Acceptability and Feasibility of a New Approach to Engage Patients With Steatotic Liver Disease in Physical Activity

Background and rationale: This pilot trial aims to evaluate the feasibility and acceptability of a counselling intervention on physical activity in patients with liver steatosis (primary aim) and changes in molecular outcomes (exploratory aim).

Liver steatosis is the build-up of fat in the form of lipid droplets inside hepatocytes (liver cells). Although it is a form of energy storage, it is considered pathological when more than 5% of hepatocytes demonstrate fat infiltration on a liver biopsy or imaging (ultrasound, magnetic resonance, or computed tomography). Until recently, liver steatosis was described as two entities with a clinicopathological continuum: non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) i.e. NAFLD with inflammation. NAFLD/NASH is strongly associated with features of the metabolic syndrome: type 2 diabetes mellitus (DM), hyperlipidemia, and obesity. Insulin resistance is considered one of the first steps to developing fatty liver infiltration. Indeed, 70% to 80% of patients with diabetes have NASH. A recent change in nomenclature now accounts for the link with cardiometabolic criteria. NAFLD is now MASLD (metabolic dysfunction-associated steatotic liver disease) i.e. steatosis and at least 1 cardiometabolic factor and NASH is MASH (metabolic dysfunction-associated steatohepatitis) i.e. MASLD with inflammation, regrouped as steatotic liver disease (SLD).

SLD is a silent disease: patients have no symptoms, are not routinely screened for the disease, and SLD is often revealed through complications of cirrhosis, at a late stage for intervention. Inflammation is confirmed when liver function tests alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are elevated. It is recommended to assess the level of associated fibrosis through non-invasive tests such as elastography that evaluates liver stiffness that increases with fibrosis, or algorithms such as Fibrosis-4 (FIB-4) that combines age, ALT, AST, and platelets count to identify fibrosis in patients over 35 years old. The SLD burden is expected to increase. An estimated 30% of the population worldwide has MASLD and 5% of Canadians have MASH (2). A Canadian study concluded that the number of people with post-MASH decompensated cirrhosis will double by 2030 and cases of liver cancer will increase by 80 % (2). MASH is a leading cause of liver transplantation in Canada (2). Despite extensive research with currently over 1350 active clinical trials (clinicaltrials.gov, accessed 19/09/2023), there is no cure for SLD, and the treatment relies on diet, weight loss, and physical activity (PA). The current North American guidelines state that patients with NAFLD should be strongly encouraged to engage in PA to the extent possible.

The effects of PA on SLD have been studied extensively. A systematic review (3) showed personalized PA improved the quality of life for cirrhotic patients without significant side effects and may reduce the 90-day readmission rates for transplant patients at the end of the program. Henri et al. showed US NAFLD adults who engaged in vigorous PA have a lower risk of death from cancer and all causes than NAFLD adults who do not engage in any PA; benefits persisted for low PA and any PA versus no PA (4). Similarly, a US study showed PA is inversely associated with NALFD and associated with better survival for NALFD patients (5). PA is also successful in preventing DM, which is now included in the MASH definition (6). Moreover, meta-analyses have concluded that PA contributes to decreasing levels of various biological markers of SLD (7), (8) and inflammatory markers (9), thus reducing intra-hepatic fat (10), (11), (12), (13). PA is thus efficacious in reducing inflammation and fibrosis in patients with SLD. However, key knowledge gaps remain including (1) scarce data on the impact of sustained PA in MASH patients, especially post-participation in studies, (2) lack of consistency in terms of eligibility criteria that are often too narrow and exclude patients seen in practice, (3) heterogeneous PA parameters (e.g., dosage, type, duration), and (4) variability of biological data collected. It is thus difficult to precisely define through meta-analyses and/or systematic reviews the optimal program to help support PA or its duration. Another critical gap is what is the influence of interventions that aim to have patients initiate and maintain PA on their own. This is important because in reality, it is not possible (or sustainable) to offer patients supervised PA sessions in the amount that is commensurate with current PA guidelines, considering patients have their own barriers to PA and the lack of support to help them initiate and maintain PA in everyday life. Indeed, from discussions with patients during clinical evaluation with Dr. Fresne, some barriers are lack of time, insufficient knowledge, fear of injury, and lack of financial resources. In the literature, perceived lack of resources and education, physical discomfort or limitations or pain, lack of space, and time constraints have been identified as barriers for PA (13),(14), (15).

We believe individualized support and guidance to help patients progressively engage in more PA is a better results-oriented sustainable approach than delivering supervised PA training sessions and propose a personalized counselling intervention to engage patients with SLD in PA.