Clinical trial NCT06942312: Elucidating Hepatic Metabolism in Non-alcoholic Fatty Liver Disease
Official title: Elucidating Hepatic Metabolism in Non-alcoholic Fatty Liver Disease
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Non-alcoholic Fatty Liver Disease (NAFLD)
Keywords: Hepatic mitochondrial dysfunction
Non-alcoholic Fatty Liver Disease NAFLD
13C-α-Ketoisocaproic Acid Breath Test
liver stiffness
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
First posted: 2025-04-24
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: General population and hospital outpatients

Brief summary: The goal of this observational, cross-sectional, case-control clinical study is to investigate the metabolic adaptations underlying the progression of nonalcoholic fatty liver disease (NAFLD), and to test the hypothesis that hepatic mitochondrial reductive stress contributes to progression of NAFLD.

The main question it aims to answer is:

Do patients with advanced NAFLD compared to patients with mild NAFLD and healthy controls have increased hepatic mitochondrial reductive stress as determined by the ketoisocaproate breath test and by plasma beta-hydroxybutyrate to acetoacetate ratio (b-OHB/AcAc)?

Detailed description: In this study the investigators study the metabolic adaptations underlying the progression of nonalcoholic fatty liver disease (NAFLD), namely hepatic mitochondrial reductive stress, ureagenesis, de novo lipogenesis and gluconeogenesis in patients with advanced and mild NAFLD and in healthy controls.

At the first visit, an informed consent will be obtained, followed by assessment of inclusion/exclusion criteria and medical history. Participants fulfilling the criteria will be enrolled in the study. A physical examination will be performed and laboratory test will be taken. Body composition will be determined with bioelectrical impedance and dual-energy x-ray absorptiometry (DEXA).

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

At the third visit, participants will pick up containers for overnight urine collection and doses of deuterated water and a standardized meal replacement bar. The fourth visit is a clinical study visit. In a specified order, participants will drink tracer doses of 15NH4Cl, 13C-bicarbonate and 13C-alpha-ketoisocaproate. An oral glucose tolerance test is performed in the end of the study day. Breath samples are collected at different time points for determination of 13C enrichment of CO2. Furthermore, "arterialized" blood samples are taken 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: The following inclusion/ exclusion criteria will be employed:

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. Participants must be aged between 18-75 years.
4. Participants are not allowed to have alcohol consumption of 350 g/week or more in women and 420 g/week or more in men.
5. Participants are not allowed to have history of liver disease other than NAFLD as judged by history and physical examination and standard laboratory tests.
6. Participants are not allowed to have claustrophobia or metal implants to allow magnetic resonance studies.
7. Participants are not allowed to be pregnant or lactating.
8. No known or anticipated difficulties in cannulation of peripheral veins.
9. 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.

Primary outcomes:
measure: Hepatic mitochondrial reductive stress as determined by plasma beta-hydroxybutyrate-to-acetoacetate ratio
timeFrame: Fourth study visit (2 months)
measure: Hepatic mitochondrial reductive stress as determined by the ketoisocaproic acid breath test
timeFrame: Fourth study visit (2 months)
Secondary outcomes:
measure: Plasma metabolomics
timeFrame: Fourth study visit (2 months)
measure: Plasma metabolomics
timeFrame: Fourth study visit (2 months)
Other outcomes:
measure: Fractional Rate of Ureagenesis
timeFrame: Fourth study visit (2 months)
measure: Fractional Rate of Hepatic de novo lipogenesis
timeFrame: Fourth study visit (2 months)
measure: Fractional Rate of Gluconeogenesis
timeFrame: Fourth study visit (2 months)
measure: Ammonia incorporation to glutamine
timeFrame: Fourth study visit (2 months)
measure: Bicarbonate pool size
timeFrame: Fourth study visit (2 months)
Locations:
city: Helsinki
country: Finland
facility: Helsinki Central University Hospital
state: Uusimaa
Study officials:
affiliation: University of Helsinki
name: Panu K. Luukkonen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: