Elucidating Hepatic Metabolism in Non-alcoholic Fatty Liver Disease

Обзор

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)?

Подробное описание

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.

Вмешательства

• Диагностический тест 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)
• Диагностический тест Ammonium Chloride
  15N-ammonium chloride stable isotope test to estimate ureagenesis (20 mg/kg body weight; oral dose; study duration 390 min)
• Диагностический тест 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)
• Диагностический тест Deuterated Water
  Deuterated water stable isotope test to estimate hepatic de novo lipogenesis and gluconeogenesis (3 g/kg body water; oral dose; duration: overnight)
• Диагностический тест Oral Glucose Tolerance Test
  A standard 2-hour 75-gram oral glucose tolerance test to assess glucose tolerance and whole body metabolism

Первичные конечные точки

• Hepatic mitochondrial reductive stress as determined by plasma beta-hydroxybutyrate-to-acetoacetate ratio [Срок оценки: Fourth study visit (2 months)]
• Hepatic mitochondrial reductive stress as determined by the ketoisocaproic acid breath test [Срок оценки: Fourth study visit (2 months)]

Вторичные конечные точки (2)

• Plasma metabolomics [Срок оценки: Fourth study visit (2 months)]
• Plasma metabolomics [Срок оценки: Fourth study visit (2 months)]

Критерии участия

The following inclusion/ exclusion criteria will be employed:

• Participants must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
• 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.
• Participants must be aged between 18-75 years.
• Participants are not allowed to have alcohol consumption of 350 g/week or more in women and 420 g/week or more in men.
• Participants are not allowed to have history of liver disease other than NAFLD as judged by history and physical examination and standard laboratory tests.
• Participants are not allowed to have claustrophobia or metal implants to allow magnetic resonance studies.
• Participants are not allowed to be pregnant or lactating.
• No known or anticipated difficulties in cannulation of peripheral veins.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

Финляндия · 1 центр

• Helsinki Central University Hospital — Helsinki

Идентификаторы

NCT: NCT06942312 · HUS/176/2025

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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