NCT06942312

Elucidating Hepatic Metabolism in Non-alcoholic Fatty Liver Disease

• Status: Enrolling By Invitation
• Phase: —
• Study type: Observational
• Enrollment: 30 (estimated)
• Sponsor: Helsinki University Central Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Accepted

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.

Conditions

• Non-alcoholic Fatty Liver Disease (NAFLD)

Interventions

Type	Name	Description
DIAGNOSTIC_TEST	Ketoisocaproic acid breath test	13C-alpha-ketoisocaproic acid breath test to estimate hepatic mitochondrial reductive stress (1 mg/kg body weight; oral dose; study duration 390 min)
DIAGNOSTIC_TEST	Ammonium Chloride	15N-ammonium chloride stable isotope test to estimate ureagenesis (20 mg/kg body weight; oral dose; study duration 390 min)
DIAGNOSTIC_TEST	Bicarbonate de sodium	13C-bicarbonate breath test to estimate body bicarbonate pool size and gastric emptying (0.5 mg/kg body weight; oral dose; study duration 390 min)
DIAGNOSTIC_TEST	Deuterated Water	Deuterated water stable isotope test to estimate hepatic de novo lipogenesis and gluconeogenesis (3 g/kg body water; oral dose; duration: overnight)
DIAGNOSTIC_TEST	Oral Glucose Tolerance Test	A standard 2-hour 75-gram oral glucose tolerance test to assess glucose tolerance and whole body metabolism

Timeline

• Start date: 2025-05-01
• Primary completion: 2029-12-31
• Completion: 2030-12-31
• First posted: 2025-04-24
• Last updated: 2025-04-24

Locations

1 site across 1 country: Finland