Liver Fibrosis/NASH, MASH - Metabolic Dysfunction-Associated Steatohepatitis, MASLD - Metabolic Dysfunction-Associated Steatotic Liver Disease
Conditions
Brief summary
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.
Interventions
BEHAVIORALExercise
The 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.
BEHAVIORALUsual Care
Participants will receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion.
Sponsors
Consorcio Centro de Investigación Biomédica en Red (CIBER)
Hospital General Universitario Gregorio Marañon
Universidad de Granada
Universidad Politecnica de Madrid
Universidad Complutense de Madrid
Instituto Mixto Universitario Deporte y Salud (iMUDS)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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. * Participating in a weight loss, a weight-management program or a supervised exercise program (more than 30 minutes three times per week, or 45 minutes twice a week, moderate/vigorous intensity). * Body weight instability. Participants must have maintained the body weight registered at screening visit (tolerance: 5%) for more than 3 months. * Regular use of medication or compounds that may affect study outcomes based on research staff criteria. * Pregnancy and lactation or planned pregnancy (within the study period). * Frequent travel over time zones during the study period. * Fear of needles and claustrophobia to magnetic resonance imaging (MRI). * Low physical function (ie, ambulation dependency) * Being unable to understand and to accept the instructions or the study objectives and protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in hepatic fat content | Change from baseline to 12 weeks | Hepatic fat content will be determined by Proton Density Fat Fraction (PDFF) assessed by Magnetic Resonance Imaging (MRI) |
| Change in liver inflammation and fibrosis | Change from baseline to 12 weeks | 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 | Change from baseline to 12 weeks. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Enhanced Liver Fibrosis (ELF) Score | Change from baseline to 12 weeks | 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 | Change from baseline to 12 weeks | 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 | Change from baseline to 12 weeks | 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) | Change from baseline to 12 weeks | 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. |
| Change in visceral adipose tissue | Change from baseline to 12 weeks | Visceral adipose tissue will be assessed by Magnetic Resonance Imaging (MRI) |
| Change in pancreatic fat content | Change from baseline to 12 weeks | Pancreatic fat content will be assessed by Magnetic Resonance Imaging (MRI) |
| Change in abdominal subcutaneous adipose tissue | Change from baseline to 12 weeks | Abdominal subcutaneous adipose tissue will be assessed by Magnetic Resonance Imaging (MRI) |
| Change in abdominal intermuscular fat content | Change from baseline to 12 weeks | Abdominal intermuscular fat content will be assessed by Magnetic Resonance Imaging (MRI) |
| Change in abdominal intramuscular fat content | Change from baseline to 12 weeks | Abdominal intramuscular fat content will be assessed by Magnetic Resonance Imaging (MRI) |
| Change in abdominal skeletal muscle tissue | Change from baseline to 12 weeks | Abdominal skeletal muscle tissue will be assessed by Magnetic Resonance Imaging (MRI) |
| Change in values of fasting glucose | Change from baseline to 12 weeks | Fasting blood samples will be used to assess glucose |
| Change in values of HbA1c | Change from baseline to 12 weeks | Fasting blood samples will be used to assess HbA1c. Higher fasting HbA1C values indicates poorer glucemic control. |
| Change in values of fasting insulin | Change from baseline to 12 weeks | Fasting blood samples will be used to assess insulin |
| Change in levels of mean glucose (Continuous Glucose Monitoring) | Change from baseline to 12 weeks. | 24-hour, diurnal and nocturnal mean glucose over 14 days will be assessed by Continuous Glucose Monitoring during 2 weeks |
| Change in fasting lipid profile | Change from baseline to 12 weeks | Fasting blood samples will be used to assess levels of triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol an total cholesterol. |
| Change in alkaline phosphatase | Baseline to 12 weeks | Fasting blood samples will be used to assess serum alkaline phosphatase using standard clinical chemistry methods. |
| Change in alanine aminotransferase (ALT) | Baseline to 12 weeks | Fasting blood samples will be used to assess serum alanine aminotransferase (ALT) using standard clinical chemistry methods. |
