Risk Assessment and Prediction of Hepatocellular Carcinoma in Noncirrhotic Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading driver of hepatocellular carcinoma (HCC) worldwide. A substantial proportion of MASLD-related HCC arises in the noncirrhotic liver, highlighting critical gaps in current surveillance strategies that rely primarily on fibrosis stage to define risk. Although the annual incidence of HCC in noncirrhotic MASLD is low and does not justify universal surveillance, the extraordinary global prevalence of MASLD translates into a considerable absolute burden of cancer. Accumulating evidence demonstrates that HCC risk in MASLD is modulated not only by histologic severity but also by metabolic comorbidities, particularly type 2 diabetes mellitus, which can significantly amplify cancer risk even in pre-cirrhotic stages. From both clinical and health economic perspectives, these observations underscore the need for more complex and targeted surveillance approaches. This review synthesizes current epidemiologic data, metabolic and histologic modifiers of HCC risk, emerging biomarkers, and predictive models in MASLD, with a focus on noncirrhotic disease. We discuss how integrated, precision-based risk assessment may identify high-risk MASLD subgroups and enable targeted, cost-effective surveillance strategies to mitigate the growing burden of MASLD-associated HCC.