Elucidating Hepatic Metabolism in Non-alcoholic Fatty Liver Disease

• Conditions: Non-alcoholic Fatty Liver Disease (NAFLD)

• Registration Number: NCT06942312
• Lead Sponsor: Helsinki University Central Hospital

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.

Study Timeline

• Study First Submitted: 2025-03-14
• Status Verified: 2025-04
• Study First Submitted QC: 2025-04-16
• Last Update Submitted: 2025-04-16
• Study First Posted: 2025-04-24
• Last Update Posted: 2025-04-24
• Study Start: 2025-05-01
• Primary Completion: 2029-12-31
• Study Completion: 2030-12-31

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Hepatic mitochondrial reductive stress as determined by plasma beta-hydroxybutyrate-to-acetoacetate ratio	Fourth study visit (2 months)	Ratio of beta-hydroxybutyrate and acetoacetate concentrations in arterialized plasma
Hepatic mitochondrial reductive stress as determined by the ketoisocaproic acid breath test	Fourth study visit (2 months)	Breath 13CO2 enrichment after ingesting 13C-alpha-ketoisocaproate measured as area under the curve

Secondary Outcome Measures

Name	Time	Method
Plasma metabolomics	Fourth study visit (2 months)	Arterialized plasma analyzed by mass spectrometry

Trial Locations

Locations (1)

Helsinki Central University Hospital; 🇫🇮 Helsinki, Uusimaa, Finland