Effect of Molecular Hydrogen in Patients With NAFLD

Non-Alcoholic Fatty Liver Disease Clinical Trial

— EMoHyNAFLD  

Official title:

Effect of Molecular Hydrogen in Patients With Non Alcoholic Faty Liver Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05325398
• Other study ID #: 09/2020/UNB/IIIrdInternal
• Status: Completed
• Phase: N/A
• Start date: May 1, 2020
• Est. completion date: December 18, 2020

Study information

• Verified date: April 2022
• Source: Comenius University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: December 18, 2020
• Est. primary completion date: December 1, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 33 Years to 69 Years

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

Intervention

Dietary Supplement:
• HRW drink, HRW Natural Health Products Inc., Made in Vancouver, Canada
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).
• placebo
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)

Locations

Country	Name	City	State
Slovakia	3rd Department of Internal Medicine Faculty of Medicine Comenius University in Bratislava	Bratislava

Sponsors (2)

Lead Sponsor	Collaborator
Comenius University	NWN & Drink HRW

Country where clinical trial is conducted

Slovakia, 

References & Publications (5)

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. — View Citation

Gvozdjáková A, Kucharská J, Sumbalová Z, Nemec M, Chládeková A, Vancová O, Rausová Z, Kubalová M, Kuzmiaková 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. — View 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. — View 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. — View Citation

