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Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment

Nature Reviews Gastroenterology & Hepatology volume 20, pages 487–503 (2023)Cite this article

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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.

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, such as obesity and type 2 diabetes mellitus, can complicate the implementation of potentially curative therapies.

  • Advanced NASH-HCC is treated with systemic therapies, including anti-angiogenic therapies and immune-checkpoint inhibitors. Distinct microenvironmental factors could be limiting the response of NASH-HCC to immunotherapy.

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Fig. 1: The global incidence of NASH-related HCC.
Fig. 2: NASH-HCC pathogenesis and progression.
Fig. 3: ICIs for advanced HCC: summary of subgroup analyses of HBV versus HCV versus non-viral HCC in key phase III studies.

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Data availability

For the data underlying the meta-analyses reported in Fig. 3, see Supplementary Figure 1.

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Acknowledgements

The authors acknowledge U. Balaseviciute and J. Huguet Pradell (Translational Research in Hepatic Oncology, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona), and F. Castet (Gastrointestinal and Endocrine Tumour Unit, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona) for their help in preparing the original versions of the figures for this manuscript.

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Authors and Affiliations

  1. Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Josep M. Llovet & Scott L. Friedman

  2. Translational Research in Hepatic Oncology, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain

    Josep M. Llovet & Catherine E. Willoughby

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain

    Josep M. Llovet

  4. Department of Internal Medicine, University of Texas Southwestern (UTSW) Medical Centre, Dallas, TX, USA

    Amit G. Singal

  5. Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA

    Tim F. Greten

  6. Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Mathias Heikenwälder

  7. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Hashem B. El-Serag

  8. Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    Hashem B. El-Serag

  9. Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Richard S. Finn

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Contributions

Introduction (J.M.L. and S.L.F.); Epidemiology (H.B.E.-S.); Pathogenesis (S.L.F.); Molecular features (T.F.G., M.H. and C.E.W.); Surveillance and prevention (A.G.S. and C.E.W.); Locoregional therapies (A.G.S.); Systemic therapies (J.M.L. and R.S.F.); Future prospects (J.M.L. and R.S.F.); Boxes (C.E.W., R.S.F. and T.F.G.); Figures (C.E.W.); and Tables (C.E.W. and A.G.S.).

Corresponding author

Correspondence to Josep M. Llovet.

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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.

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Nature Reviews Gastroenterology & Hepatology thanks Jean-Francois Dufour, James Harding and Frank Tacke for their contribution to the peer review of this work.

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Llovet, J.M., Willoughby, C.E., Singal, A.G. et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol 20, 487–503 (2023). https://doi.org/10.1038/s41575-023-00754-7

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