Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation, nonalcoholic steatohepatitis (NASH), has a global prevalence of 20–25% and is a major public health problem. Its incidence is increasing in parallel to the rise in obesity, diabetes and metabolic syndrome. Progression from NASH to NASH-related hepatocellular carcinoma (HCC) (~2% of cases per year) is influenced by many factors, including the tissue and immune microenvironment, germline mutations in PNPLA3 , and the microbiome. NASH-HCC has unique molecular and immune traits compared with other aetiologies of HCC and is equally prevalent in men and women. Comorbidities associated with NASH, such as obesity and diabetes mellitus, can prevent the implementation of potentially curative therapies in certain patients; nonetheless, outcomes are similar in patients who receive treatment. NASH-HCC at the early to intermediate stages is managed with surgery and locoregional therapies, whereas advanced HCC is treated with systemic therapies, including anti-angiogenic therapies and immune-checkpoint inhibitors. In this Review, we present the latest knowledge of the pathogenic mechanisms and clinical management of NASH-HCC. We discuss data highlighting the controversy over varying responses to immune-checkpoint inhibitors according to underlying aetiology and suggest that the future of NASH-HCC management lies in improved surveillance, targeted combination therapies to overcome immune evasion, and identifying biomarkers to recognize treatment responders. In this Review, Llovet and colleagues discuss advances in our knowledge of the pathogenesis and clinical management of nonalcoholic steatohepatitis-related hepatocellular carcinoma. They also discuss future prospects and unmet needs. Key points Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is a major public health problem, the incidence of which is increasing in parallel to the rise in obesity, diabetes and metabolic syndrome. Progression from NASH to NASH-HCC occurs at an approximate rate of 2% per year and is influenced by many factors, including the tissue and immune microenvironment, germline mutations in PNPLA3 , and the microbiome. HCC surveillance in these at-risk patients with NASH-related cirrhosis is associated with earlier detection and improved survival. NASH-HCC in the early to intermediate stages is managed with surgery and locoregional therapies; however, comorbidities associated with NASH, suc