Hepatic Mitochondrial Metabolism in Fatty Liver Disease in Humans (ALPHA)

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?

Study Overview

• Status: Enrolling by invitation
• Conditions: Non-alcoholic Fatty Liver Disease NAFLD
• Intervention / Treatment: Diagnostic test: 13C-α-Ketoisocaproic Acid Breath Test; Dietary supplement: Ethanol; Dietary supplement: Lipid Emulsion; Other: Normal Saline

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.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00290
      • Helsinki Central University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: The order of metabolic visits: 1.Normal saline, 2.Lipid emulsion, 3.Ethanol	Diagnostic test: 13C-α-Ketoisocaproic Acid Breath Test; 13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).; Dietary supplement: Ethanol; 6% ethanol soluted in normal saline is given intravenously during one metabolic visit.; Other Names: Alcohol; Dietary supplement: Lipid Emulsion; Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.; Other: Normal Saline; Normal saline is given intravenously during one metabolic visit.
Experimental: The order of metabolic visits: 1. Normal saline, 2. Ethanol, 3. Lipid emulsion	Diagnostic test: 13C-α-Ketoisocaproic Acid Breath Test; 13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).; Dietary supplement: Ethanol; 6% ethanol soluted in normal saline is given intravenously during one metabolic visit.; Other Names: Alcohol; Dietary supplement: Lipid Emulsion; Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.; Other: Normal Saline; Normal saline is given intravenously during one metabolic visit.
Experimental: The order of metabolic visits: 1.Lipid emulsion, 2.Normal saline, 3.Ethanol	Diagnostic test: 13C-α-Ketoisocaproic Acid Breath Test; 13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).; Dietary supplement: Ethanol; 6% ethanol soluted in normal saline is given intravenously during one metabolic visit.; Other Names: Alcohol; Dietary supplement: Lipid Emulsion; Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.; Other: Normal Saline; Normal saline is given intravenously during one metabolic visit.
Experimental: The order of metabolic visits: 1.Lipid emulsion, 2.Ethanol, 3.Normal saline	Diagnostic test: 13C-α-Ketoisocaproic Acid Breath Test; 13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).; Dietary supplement: Ethanol; 6% ethanol soluted in normal saline is given intravenously during one metabolic visit.; Other Names: Alcohol; Dietary supplement: Lipid Emulsion; Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.; Other: Normal Saline; Normal saline is given intravenously during one metabolic visit.
Experimental: The order of metabolic visits: 1. Ethanol, 2. Normal saline, 3. Lipid emulsion	Diagnostic test: 13C-α-Ketoisocaproic Acid Breath Test; 13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).; Dietary supplement: Ethanol; 6% ethanol soluted in normal saline is given intravenously during one metabolic visit.; Other Names: Alcohol; Dietary supplement: Lipid Emulsion; Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.; Other: Normal Saline; Normal saline is given intravenously during one metabolic visit.
Experimental: The order of metabolic visits: 1. Ethanol, 2. Lipid emulsion, 3. Normal saline	Diagnostic test: 13C-α-Ketoisocaproic Acid Breath Test; 13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).; Dietary supplement: Ethanol; 6% ethanol soluted in normal saline is given intravenously during one metabolic visit.; Other Names: Alcohol; Dietary supplement: Lipid Emulsion; Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.; Other: Normal Saline; Normal saline is given intravenously during one metabolic visit.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in arterialized plasma b-OHB to AcAc ratio	Arterialized plasma b-OHB and AcAc concentrations	From baseline to the end of treatment at 240 minutes
Breath 13CO2 enrichment after ingesting 13C-alpha-ketoisocaproate	Measured as area under the curve	From baseline to the end of treatment at 330 minutes.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma metabolomics	Arterialized plasma analyzed by nuclear magnetic resonance and mass spectrometry	From baseline until the end of treatment at 240 minutes.

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Investigators: Principal Investigator: Panu Luukkonen, MD, PhD, Helsinki University Central Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): February 28, 2026
• Study Completion (Estimated): January 31, 2027

Study Registration Dates

• First Submitted: August 12, 2024
• First Submitted That Met QC Criteria: August 14, 2024
• First Posted (Actual): August 19, 2024

Study Record Updates

• Last Update Posted (Actual): August 19, 2024
• Last Update Submitted That Met QC Criteria: August 14, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: MAFLD; Hepatic mitochondrial dysfunction; Non-alcoholic Fatty Liver Disease NAFLD; 13C-α-Ketoisocaproic Acid Breath Test
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Ethanol
• Other Study ID Numbers: HUS/8748/2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Due to European Union GDPR regulations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No