Key Risk Factors Driving MASLD Across Populations: Insights from Metabolic and Clinical Data

A new study using data from the All of Us Research Program has identified key metabolic risk factors driving metabolic dysfunction-associated steatotic liver disease (MASLD) across diverse populations in the United States, highlighting obesity, insulin resistance, and Type 2 diabetes as central contributors to the disease’s development, and progression.

The research, published in the Journal of Clinical and Translational Science, analyzed electronic health records and clinical data from a large, nationally representative cohort to assess the prevalence and risk profiles associated with MASLD, formerly known as non-alcoholic fatty liver disease (NAFLD). Findings confirm that metabolic dysfunction — particularly excess body weight and impaired glucose metabolism — plays a dominant role in the onset of liver fat accumulation, inflammation, and fibrosis, even in the absence of significant alcohol use.

According to the study, individuals with obesity were significantly more likely to exhibit signs of MASLD, including elevated liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as imaging evidence of hepatic steatosis. The presence of Type 2 diabetes further increased the likelihood of advanced liver pathology, including metabolic dysfunction-associated steatohepatitis (MASH) and early-stage fibrosis.

Insulin resistance emerged as a consistent predictor across age, sex, and racial and ethnic groups, underscoring its role as a core biological mechanism linking systemic metabolic health to liver outcomes. Researchers noted that even modest improvements in insulin sensitivity were associated with reduced liver fat content and improved enzyme profiles in follow-up assessments.

The study also examined the influence of comorbid conditions such as hyperlipidemia, hypothyroidism, and obstructive sleep apnea, all of which showed statistically significant associations with MASLD prevalence. However, the strength of these links was consistently secondary to the primary drivers of obesity and insulin dysregulation.

Researchers emphasized that MASLD remains underdiagnosed in clinical practice due to its often asymptomatic nature in early stages. Many individuals progress to more severe liver disease before symptoms such as fatigue, abdominal discomfort, or unexplained weight loss prompt medical evaluation. The use of routine blood tests — including ALT, AST, alkaline phosphatase, and gamma-glutamyl transferase (GGT) — combined with risk factor screening, was highlighted as a practical approach for early detection in primary care settings.

Public health experts cited in related analyses warn that without broader screening and lifestyle intervention strategies, the global burden of MASLD is expected to rise in tandem with increasing rates of metabolic syndrome. Projections suggest that by 2030, the number of people living with advanced MASLD-related liver disease could increase significantly, particularly in regions experiencing rapid urbanization and dietary shifts toward processed foods and sedentary lifestyles.

The study’s reliance on the All of Us Research Program — a longitudinal initiative aimed at gathering health data from one million or more participants reflecting the diversity of the U.S. Population — allowed researchers to analyze trends across underrepresented groups, including Hispanic, Black, and rural communities, where MASLD prevalence has historically been higher but less studied.

While the findings reinforce the importance of metabolic health in liver disease prevention, researchers cautioned that the study was observational and cannot establish direct causation between individual risk factors and disease outcomes. They called for future longitudinal and interventional studies to determine whether targeted treatments for insulin resistance or weight management can reliably prevent MASLD progression in high-risk populations.

As MASLD continues to emerge as a leading cause of chronic liver disease worldwide, the study underscores the need for integrated care approaches that address obesity, diabetes, and metabolic syndrome not as isolated conditions, but as interconnected drivers of liver health. Early identification and management of these risk factors remain the most effective strategies for reducing the long-term burden of MASLD on individuals and healthcare systems.