Highlight
• Weight gain greater than 5% in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is significantly associated with increased risk of liver-related events (LREs) and progression of liver stiffness.
• Weight loss exceeding 5% correlates with liver stiffness improvement and may decrease LRE risk, particularly in patients achieving obesity reversal.
• Transitioning into or persisting with obesity heightens LRE risks, whereas reverting from obesity to non-obesity aligns risk similarly to persistent non-obese individuals.
• Adjusted analyses accounted for critical confounders including baseline BMI, diabetes, hypertension, liver stiffness measurement (LSM), steatosis assessment (CAP), and specific antidiabetic therapies (SGLT-2 inhibitors, GLP-1 receptor agonists).
Study Background
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), represents a spectrum of liver pathologies characterized by excessive hepatic fat accumulation associated with metabolic risk factors such as obesity, type 2 diabetes (T2D), and hypertension. MASLD prevalence has been rising globally in parallel with obesity and metabolic syndrome. Liver-related complications—progression to fibrosis, cirrhosis, and hepatocellular carcinoma—as well as cardiovascular morbidity, make effective management imperative. Currently, body weight control remains the cornerstone of MASLD treatment as weight loss can reverse steatosis and improve liver histology. However, the longitudinal impact of dynamic weight changes, including weight gain and obesity status transitions, on hard clinical outcomes like liver-related events (LREs) and noninvasive markers of liver fibrosis (such as liver stiffness) in MASLD remains incompletely defined. This large multicenter study aims to elucidate these associations to inform clinical monitoring and intervention strategies.
Study Design
This observational cohort study enrolled 10,014 adult MASLD patients drawn from 16 tertiary referral centers. Eligibility required at least two weight assessments, enabling longitudinal evaluation. The median interval between measurements was approximately 29.2 months, with subsequent follow-up averaging 12.4 months after the final weight measurement to observe incident liver-related events. Weight changes were categorized as stable (≤5% change), weight loss (>5% decrease), or weight gain (>5% increase). Obesity status transitions were also tracked across four groups: persistent non-obesity, persistent obesity, transition from non-obesity to obesity, and transition from obesity to non-obesity. Covariates adjusted in multivariable models included age, sex, ethnicity, baseline body mass index (BMI), hypertension, type 2 diabetes, liver stiffness measurement (LSM), controlled attenuation parameter (CAP) for hepatic steatosis, and usage of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs). The main outcomes were incidence of liver-related events (including liver failure, decompensation, and hepatocellular carcinoma) and changes in liver stiffness as a surrogate for fibrosis progression or regression.
Key Findings
Over the follow-up period, 123 liver-related events occurred among the cohort. Compared with stable weight, patients experiencing weight gain greater than 5% showed significantly increased risk for LREs, with an adjusted hazard ratio (aHR) of 1.84 (95% confidence interval [CI]: 1.01-3.09; p=0.020). Similarly, weight gain was strongly associated with progression of liver stiffness (adjusted odds ratio [aOR]=2.07; 95% CI: 1.55-2.74; p<0.001), indicating worsening fibrosis or liver damage. Conversely, weight loss greater than 5% was linked to improved liver stiffness, suggesting fibrosis regression or reduced liver injury risk.
Regarding obesity status, patients who remained obese or transitioned from non-obese to obese status had higher risks of liver-related events. Critically, patients who reversed obesity (transitioned from obese to non-obese) demonstrated a risk comparable to those persistently non-obese, with an aHR of 1.44 (95% CI: 0.57-3.61; p=0.435), suggesting that obesity reversal mitigates LRE risk. These findings underline the dynamic effect of weight and obesity status changes on clinical outcomes independent of baseline metabolic and liver parameters.
Expert Commentary
This well-powered, multicenter study robustly reinforces the clinical imperative of weight management in MASLD beyond static assessments, emphasizing the prognostic significance of longitudinal weight trends. The use of objective noninvasive fibrosis measures (liver stiffness) and clinically meaningful endpoints (LREs) enhances the study’s translational relevance. Adjusting for diabetes and use of novel antidiabetic agents with known hepatic benefits strengthens confidence in the independent association of weight dynamics with liver outcomes.
Notably, findings align mechanistically with the established pathophysiology of MASLD whereby excess adiposity drives hepatic inflammation, fibrogenesis, and carcinogenesis. Weight gain exacerbates metabolic overload and hepatic injury, whereas weight loss ameliorates these pathways, potentially reversing fibrosis and lowering event risk. The demonstrated equivalence of obesity reversal with stable non-obese status for LRE risk offers pragmatic clinical insight: effective weight normalization should be a therapeutic target.
Study limitations include the observational design that, while adjusted for numerous confounders, cannot confirm causality. The relatively short follow-up for events and lack of histological fibrosis staging are acknowledged limitations but are mitigated by use of validated noninvasive markers and robust statistical methods. Future prospective intervention studies with longer follow-up and mechanistic biomarker profiling could further elucidate these associations.
Conclusion
In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), dynamic weight changes are critically linked to clinical liver outcomes. Weight gain significantly increases the risk of liver-related events and promotes liver fibrosis progression, whereas weight loss confers beneficial effects on liver stiffness and may lower adverse outcomes, especially in those achieving obesity reversal. These data emphasize the importance of longitudinal weight monitoring and targeted therapeutic strategies to achieve and maintain weight loss to improve prognosis in MASLD. Integrating weight management with comprehensive metabolic control and emerging pharmacotherapies remains essential for personalized MASLD care.
Funding and Disclosures
The study was conducted by the VCTE-Prognosis Study Group with support from participating institutions across multiple countries. No specific funding or conflicts of interest were detailed in the abstract.
References
Shi Y, Zhou R, Kim SU, et al. Association between longitudinal weight change and clinical outcome in individuals with MASLD. Hepatology. 2025;84(2):514-528. PMID: 41061041.
European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2021;75(3):659-689.
Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of NAFLD: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357.
