The versatile interplay between steatotic liver disease and liver cancer.

This article is a narrative review of how steatotic liver diseases drive hepatocarcinogenesis and how this should inform risk assessment and management.

Key points:

1. Disease spectrum and terminology

   • • Steatotic liver diseases include metabolic dysfunction-associated steatotic liver disease (MASLD) and alcoholic liver disease.
   • • Severe forms are metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic steatohepatitis (ASH).
   • • Mixed etiologies are increasingly recognized as metabolic dysfunction and alcohol-associated liver disease.
   • • These conditions are now a leading cause of chronic hepatitis, liver dysfunction, cirrhosis, and liver cancer.

2. Shared versus distinct features in MASH- and ASH-related liver cancer

   • • Liver cancers arising from MASH and ASH share overlapping histopathologic features.
   • • Despite this, the cellular and molecular mechanisms driving cancer development differ between metabolic and alcohol-related injury.
   • • This has implications for pathogenesis, biomarker development, and tailored therapy.

3. Heterogeneity of SLDs

   • • SLDs are not a single disease entity but a heterogeneous group with:
   • • Distinct metabolic, immunologic, and genetic profiles.
   • • Strong modulation by lifestyle factors and comorbidities (e.g., obesity, diabetes, cardiovascular risk).
   • • This heterogeneity affects both progression to cancer and response to therapies.

4. Mechanisms of progression to liver cancer

   • • The review synthesizes current knowledge on:
   • • Molecular changes (e.g., signaling pathways and metabolic reprogramming) associated with chronic steatosis and inflammation.
   • • Genetic and epigenetic alterations that accumulate from MASH or ASH to malignancy.
   • • Cellular contributors, including hepatocytes, stromal cells, and immune cells, in sustaining chronic injury and tumor promotion.

5. Risk assessment in SLD-related liver cancer

   • • Emerging tools and concepts for liver cancer risk stratification in SLDs are summarized.
   • • The review highlights that standard cirrhosis-based risk models are inadequate for the full SLD spectrum, particularly given non-cirrhotic HCC in metabolic disease.
   • • It emphasizes the search for better clinical, biochemical, imaging, and molecular markers to refine surveillance strategies.

6. Diagnostic challenges

   • • There are practical obstacles in distinguishing MASH-related from ASH-related carcinogenesis, particularly in patients with mixed metabolic and alcohol exposures.
   • • Overlapping histology and under-reporting of alcohol intake complicate etiologic classification and may blur therapeutic decisions and trial design.

7. Therapeutic implications and current developments

   • • The review discusses how the unique biology of SLD-related liver cancers may influence:
   • • Response to systemic therapies (e.g., immunotherapy, targeted agents).
   • • The design of etiologically informed treatment algorithms.
   • • It outlines ongoing developments in medical management of underlying MASH/ASH, and how modifying the underlying liver disease may alter cancer risk and outcomes.

Overall, the article underscores that liver cancers arising in the context of steatotic liver diseases are etiologically and biologically distinct, requiring refined risk assessment, improved differential diagnosis, and increasingly etiology-tailored prevention and treatment strategies.