Unveiling the Role of Obesity in MASLD Progression

Obesity-related liver disease is a growing contributor to chronic liver pathology worldwide. As the prevalence of type 2 diabetes and central obesity increases, liver dysfunction now frequently occurs in the absence of alcohol or viral hepatitis.

The updated classification of steatotic liver disease, introduced through a 2023 consensus, defines metabolic dysfunction-associated steatotic liver disease (MASLD) as the most prevalent subtype. Current estimates place its global adult prevalence at 38%, with projections suggesting it may affect over half of the world’s population by 2040. These increases correspond with the sustained global rise in obesity and type 2 diabetes mellitus (T2DM), both identified as principal contributors to MASLD risk.

To examine this further, a review published in the Journal of Diabetes and Metabolic Disorders in October 2025 assessed how excess adiposity mechanistically accelerates the progression of MASLD from hepatic fat accumulation to cirrhosis and cancer.

Here’s a quick look at its findings.

Mechanisms Linking Obesity to Liver Injury

The review outlines insulin resistance as a primary pathway connecting obesity to hepatic lipid accumulation. The disruption of glucose and lipid metabolism caused by insulin resistance increases lipolysis, circulating non-esterified fatty acids, and hepatic lipid accumulation. Dysfunctional adipose tissue also contributes to MASLD via altered adipokine signaling, tissue hypoxia, and systemic inflammation, all of which promote hepatic steatosis, lipotoxicity, oxidative stress, and initiate pathways leading to fibrosis.

The lipotoxicity and oxidative stress further impair hepatocyte integrity, activating hepatic stellate cells and fibrotic signaling networks. These mechanisms are supported by studies showing elevated liver stiffness in populations with metabolic abnormalities, and by histologic evidence of progressive injury in individuals with obesity and MASLD.

Diagnostic Tools and Clinical Gaps

Diagnostic limitations are noted throughout the study. Liver biopsy remains the historical reference standard for staging, but its invasiveness has led to increased reliance on noninvasive imaging techniques.

Serum markers such as ALT and AST offer limited specificity; however, magnetic resonance elastography (MRE) demonstrates the highest accuracy for detecting advanced fibrosis but is limited by cost and availability. Vibration-controlled transient elastography (VCTE) shows comparable prognostic value and is more accessible. 

Composite indices, including the Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI), are described as potentially useful tools for screening in non-specialist settings, though none currently serve as definitive diagnostic endpoints for intermediate-stage fibrosis.

Systemic Implications Beyond the Liver

The systemic nature of MASLD is addressed in relation to cardiovascular, renal, and endocrine comorbidities. Cardiovascular disease remains the leading cause of death among individuals with MASLD, with meta-analyses indicating a significantly elevated risk for both fatal and non-fatal events.

Renal involvement is also prevalent, with the incidence of chronic kidney disease increasing in parallel with the degree of hepatic fibrosis. T2DM is both a risk factor for MASLD and a condition worsened by its presence, complicating glycemic control and elevating the likelihood of vascular complications.

Interventions and Emerging Therapies

Lifestyle modification is outlined as the primary intervention. Data suggest that even modest weight reduction can reduce hepatic fat content, improve insulin sensitivity, and reverse early stages of fibrosis. Among dietary strategies, the Mediterranean diet is associated with improved liver-related outcomes and greater adherence.

Pharmacological treatments are in development. The recent approval of resmetirom, a selective thyroid hormone receptor-β agonist, marks the first targeted pharmacotherapy for non-cirrhotic MASH. Early-phase trials of GLP-1 receptor agonists and fibroblast growth factor analogs suggest potential utility in reducing liver fat and fibrosis, though data are still emerging. Bariatric surgery is discussed as an intervention for selected patients.

Public Health and Clinical Priorities

The review positions obesity not as a comorbidity but as a central factor in the initiation and progression of MASLD. Without addressing adiposity and its metabolic consequences, clinical interventions are unlikely to alter the long-term trajectory of disease.

Although pharmacological options are expanding, access remains uneven, and many agents are not approved for individuals with advanced fibrosis or cirrhosis. This underscores the importance of early identification and risk stratification in primary care, where most cases are currently missed due to lack of routine screening. Public health strategies addressing obesity prevention and treatment remain central to altering the epidemiology of MASLD and limiting its transition to end-stage liver disease.

Reference:
Nowak K, Paluch M, Cudzik M, Syska K, Gawlikowska W, Janczura J. From steatosis to cirrhosis: the role of obesity in the progression of liver disease. J Diabetes Metab Disord. 2025;24(2):227. doi:10.1007/s40200-025-01754-x