Clinical trial NCT06559878: Hepatic Mitochondrial Metabolism in Fatty Liver Disease in Humans
Official title: Hepatic Mitochondrial Metabolism in Fatty Liver Disease in Humans
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Non-alcoholic Fatty Liver Disease NAFLD
Keywords: Hepatic mitochondrial dysfunction
MAFLD
Non-alcoholic Fatty Liver Disease NAFLD
13C-α-Ketoisocaproic Acid Breath Test
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
First posted: 2024-08-19
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The study protocol includes five clinical visits. At first visit, an informed consent will be obtained, followed by assessment of inclusion/exclusion criteria. Participants fulfilling the criteria will be enrolled in the study. At second visit, magnetic resonance studies will be performed to quantify liver fat content. Visits 3-5 consist of metabolic studies using the 13C-ketoisocaproate breath test and, in a random order, infusions of either a) saline alone, b) saline, a lipid emulsion and heparin or c) saline and ethanol.
Primary purpose: BASIC_SCIENCE

Brief summary: The goal of this clinical trial is to investigate in healthy volunteers the mechanisms by which ethanol and lipids, the two key risk factors of steatotic liver disease (SLD), affect liver mitochondrial metabolism.

The main question it aims to answer is:

• Does acute administration of ethanol and lipids increase hepatic mitochondrial reductive stress as determined by orally ingested stable isotope tracer 13C-alpha-ketoisocaproate and by plasma beta-hydroxybutyrate to acetoacetate ratio (b-OHB/AcAc) in humans?

Detailed description: In this study we investigate the effects of ethanol and lipids on hepatic mitochondrial metabolism in healthy volunteers.

At first visit, an informed consent will be obtained, followed by assessment of inclusion/exclusion criteria. Participants fulfilling the criteria will be enrolled in the study. Body composition will be determined with bioelectrical impedance.

At second visit hepatic lipid content will be measured with magnetic resonance spectroscopy.

Participants will be given in random order on three separate visits (3-5):

* Intravenous infusion of ethanol and normal saline (breath alcohol content target and upper limit corresponding to 0.6 per mil in blood)
* Intravenous infusions of lipid emulsion, heparin and normal saline
* Intravenous infusion of normal saline

On study visits participant will drink a tracer dose of 13C-alpha-ketoisocaproate and L-Leucine. Breath samples are collected at different time points for determination of 13C enrichment of CO2. Furthermore "arterialized" blood samples are taken during study visits to obtain beta-hydroxybutyrate to acetoacetate ratios (b-OHB/AcAc) at different timepoints.

Whole-body oxidation of lipids, carbohydrates and protein will be determined using indirect calorimetry.

Eligibility criteria: 1. Participants must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
2. Subject must be likely to be available to complete all protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge.
3. Age range from 18-75 years.
4. No known hypersensitivity to egg, soy, or peanut protein, or to any of the substances of Intralipid 20%, or to any other substance to be administered during the study.
5. No severe hyperlipidemia or hemophagocytotic syndrome as judged by history and physical examination and standard laboratory tests.
6. No other liver disease except for SLD.
7. No advanced liver disease as judged by history and physical examination and standard laboratory tests.
8. No claustrophobia or metal implants to allow magnetic resonance studies.
9. No pregnancy or lactation in women.
10. No known or anticipated difficulties in cannulation of peripheral veins.
11. No history or evidence of any other clinically significant disorder, condition or disease other than those outlined above that, in the opinion of the investigator may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion.
12. No drinking problem based on AUDIT questionnaire.
13. No use of medications interacting with alcohol.
14. No history of heparin induced thrombosytopenia (HIT) or bleeding tendency.
15. No current use of warfarin, direct anticoagulants, or thrombocyte inhibitors.

Primary outcomes:
measure: Change in arterialized plasma b-OHB to AcAc ratio
timeFrame: From baseline to the end of treatment at 240 minutes
measure: Breath 13CO2 enrichment after ingesting 13C-alpha-ketoisocaproate
timeFrame: From baseline to the end of treatment at 330 minutes.
Secondary outcomes:
Other outcomes:
measure: Plasma metabolomics
timeFrame: From baseline until the end of treatment at 240 minutes.
Locations:
city: Helsinki
country: Finland
facility: Helsinki Central University Hospital
state: Uusimaa
Study officials:
affiliation: Helsinki University Central Hospital
name: Panu Luukkonen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: