Effect of High Intensity Exercise Rehabilitation on Liver Function and Insulin Sensitivity in Patients With MASLD (CENSORIAL)

Effect of High Intensity Exercise Rehabilitation on Hepatic Fatty Acids (Liver Function), Insulin Sensitivity and Cardiovascular Risk in Patients With MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, and is associated with obesity and the metabolic syndrome. Physical activity and lifestyle interventions are among the most recommended treatments for individuals with MASLD.

In this RCT, we will evaluate the effect of combined exercise training "strength and aerobic training" versus "strength and high intensity training (HIIT)". The main outcome parameter is the severity of liver steatosis. Patients will be recruited at the fatty liver clinic of the UZ Gent.

Study Overview

• Status: Recruiting
• Conditions: Exercise Therapy; Metabolic Dysfunction-associated Steatotic Liver Disease
• Intervention / Treatment: Other: Combined aerobic + strength training; Other: Combined strength + HIIT training

Detailed Description

Physical activity and lifestyle interventions, including exercise, are recommended for individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). Weight loss has been found to improve MASLD histologically, but exercise alone can also reduce liver fat accumulation, even without significant weight loss. Exercise has positive effects on chronic inflammation, type 2 diabetes mellitus (T2DM), and mitochondrial function in MASLD patients. Studies suggest that both aerobic and resistance exercise are effective in reducing fat content and liver enzyme levels in MASLD, and thereby generate positive effects on insulin sensitivity and cardiovascular risk. The potential of high-intensity interval training (HIIT) is large in various settings, but was never explored in this population. Moreover, the combination with strength training can have additional health effects which remain to be explored.

All subjects are recruited in the liver steatosis outpatient clinic of the university hospital in Ghent by the physicians and researchers of this study. After patient selection and obtaining informed consent, they will be screened in the rehabilitation center for cardiorespiratory fitness.

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Patrick Calders, Prof. dr.; Phone Number: 0032498354766; Email: patrick.calders@ugent.be
• Study Contact Backup: Name: Sander Lefere, dr.; Email: sander.lefere@ugent.be

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Recruiting
    • Ghent University Hospital
    • Contact: Anja Geerts, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed with MASLD by ultrasound, CAP and/or biopsy
• Age between 18 and 75 years old
• No significant liver fibrosis (Fibroscan < 7.5 kPa; if it is between >7.5 and <10, there must be absence of liver fibrosis in the biopsy)

Exclusion Criteria:

• Presence of other liver diseases that may contribute to the clinical presentation in the patient
• Severe cardiovascular, orthopedic, physical or other illnesses that make it impossible to participate in the study's exercise rehabilitation program or where safety cannot be guaranteed
• Pregnancy
• Pharmacological treatment that directly affects MASLD (e.g. GLP-1 analogues)
• A change in medication in the last three months before the study that affects metabolic disease stability

