The goal of this clinical trial is to learn how physical exercise affects liver health in adults with metabolic dysfunction-associated steatotic liver disease (MASLD) or at-risk metabolic dysfunction-associated steatohepatitis (MASH); comparing responses between middle-aged adults (40-60 years old) and older adults (70 years and older) of any sex, as well as between participants with low-risk MASLD and high-risk MASH. The main question it aims to answer is:
Could an exercise program reduce liver fat, inflammation and fibrosis, regardless of age and disease severity?
Researchers will compare 4 different groups:
A) older adults with at risk MASH who will exercise B) middle-aged people with at risk MASH who will exercise C) middle-aged people with low-risk MASLD who will exercise D) middle-aged people with low-risk MASLD who will not exercise, receiving usual care.
Participants in the exercise groups will take part in a supervised 12-week exercise program that includes both strength and aerobic training, completed twice a week.
All participants, including those receiving usual care, will have health asssessments before and after the 12-week period to measure changes in liver health.
Middle-aged adults (40 to 60 years old) and older adults (aged 70 years or older)
People diagnosed with Metabolic Disfunction-Associated Steatotic Liver Disease (MASLD); defined as the presence of hepatic steatosis (≥5% fat content) in conjunction with at least one cardiometabolic risk factor (overweight or obesity, dysglycaemia or Type II diabetes, elevated plasma triglycerides, reduced HDL-cholesterol or high blood preassure) with no other discernable cause.
People diagnosed with at-risk Metabolic Disfunction-Associated SteatoHepatitis (MASH) according to the following criteria: I) a positive liver biopsy (NAS score ≥ 4 points (with at least one point in each of the components of the score: steatosis, lobular inflammation and ballooning, AND significant (F2) or advanced (F3) fibrosis), or II) a FAST score >0.65.
Descompensated cirrhosis or end-stage liver disease.
Other causes of liver disease, such as alcohol abuse or drug-induced, virus-related, or hereditary disease.
History of a major adverse cardiovascular event, clinically significant kidney, endocrine, or neurological disease, bariatric surgery, HIV/AIDS, known inflammatory and/or rheumatologic disease, cancer, or other medical condition in which exercise is absolute contraindicated.
Recent or planned major surgery, as well as anticancer therapies.
Parallel
Exercise
BehavioralThe exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion \>7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at \>85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). Moreover, participants will receive an individualized moderate-intensity goal-setting aerobic (walking) program to achieve a minimum of 135 minutes per week.
Usual Care
BehavioralParticipants will receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion.
Change in hepatic fat content
Hepatic fat content will be determined by Proton Density Fat Fraction (PDFF) assessed by Magnetic Resonance Imaging (MRI)
Change in liver inflammation and fibrosis
Iron-corrected T1 (cT1) will be determined though MRI to reflect liver tissue water content, correlating with histological features of fibroinflammation (ballooning, fibrosis, and NAS)
Change in liver stiffness
Determined by vibration-controlled Transient Elastography (Fibroscan ®, VCTE). This is an ultrasound-based technique widely used in clinical practice to diagnose and monitor fibrosis progression. Liver stifness measurement increases with liver fibrosis.
Change in Enhanced Liver Fibrosis (ELF) Score
Fasting blood samples will be used to assess the Enhanced Liver Fibrosis (ELF) serum biomarker. The ELF score reflects the risk of advanced liver fibrosis, with higher values indicating higher risk.
Change in Pro-C3 serum levels
Fasting blood samples will be used to asses Pro-C3 serum levels, a biomarker of liver fibrosis. Higher PRO-C3 levels indicate ongoing fibrotic activity
Change in NIS4 serum biomarker of liver fibrosis
Fasting blood samples will be used to asses NIS4, a blood-based diagnostic tool designed to identify patients with at-risk MASH. It generates a composite score stratifying patients by risk.
Change in Metabolomics Advanced Steatohepatitis Fibrosis Score (MASEF)
Fasting blood samples will be used to asses Metabolomics Advanced Steatohepatitis Fibrosis Score (MASEF) in serum samples. Is a proprietary algorithm that generates a numeric score that reflects the likelihood of a patient having at-risk MASH.
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Consorcio Centro de Investigación Biomédica en Red (CIBER)
Lead sponsor
Hospital General Universitario Gregorio Marañon
Collaborator
Universidad de Granada
Collaborator
Universidad Politecnica de Madrid
Collaborator
Universidad Complutense de Madrid
Collaborator
Instituto Mixto Universitario Deporte y Salud (iMUDS)
Collaborator
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