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From NASH to HCC: current concepts and future challenges

Abstract

Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.

Key points

  • Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver disease that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and is strongly associated with metabolic syndrome.

  • NAFLD dramatically increases the prevalence of hepatocellular carcinoma (HCC) development; however, the increased HCC risk of patients with NAFLD is often misdiagnosed.

  • The degree of fibrosis is considered the strongest predictive factor for correlating the progression of NAFLD with life-threating complications.

  • Several factors contribute to the development of NAFLD or NASH and subsequent HCC development; these factors include genetic and environmental modifiers such as diet or lifestyle.

  • The pathogenesis of NAFLD-associated HCC is a complex landscape composed of mechanisms involved in immune and inflammatory responses, DNA damage, oxidative stress and autophagy.

  • Currently, the diagnosis of NAFLD-associated HCC depends on imaging, whereas proper HCC staging is necessary for the evaluation of prognosis.

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Fig. 1: The sequential pathophysiological states of NAFLD and HCC.
Fig. 2: Environmental and gut-derived factors in NASH pathogenesis and the increased risk of liver tumorigenesis.
Fig. 3: Metabolic reprogramming and tumorigenesis induced by adaptive and innate chronic inflammation of the liver.
Fig. 4: Staging and treatment options for patients with HCC.
Fig. 5: Different treatment options for NASH-associated liver cancer development.

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Acknowledgements

Q.M.A., O.G. and H.L.R. are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Programme of the European Union under Grant Agreement 634413 and the Newcastle National Institute for Health Research Biomedical Research Centre. At the Northern Institute for Cancer Research, H.L.R. is supported by the Bobby Robson Foundation, Cancer Research UK (CRUK) Newcastle Experimental Cancer Medicine Centre award C9380/A18084 and CRUK programme grant C18342/A23390. This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme (no. 667273/HEPCAR) to M.H.; a European Research Council Consolidator grant ‘HepatoMetaboPath’; the MOST (Ministry of Science and Technology) programme; Research Foundation Flanders (FWO) under grant 30826052 (EOS Convention MODEL-IDI); the Sonderforschungsbereiche (SFB) Transregio (TR) SFB/TR179, 209 and SFB1335 to M.H.; Graduiertenkolleg (GRK482) to E.K. and M.H.; and the German Cancer Research Center (DKFZ)–MOST cooperation program to M.H.

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Nature Reviews Gastroenterology & Hepatology thanks M. Machado and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Anstee, Q.M., Reeves, H.L., Kotsiliti, E. et al. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 16, 411–428 (2019). https://doi.org/10.1038/s41575-019-0145-7

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