| Change in gamma-glutamyl transferase (GGT) | Baseline to 12 weeks | Fasting blood samples will be used to assess serum gamma-glutamyl transferase (GGT) using standard clinical chemistry methods. |
| Change in total bilirubin | Baseline to 12 weeks | Fasting blood samples will be used to assess total serum bilirubin using standard clinical chemistry methods. |
| Change in creatinine | Baseline to 12 weeks | Fasting blood samples will be used to assess serum creatinine using standard clinical chemistry methods. |
| Change in estimated glomerular filtration rate (eGFR) | Baseline to 12 weeks | eGFR will be calculated from serum creatinine using a standard equation (e.g., CKD-EPI 2021), as implemented by the study laboratory. |
| Change in values of C-reactive protein | Change from baseline to 12 weeks | Fasting blood samples will be used to assess levels of C-reactive protein. Higher values indicate inflammation in the body. |
| Change in values of interleukin 6 | Change from baseline to 12 weeks] | Fasting blood samples will be used to assess levels of interleukin 6. Higher basal levels often indicating greater inflammation or metabolic stress. |
| Change in blood pressure | Change from baseline to 12 weeks | Systolic and Diastolic blood pressure will be assessed by blood pressure monitor |
| Change in waist, hip and neck circumference | Change from baseline to 12 weeks. | Circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry |
| Change in body weight | Change from baseline to 12 weeks | Body weight will be measured by a digital scale |
| Change in moderate-to-vigorous physical activity (MVPA) | Baseline to 12 weeks | Moderate-to-vigorous physical activity (minutes per day) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period. |
| Change in light physical activity | Baseline to 12 weeks | Light physical activity (minutes per day) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period. |
| Change in sedentary time | Baseline to 12 weeks | Sedentary time (minutes per day) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period. |
| Change in total activity counts | Baseline to 12 weeks | Total activity counts per day will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period. |
| Change in Subjective sleep quality | Baseline to 12 weeks | Subjective sleep quality will be assessed by the Pittsburgh Sleep Quality Index (PSQI). Minimum value is 0 (never) and maximum value is 3 (3 or more times per week). Higher values mean a worse outcome. |
| Change in total sleep time | Baseline to 12 weeks | Total sleep time (minutes per night) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period. |
| Change in Cardiorespiratory Fitness | Change from baseline to 12 weeks | Cardiorespiratory fitness measured by maximum treadmill test |
| Change in Lower-body muscular performance | Change from baseline to 12 weeks | Lower body muscular performance measured by chair stand test. |
| Change in Upper muscular strength | Change from baseline to 12 weeks | Upper body muscular strength measured by hand grip strength test. |
| Change in Quality of life | Changes from baseline to 12-weeks | Quality of life will be assessed by the Rand Short Form 36 (SF-36). This questionnaire provides an score ranged from 0 to 100. Higher values mean better quality of life. |
| Change EuroQol Visual Analogue Scale (EQ-VAS) score | Changes from baseline to 12-weeks | The EQ-VAS is a vertical 0-100 scale used in the EuroQol EQ-5D instrument to measure a patient's self-rated, current overall health. It ranges from 0 (worst imaginable health) to 100 (best imaginable health), allowing patients to quantify their perceived health status. |
| Change in mid-thigh subcutaneous adipose tissue area | Baseline to 12 weeks | Mid-thigh subcutaneous adipose tissue area will be quantified from segmented magnetic resonance imaging (MRI) slices. |
| Change in mid-thigh intramuscular fat content | Baseline to 12 weeks | Mid-thigh intramuscular fat content will be quantified from segmented magnetic resonance imaging (MRI) slices. |
| Change in mid-thigh intermuscular fat content | Baseline to 12 weeks | Mid-thigh intermuscular fat content will be quantified from segmented magnetic resonance imaging (MRI) slices. |
| Change in mid-thigh skeletal muscle cross-sectional area | Baseline to 12 weeks | Mid-thigh skeletal muscle cross-sectional area will be quantified from segmented magnetic resonance imaging (MRI) slices. |
Countries
Spain
Contacts
CONTACTJose Serra-Rexach, PhD
Outcome results
None listed