Jonathan Stine, MD: Exercise’s Benefit in MASH is Independent of Weight Loss

New research is calling attention to the value of exercise training for metabolic dysfunction-associated steatohepatitis (MASH) resolution, even in the absence of body weight loss.

Findings from the post hoc analysis of the NASHFit trial were presented at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) by Jonathan Stine, MD, MSc, an associate professor of medicine and public health science at Penn State University. In addition to the histological benefit of exercise, the study also provides novel evidence supporting the utility of the noninvasive MASH Resolution Index for discerning therapeutic response to lifestyle interventions.

Conducted from May 2018 to February 2021, NASHFit randomly assigned 28 adults 18-69 years of age with biopsy-proven MASH to receive either 150 minutes per week of moderate-intensity aerobic exercise training or standard of care for 20 weeks. Additionally, Mediterranean-informed dietary counseling was provided to each group.

Data was available to calculate the MASH Resolution Index in 23 participants (n = 15 exercise; n = 8 standard of care). The change in MASH Resolution Index was measured and compared between the groups. Investigators noted baseline characteristics were similar between the groups, which were well-matched for age, sex, BMI, metabolic comorbidities, and MASH stage.

Although no clinically significant weight loss (>5%) occurred in either group, applying the MASH Resolution Index, those who received exercise training achieved MASH resolution, defined as MASH Resolution Index ≥ −0.67, nearly 3 times more often than those who received standard of care (33% vs 13%; P <.01). Of note, each dynamic parameter of the MASH Resolution Index changed more significantly with exercise intervention.

Furthermore, exercise training participants experienced a 24% reduction in ALT (-14 ± 14 IU/L) compared with standard clinical care subjects, who had a 10% reduction in ALT (-6 ± 16 IU/L; P = .06). Exercise training also reduced absolute MRI-PDFF by -4.3% compared with a +1.2% gain with standard of care (P = .01).

For additional insight into the hepatic effects of exercise training in patients with MASH and what this research adds to our understanding of this topic in the context of weight loss, the editorial team of HCPLive Hepatology spoke with Stine in the following Q&A:

HCPLive: Even with an FDA-approved MASH therapeutic, what role do lifestyle interventions like exercise continue to play in disease management?

Stine: Lifestyle interventions, particularly exercise, continue to play a critical role in managing MASLD and MASH. While pharmacologic therapies are promising, exercise is a weight-neutral, non-invasive option that addresses metabolic risk integral to disease progression.

Our study's findings demonstrate that moderate-intensity aerobic exercise can lead to significant improvements in liver health, as measured by non-invasive MASH biomarkers, even without substantial weight loss. This highlights the potential of exercise to complement pharmacologic approaches, offering additional benefits in liver histology and overall metabolic health.

Regardless of how many FDA-approved drug treatments we will ultimately have, everyone living with MASLD and MASH will need to be engaged in leading a healthy lifestyle if they wish to be successful in improving their liver health.

HCPLive: Can you explain some of the limitations of liver biopsy and how this translates to a greater reliance on noninvasive biomarkers of histologic improvement?

Stine: Liver biopsy, while historically considered the gold standard for assessing liver histology, has several limitations. Because it is invasive, it carries risks of procedural complications, including pain, bleeding, and inadvertent organ injury. Liver biopsy results are also subject to sampling variability and interpretation differences among pathologists. Combined with cost, these factors make liver biopsy impractical for repeated monitoring in large populations, especially over shorter intervals.

Non-invasive biomarkers provide a safer, more scalable method for monitoring disease progression and treatment response, which is especially useful for individuals living with MASLD/MASH who require long-term disease management.

HCPLive: Prior to your study, what was known about exercise training’s impact on liver histology in relation to body weight loss? How did your research explore this concept?

Stine: Prior research, including several studies from our group, suggests that exercise could positively affect liver health by leading to clinically significant improvements in MRI-measured liver fat. When coupled with 7-10% weight loss, lifestyle intervention, including those which employ an exercise training program, are well known to lead to histologic improvement in MASH activity and liver fibrosis. However, the independent effect of exercise on liver histology without significant weight loss has remained unclear.

Our study aimed to address this gap by levering data from our previously completed NASHFit study which showed multiple benefits in liver and metabolic health without significant weight loss. This new post hoc analysis indicated that exercise could lead to MASH resolution, providing valuable evidence that exercise can have direct benefits on liver health beyond just promoting weight loss.

HCPLive: What were some of the key findings? What is their clinical significance?

Stine: The key findings from this study include a nearly threefold increase in MASH resolution rates among participants who engaged in 150 minutes per week of moderate-intensity aerobic exercise compared to those receiving standard care (33% vs. 13%). Additionally, guideline-based amounts of exercise training led to reductions in ALT levels and MRI-PDFF scores, which are indicators of liver inflammation and fat content, respectively.

Clinically, these findings suggest that exercise is a viable treatment option that can lead to histologic improvements without requiring weight loss. This could have a significant impact on treatment strategies for MASLD/MASH, particularly for patients unable to achieve substantial weight loss, offering us as providers a way to reframe our conversation with patients about the benefits of exercise training and moving beyond the focus on weight loss.

Reference

^{Stine J, Channapragrada T, Hummer B, et al. Aerobic exercise training leads to MASH resolution as defined by the MASH Resolution Index without body weight loss. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.}