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Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention

  • Review Article
  • Published:

From Nature Reviews Gastroenterology & Hepatology

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Abstract

One quarter of the global population is estimated to have nonalcoholic fatty liver disease (NAFLD). The incidence of nonalcoholic steatohepatitis (NASH) is projected to increase by up to 56% in the next 10 years. NAFLD is already the fastest growing cause of hepatocellular carcinoma (HCC) in the USA, France and the UK. Globally, the prevalence of NAFLD-related HCC is likely to increase concomitantly with the growing obesity epidemic. The estimated annual incidence of HCC ranges from 0.5% to 2.6% among patients with NASH cirrhosis. The incidence of HCC among patients with non-cirrhotic NAFLD is lower, approximately 0.1 to 1.3 per 1,000 patient-years. Although the incidence of NAFLD-related HCC is lower than that of HCC of other aetiologies such as hepatitis C, more people have NAFLD than other liver diseases. Urgent measures that increase global awareness and tackle the metabolic risk factors are necessary to reduce the impending burden of NAFLD-related HCC. Emerging evidence indicates that reduced immune surveillance, increased gut inflammation and gut dysbiosis are potential key steps in tumorigenesis. In this Review, we discuss the global epidemiology, projections and risk factors for NAFLD-related HCC, and propose preventive strategies to tackle this growing problem.

Key points

  • Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis and nonalcoholic steatohepatitis (NASH); NASH can be progressive and predisposes individuals to the development of fibrosis and cancer.

  • NAFLD-related hepatocellular carcinoma (HCC) can develop in the absence of cirrhosis.

  • NAFLD is the fastest growing cause of HCC in many parts of the world, including the USA and parts of Europe.

  • The incidence of NAFLD-related HCC is projected to increase dramatically by 2030, with increases of 82%, 117% and 122% from 2016 in China, France and the USA, respectively.

  • Diabetes is the most important risk factor for HCC development in patients with NAFLD; thus, screening and early treatment are essential.

  • Dysregulation of the gut microbiota and reduced immune surveillance are two new mechanisms that have been implicated in NAFLD hepatocarcinogenesis, and further research is warranted.

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Fig. 1: The estimated proportion of HCC attributed to NAFLD.
Fig. 2: Pathogenesis and prevention of NAFLD-related HCC.
Fig. 3: Proposed algorithm for HCC screening in NAFLD.

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Acknowledgements

The authors acknowledge K.H. Sippel and S.M. Kim for reading the manuscript and providing comments. R.L. receives funding support from NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (U01DK061734, R01DK106419, P30DK120515, R01DK121378, R01DK124318), NHLBI (P01HL147835), and DOD PRCRP (W81XWH-18-2-0026). D.Q.H. receives funding support from Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship and Exxon Mobil-NUS Research Fellowship for Clinicians. H.B.E.-S. receives funding support from the Department of Veterans Affairs (5I01CX001616-04), the Cancer Prevention and Research Institute of Texas (grant RP150587) and the National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK 56338).

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore

    Daniel Q. Huang

  2. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Daniel Q. Huang

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

    Hashem B. El-Serag

  4. Section of Gastroenterology, Michael E. DeBakey VA Medical Center, Houston, TX, USA

    Hashem B. El-Serag

  5. Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    Hashem B. El-Serag

  6. Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Hashem B. El-Serag

  7. Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, CA, USA

    Rohit Loomba

  8. NAFLD Research Center, Division of Gastroenterology. University of California at San Diego, La Jolla, CA, USA

    Rohit Loomba

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  1. Daniel Q. Huang
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All authors researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission.

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Correspondence to Rohit Loomba.

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Competing interests

R.L. serves as a consultant or advisory board member for Anylam/Regeneron, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen Inc., Merck, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Promethera, Sagimet, 89 bio, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer Ingelheim, Bristol Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, pH Pharma, and Siemens. He is also co-founder of Liponexus, Inc.

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Huang, D.Q., El-Serag, H.B. & Loomba, R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 18, 223–238 (2021). https://doi.org/10.1038/s41575-020-00381-6

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