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Review
. 2023 Aug;20(8):487-503.
doi: 10.1038/s41575-023-00754-7. Epub 2023 Mar 17.

Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment

Josep M Llovet  1   2   3 , Catherine E Willoughby  4 , Amit G Singal  5 , Tim F Greten  6 , Mathias Heikenwälder  7 , Hashem B El-Serag  8   9 , Richard S Finn  10 , Scott L Friedman  11
Affiliations
Review

Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment

Josep M Llovet et al. Nat Rev Gastroenterol Hepatol. 2023 Aug.

Abstract

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.

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Conflict of interest statement

Competing interests

J.M.L. received research support from Bayer HealthCare Pharmaceuticals, Eisai Inc., Bristol Myers Squibb, Boehringer-Ingelheim and Ipsen and consulting fees from Merck, Eli Lilly, Eisai Inc., Bayer HealthCare Pharmaceuticals, Bristol Myers Squibb, Exelixis, Ipsen, Genentech, Roche, Glycotest, Nucleix, Mina Alpha Ltd. and AstraZeneca. A.G.S. has served as a consultant or on advisory boards for Bayer, Eisai, Genentech, BMS, Exelixis, AstraZeneca, Wako Diagnostics, Exact Sciences, Roche, Glycotest, GRAIL and TARGET PharmaSolutions. H.B.E.-S. received research support from Glycotest, Gilead Sciences, Merck Sharp & Dohme BV and AbbVie. R.S.F. reports consulting fees from AstraZeneca, Bayer, CStone, BMS, Eisai, Exilixis, Eli Lilly, Pfizer, Merck, Roche/Genentech and Hengrui. S.L.F. is a consultant to 89 Bio, Amgen, Axcella Health, Blade Therapeutics, Bristol Myers Squibb, Can-Fite Biopharma, Casma Therapeutics, ChemomAb, Escient Pharmaceuticals, Forbion, Galmed, Gordian Biotechnology, Glycotest, Glympse Bio, Insitro, Morphic Therapeutics, North Sea Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Scholar Rock and Surrozen and has stock options (all less than 1% of company value) in Blade Therapeutics, Escient, Galectin, Galmed, Genfit, Glympse, Hepgene, Lifemax, Metacrine, Morphic Therapeutics, Nimbus, North Sea Therapeutics, Scholar Rock and Surrozen. All other authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. The global incidence of NASH-related HCC.
a, The estimated global incidence of hepatocellular carcinoma (HCC) per 100,000 people. b, The estimated global incidence of nonalcoholic steatohepatitis (NASH)-related HCC per 100,000 people,,,–. Please note that Fig. 1 is derived from data from studies with varying methodologies.
Fig. 2 |
Fig. 2 |. NASH-HCC pathogenesis and progression.
Contributing factors and mechanisms behind the pathogenesis from a healthy liver to nonalcoholic fatty liver disease (NAFLD) and subsequent hepatocellular carcinoma (HCC),,,,,,. NASH, nonalcoholic steatohepatitis; TH, T helper.
Fig. 3 |
Fig. 3 |. ICIs for advanced HCC: summary of subgroup analyses of HBV versus HCV versus non-viral HCC in key phase III studies.
Meta-analyses of trials expanding on data previously reported about three randomized controlled trials (RCTs) in ref. . Two meta-analyses are reported, one involving single-agent immune-checkpoint inhibitor (ICI) therapy with or without targeted therapies (IMbrave150 (ref. ), CheckMate 459 (ref. ), KEYNOTE-240 (ref. ) and COSMIC-312 (ref. ) trials; four RCTs) and the other including five studies (previous four plus HIMALAYA), testing combinations of ICIs. P*, indicates P of heterogeneity. For single RCT subgroup analysis according to aetiology, see Supplementary Figure 1.
See this image and copyright information in PMC

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