Elucidating Hepatic Metabolism in Non-alcoholic Fatty Liver Disease

NCT ID: NCT06942312

Last Updated: 2025-04-24

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ENROLLING_BY_INVITATION

Total Enrollment

30 participants

Study Classification

OBSERVATIONAL

Study Start Date

2025-05-01

Study Completion Date

2030-12-31

Brief Summary

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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

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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

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Non-alcoholic Fatty Liver Disease (NAFLD)

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

CROSS_SECTIONAL

Study Groups

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Advanced NAFLD

Intrahepatic triglyceride content ≥ 5.56 % as determined by magnetic resonance specroscopy and liver stiffness measurement ≥ 8 kPa using transient elastography (Fibroscan)

Ketoisocaproic acid breath test

Intervention Type DIAGNOSTIC_TEST

13C-alpha-ketoisocaproic acid breath test to estimate hepatic mitochondrial reductive stress (1 mg/kg body weight; oral dose; study duration 390 min)

Ammonium Chloride

Intervention Type DIAGNOSTIC_TEST

15N-ammonium chloride stable isotope test to estimate ureagenesis (20 mg/kg body weight; oral dose; study duration 390 min)

Bicarbonate de sodium

Intervention Type DIAGNOSTIC_TEST

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)

Deuterated Water

Intervention Type DIAGNOSTIC_TEST

Deuterated water stable isotope test to estimate hepatic de novo lipogenesis and gluconeogenesis (3 g/kg body water; oral dose; duration: overnight)

Oral Glucose Tolerance Test

Intervention Type DIAGNOSTIC_TEST

A standard 2-hour 75-gram oral glucose tolerance test to assess glucose tolerance and whole body metabolism

Mild NAFLD

Intrahepatic triglyceride content ≥ 5.56 % as determined by magnetic resonance specroscopy and liver stiffness measurement \< 8 kPa using transient elastography (Fibroscan)

Ketoisocaproic acid breath test

Intervention Type DIAGNOSTIC_TEST

13C-alpha-ketoisocaproic acid breath test to estimate hepatic mitochondrial reductive stress (1 mg/kg body weight; oral dose; study duration 390 min)

Ammonium Chloride

Intervention Type DIAGNOSTIC_TEST

15N-ammonium chloride stable isotope test to estimate ureagenesis (20 mg/kg body weight; oral dose; study duration 390 min)

Bicarbonate de sodium

Intervention Type DIAGNOSTIC_TEST

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)

Deuterated Water

Intervention Type DIAGNOSTIC_TEST

Deuterated water stable isotope test to estimate hepatic de novo lipogenesis and gluconeogenesis (3 g/kg body water; oral dose; duration: overnight)

Oral Glucose Tolerance Test

Intervention Type DIAGNOSTIC_TEST

A standard 2-hour 75-gram oral glucose tolerance test to assess glucose tolerance and whole body metabolism

Healthy control

Intrahepatic triglyceride content \< 5.56 % as determined by magnetic resonance specroscopy and liver stiffness measurement \< 8 kPa using transient elastography (Fibroscan)

Ketoisocaproic acid breath test

Intervention Type DIAGNOSTIC_TEST

13C-alpha-ketoisocaproic acid breath test to estimate hepatic mitochondrial reductive stress (1 mg/kg body weight; oral dose; study duration 390 min)

Ammonium Chloride

Intervention Type DIAGNOSTIC_TEST

15N-ammonium chloride stable isotope test to estimate ureagenesis (20 mg/kg body weight; oral dose; study duration 390 min)

Bicarbonate de sodium

Intervention Type DIAGNOSTIC_TEST

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)

Deuterated Water

Intervention Type DIAGNOSTIC_TEST

Deuterated water stable isotope test to estimate hepatic de novo lipogenesis and gluconeogenesis (3 g/kg body water; oral dose; duration: overnight)

Oral Glucose Tolerance Test

Intervention Type DIAGNOSTIC_TEST

A standard 2-hour 75-gram oral glucose tolerance test to assess glucose tolerance and whole body metabolism

Interventions

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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)

Intervention Type DIAGNOSTIC_TEST

Ammonium Chloride

15N-ammonium chloride stable isotope test to estimate ureagenesis (20 mg/kg body weight; oral dose; study duration 390 min)

Intervention Type 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)

Intervention Type 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)

Intervention Type DIAGNOSTIC_TEST

Oral Glucose Tolerance Test

A standard 2-hour 75-gram oral glucose tolerance test to assess glucose tolerance and whole body metabolism

Intervention Type DIAGNOSTIC_TEST

Eligibility Criteria

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Exclusion 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. 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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Helsinki University Central Hospital

OTHER

Sponsor Role lead

Responsible Party

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Panu Luukkonen

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Panu K. Luukkonen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Helsinki

Locations

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Helsinki Central University Hospital

Helsinki, Uusimaa, Finland

Site Status

Countries

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Finland

Other Identifiers

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HUS/176/2025

Identifier Type: -

Identifier Source: org_study_id

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