd Department of Internal Medicine Faculty of Medicine Comenius University in Bratislava
Study officials:
References:
citation: Gvozdjakova A, Klauco F, Kucharska J, Sumbalova Z. Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19? Bratisl Lek Listy. 2020;121(11):775-778. doi: 10.4149/BLL_2020_126.
citation: Gvozdjakova A, Sumbalova Z, Kucharska J, Komlosi M, Rausova Z, Vancova O, Szamosova M, Mojto V. Platelet Mitochondrial Respiration, Endogenous Coenzyme Q10 and Oxidative Stress in Patients with Chronic Kidney Disease. Diagnostics (Basel). 2020 Mar 23;10(3):176. doi: 10.3390/diagnostics10030176.
citation: Gvozdjakova A, Kucharska J, Sumbalova Z, Rausova Z, Chladekova A, Komlosi M, Szamosova M, Mojto V. The importance of coenzyme Q10 and its ratio to cholesterol in the progress of chronic kidney diseases linked to non- -communicable diseases. Bratisl Lek Listy. 2020;121(10):693-699. doi: 10.4149/BLL_2020_113.
citation: Gvozdjakova A, Kucharska J, Sumbalova Z, Nemec M, Chladekova A, Vancova O, Rausova Z, Kubalova M, Kuzmiakova Z, Mojto V. Platelets mitochondrial function depends on CoQ10 concentration in winter, not in spring season. Gen Physiol Biophys. 2019 Jul;38(4):325-334. doi: 10.4149/gpb_2019012. Epub 2019 Jun 26.
citation: Gvozdjakova A, Sumbalova Z, Kucharska J, Chladekova A, Rausova Z, Vancova O, Komlosi M, Ulicna O, Mojto V. Platelet mitochondrial bioenergetic analysis in patients with nephropathies and non-communicable diseases: a new method. Bratisl Lek Listy. 2019;120(9):630-635. doi: 10.4149/BLL_2019_104.