Gvozdjáková A, Sumbalová Z, Kucharská J, Komlósi M, Rausová Z, Vancová O, Számošová M, Mojto V. Platelet Mitochondrial Respiration, Endogenous Coenzyme Q(10) and Oxidative Stress in Patients with Chronic Kidney Disease. Diagnostics (Basel). 2020 Mar 23;10(3). pii: E176. doi: 10.3390/diagnostics10030176. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Entry check of patients health status- clinical examination SPG and SPL	Entry examination will include: SPG: Status presens generalis (consciousness, body habitus, skin, nutrition), SPL: status presens localis (head, neck, chest, abdomen, limbs)- described generally as number of participants with changes in healt status	2 hours
Other	Entry check of patients health status- urinary sediment	Urinary sediment normal : leucocyte 1-2 , erythrocyte: 0-1, cultivation: negative or bacterial agens more than 10^5 - described generally as number of participants with changes in urinary sedinent status (normal/abnormal)	2 hours
Other	Entry check of patients health status- USG	USG: Ultrasonographic examination: fatty liver: enlargement of the liver more than 130 mm in anteroposterior position, enlarged echogenity of the liver, curved anterior liver lobe. 1 of these parameter is sufficient for diagnosis of fatty liver - described generally as number of participants with changes in urinary sedinent status (normal/abnormal)	2 hours
Other	Entry check of patients health status- Life style risk factors questionnaire	Filling of the following Questionnaire: Life style risk factors questionnaire Part A/ NAFLD score more as 7 points means risk of nonalcoholic fatty liver disease (NAFLD) Minimum: 0 points Maximum: 14 points Part. B/ ALD score (AUDIT C questionnaire) more than 5 points = risk of alcoholic liver disease (ALD) Minimum: 0 points Maximum: 12 points 5 points and more = risk of ALD , risk of worse outcome	1 hours
Other	Entry check of patients health status- AUDIT questionnaire of alcohol intake	Filling of the following Questionnaire: AUDIT questionnaire of alcohol intake Minimum: 0 points Maximum: 40 points 8 points and more= risky alcohol drinking , risk of ALD , risk of worse outcome	30 minutes
Other	Entry check of patients health status- Fast Depression screening by Patient Health Questionnaire	Filling of the following Questionnaire: Fast Depression screening by Patient Health Questionnaire (2 questions) Minimum: 0 points Maximum: 6 points 3 points and more: risk for depression, risk of worse outcome	10 minutes
Other	Entry check of patients health status- Generalized Anxiety Disorder	Filling of the following Questionnaire: Generalized Anxiety Disorder (2 questions) Minimum: 0 points Maximum: 4 points 3 points and more: risk for generalized anxiety disorder, risk of worse outcome	10 minutes
Primary	Changes in body parameters: Weight in kilograms, height in meters, waist circumference in centimeters	The following parameters will be measured for each proband before (time 0) and after the study (time 8 weeks): a) weight and height will be combined to report BMI in kg/m^2, waist circumference in cm.	8 weeks
Primary	Changes in blood parameters ALT	ALT (alaninaminotransferase) ukat/L	8 weeks
Primary	Changes in blood parameters AST	AST (aspartataminotransferase) ukat/L	8 weeks
Primary	Changes in blood parameters ALP	ALP (alkaline phosphatase) ukat/L	8 weeks
Primary	Changes in blood parameters GMT	GMT (gamaglutamyltransferase) ukat/L	8 weeks
Primary	Changes in blood parameters Albumin	Albumin (g/L)	8 weeks
Primary	Changes in blood parameters Cholinesterase	Cholinesterase (ukat/L)	8 weeks
Primary	Changes in blood parameters Bilirubin	Bilirubin total (umol/L)	8 weeks
Primary	Changes in blood parameters Glucose	Glucose (mmol/L)	8 weeks
Primary	Changes in blood parameters Cholesterol	Cholesterol (mmol/L)	8 weeks
Primary	Changes in blood parameters Triacylglycerol	Triacylglycerol (mmol/L)	8 weeks
Primary	Changes in blood parameters Insulin	Insulin (mIU/L)	8 weeks
Primary	Changes in blood parameters HOMA index	HOMA index (calculation)	8 weeks
Primary	Changes in blood parameters Leucocytes	Leucocytes (x10^9/L)	8 weeks
Primary	Changes in blood parameters Hemoglobin	Hemoglobin (g/L)	8 weeks
Primary	Changes in blood parameters Platelets	Platelets (x10^9/L)	8 weeks
Primary	Changes in blood parameters TBARS	TBARS (µmol/L)	8 weeks
Primary	Changes in blood parameters MDA	MDA (malondialdehyde) (µmol/L)	8 weeks
Primary	Changes in blood parameters LDH	LDH (lactatdehydrogenase) (mU/mL)	8 weeks
Primary	Changes in blood parameters MMP-2	MMP-2 (matrix metalloproteinase2) (% of change)	8 weeks
Primary	Changes in blood parameters MMP-9	MMP-9 (matrix-metalloproteinase 9) (% of change)	8 weeks
Primary	Changes in blood parameters 8-OHdG	8-OHdG (8-hydroxy-2-deoxyguanosine) (ng/mL)	8 weeks
Primary	Changes in blood parameters SOD	SOD (superoxiddismutase) (ng/mL)	8 weeks
Primary	Changes in blood parameters NFkB	NFkB (nuclear factor kappa B) (% of change)	8 weeks
Primary	Changes in blood parameters TNF alfa	TNF alfa (tumor necrosis factor alpha) (% of change)	8 weeks
Primary	Changes in blood parameters HSP 60	HSP 60 (heat shock protein 60) (% of change)	8 weeks
Primary	Changes in blood parameters HSP 70	HSP 70 (heat shock protein 70) (% of change)	8 weeks
Primary	Changes in blood parameters Alpha tocopherol	Alpha tocopherol (µmol/L)	8 weeks
Primary	Changes in blood parameters Gama tocopherol	Gama tocopherol (µmol/L)	8 weeks
Primary	Changes in blood parameters Beta carotene	Beta carotene (µmol/L)	8 weeks
Primary	Changes in blood parameters Coenzyme Q 10 in platelets	Coenzyme Q 10 in platelets (pmol/10^9 cells)	8 weeks
Primary	Changes in blood parameters Coenzyme Q 10 in plasma	Coenzyme Q 10 in plasma (µmol/L)	8 weeks
Primary	Changes in blood parameters Coenzyme Q 10 in whole blood	Coenzyme Q 10 in whole blood (µmol/L)	8 weeks