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Combined strength + aerobic training; The patients in this group will exercise for 14 weeks. It is a combination of strength and aerobic exercise.	Other: Combined aerobic + strength training; Participants will follow a combination of endurance and strength training for 14 weeks. There will be three sessions every week: two at Ghent university department of rehabilitation and one at home. Each session will last approximately one hour.
Experimental: Combined strength + HIIT; The patients in this group will exercise for 14 weeks. The first 6 weeks consists of combined aerobic and strength exercise, following the protocol from the active comparator group. They will switch to combined strength and HIIT exercise for the remaining 8 weeks.	Other: Combined strength + HIIT training; 6 weeks of endurance training and strength training, 8 weeks of strength training and HIIT. Participants will follow the same combination of endurance and strength training for the first six weeks, to build up to a baseline level of physical fitness. They will then switch to eight weeks of a combination of strength training and High Intensity Interval Training (HIIT). There will be three sessions every week: two at Ghent university department of rehabilitation and one at home. Each session will last approximately one hour.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver steatosis by CAP	Liver stiffness measurement will be performed using vibration-controlled transient elastography, more specifically the Fibroscan. This method measures the fat accumulation in the liver (dB/m) and the level of scar tissue (kPa), represented as the CAP or steatosis score and the fibrosis score respectively.	before training and after training (14 weeks)
Liver steatosis on ultrasound	Ultrasound can demonstrate hepatic fatty tissue, estimating severity based on liver-kidney contrast, resolution loss thv the intrahepatic blood vessels, and visibility of the diaphragm. On this basis, a score 0-3 can be assigned.	before training and after training (14 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity	Insulin sensitivity will be assessed by calculation of the HOMA-IR index (fasting glucose x insulin)	before training and after training (14 weeks)
Liver transaminases	Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are enzymes located primarily in liver cells. An elevation of these enzymes in the bloodstream may indicate liver damage or inflammation.	before training and after training (14 weeks)
Maximal exercise test	A ramp protocol will be performed starting at 25 watts, adding 25 watts per minute each time. This test will be administered using ergospirometry to derive measures for aerobic physical condition.	before training and after training (14 weeks)
Strength	Strength will be measured by 1RM determination of the muscle groups that will be trained (leg press, adductors, vertical traction, chest press, abdominal and back muscles). This measurement will be performed at baseline, after 10 weeks and at the end of the study	before training and after training (14 weeks)
Cardiovascular function	Blood pressure measurements: Before and after exercise, systole and diastole blood pressure will be measured. Blood pressure will be measured three times and the average value recorded.	before training and after training (14 weeks)
Weight	Weight will be measured using a scale to the nearest 0.1 kilogram (kg).	before training and after training (14 weeks)
Heigth	Height will be measured to the nearest 0.1 meter (m) with a stadiometer.	before training and after training (14 weeks)
BMI	BMI will be calculated.	before training and after training (14 weeks)
waist	Waist circumference is measured in standing position with a measuring tape just above the iliac crest, to the nearest 0.1 centimeter (cm).	before training and after training (14 weeks)
BIA	Bioelectrical impedance analysis (BIA) will be performed to determine lean mass and fat percentage.	before training and after training (14 weeks)
Interleukine	IL-6 and IL-8 serum levels will be measured in blood. These are correlate with the progression of liver fibrosis and are elevated in patients with chronic liver disease.	before training and after training (14 weeks)
TNF-alfa	TNF-α is a pro-inflammatory cytokine produced by macrophages and will be measured in blood. Inflammation in NAFLD causes TNF-α to be released into the body. The amount is increased in patients with NAFLD and correlates with the level of fat mass and insulin resistance.	before training and after training (14 weeks)
Hepatokines	Hepatokines will be measured in blood. These are proteins secreted by the liver which have a demonstrated association with metabolic function/dysfunction. These include fetuin-A, FGF-21, follistatin etc.	before training and after training (14 weeks)
Myokines	Myokines will be measured in blood. These are proteins secreted by the muscle which have a demonstrated association with metabolic function/dysfunction. These include myostatin, brain-derived neurotrophic factor, etc....	before training and after training (14 weeks)
Adipokines	Adipokines will be measured in blood. These are proteins secreted by the adipose tissue which have a demonstrated association with metabolic function/dysfunction. These include leptin, adiponectin, etc.	before training and after training (14 weeks)
SF-36	Quality of life will be measured using SF-36 (a standard questionnaire).	before training and after training (14 weeks)

Collaborators and Investigators

• Sponsor: University Ghent
• Collaborators: University Hospital, Ghent
• Investigators: Principal Investigator: Patrick Calders, Prof. dr., University Ghent; Principal Investigator: Anja Geerts, Prof. dr., University Hospital, Ghent; Study Chair: Sander Lefere, dr., University Ghent

Publications and helpful links

General Publications

• Keating SE, Hackett DA, George J, Johnson NA. Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012 Jul;57(1):157-66. doi: 10.1016/j.jhep.2012.02.023. Epub 2012 Mar 10.
• Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H, Nago T, Takano Y, Ueno T, Koga H, George J, Shiba N, Torimura T. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review. J Hepatol. 2017 Jan;66(1):142-152. doi: 10.1016/j.jhep.2016.08.023. Epub 2016 Sep 14.
• Oh S, Tsujimoto T, Kim B, Uchida F, Suzuki H, Iizumi S, Isobe T, Sakae T, Tanaka K, Shoda J. Weight-loss-independent benefits of exercise on liver steatosis and stiffness in Japanese men with NAFLD. JHEP Rep. 2021 Feb 10;3(3):100253. doi: 10.1016/j.jhepr.2021.100253. eCollection 2021 Jun.
• Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Ledinghen V, Kumar M, Lupsor-Platon M, Han KH, Cardoso AC, Ferraioli G, Chan WK, Wong VW, Myers RP, Chayama K, Friedrich-Rust M, Beaugrand M, Shen F, Hiriart JB, Sarin SK, Badea R, Jung KS, Marcellin P, Filice C, Mahadeva S, Wong GL, Crotty P, Masaki K, Bojunga J, Bedossa P, Keim V, Wiegand J. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017 May;66(5):1022-1030. doi: 10.1016/j.jhep.2016.12.022. Epub 2016 Dec 28.

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2024
• Primary Completion (Estimated): March 15, 2026
• Study Completion (Estimated): March 15, 2026

Study Registration Dates

• First Submitted: February 1, 2024
• First Submitted That Met QC Criteria: April 5, 2024
• First Posted (Actual): April 11, 2024

Study Record Updates

• Last Update Posted (Actual): June 7, 2024
• Last Update Submitted That Met QC Criteria: June 6, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: exercise; liver diseases; MASLD
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Liver Diseases; Insulin Resistance
• Other Study ID Numbers: ONZ-2023-0453

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No