Author information

¹Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia. harrygcrane@gmail.com.

²Department of Gastroenterology and Hepatology, Royal North Shore Hospital, 1 Reserve Road, St Leonards, New South Wales, Australia. harrygcrane@gmail.com.

³Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.

⁴Department of Gastroenterology and Hepatology, Royal North Shore Hospital, 1 Reserve Road, St Leonards, New South Wales, Australia.

⁵Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, 6 Verdun Street, Nedlands, Perth, WA, 6009, Australia.

⁶Curtin Medical School, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, 6102, Australia.

Abstract

Hepatocellular carcinoma has a substantial global mortality burden which is rising despite advancements in tackling the traditional viral risk factors. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is the most prevalent liver disease, increasing in parallel with the epidemics of obesity, diabetes and systemic metabolic dysregulation. MAFLD is a major factor behind this sustained rise in HCC incidence, both as a single disease entity and often via synergistic interactions with other liver diseases. Mechanisms behind MAFLD-related HCC are complex but is crucially underpinned by systemic metabolic dysregulation with variable contributions from interacting disease modifiers related to environment, genetics, dysbiosis and immune dysregulation. MAFLD-related HCC has a distinct clinical presentation, most notably its common occurrence in non-cirrhotic liver disease. This is just one of several major challenges to effective surveillance programmes. The response of MAFLD-related HCC to immune-checkpoint therapy is currently controversial, and is further complicated by the high prevalence of MAFLD in individuals with HCC from viral aetiologies. In this review, we highlight the current data on epidemiology, clinical characteristics, outcomes and screening controversies. In addition, concepts that have arisen because of the MAFLD paradigm such as HCC in MAFLD/NAFLD non-overlapping groups, dual aetiology tumours and MAFLD sub-phenotypes is reviewed.