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NAFLD, NASH and liver cancer

Nature Reviews Gastroenterology & Hepatology volume 10, pages 656–665 (2013)Cite this article

Subjects

Abstract

NAFLD affects a large proportion of the US population and its incidence and prevalence are increasing to epidemic proportions around the world. As with other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. The incidences of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are also rising, and HCC is now the leading cause of obesity-related cancer deaths in middle-aged men in the USA. In this Review, we summarize the correlations between liver cancer and NAFLD-related cirrhosis, and the role of the metabolic syndrome in the development of liver cancer from diverse aetiologies, including HCV-mediated cirrhosis. Recent advances in understanding the progression of NAFLD to HCC from preclinical models will also be discussed. Targeted genetic manipulation of certain metabolic or stress-response pathways, including one-carbon metabolism, NF-κB, PTEN and microRNAs, has been valuable in elucidating the pathways that regulate carcinogenesis in NAFLD. Although tremendous advances have occurred in the identification of diagnostic and therapeutic opportunities to reduce the progression of NAFLD, considerable gaps in our knowledge remain with regard to the mechanisms by which NAFLD and its risk factors promote liver cancer.

Key Points

  • NAFLD is strongly associated with obesity and the metabolic syndrome; as with these conditions, the incidence and prevalence of NAFLD are increasing to epidemic proportions

  • Similar to other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer

  • Liver cancers generally arise after NAFLD-related cirrhosis has developed, but can also occur in patients with NAFLD before cirrhosis ensues

  • The metabolic syndrome increases the risk of liver cancer in individuals with other liver diseases (for example, cirrhosis caused by chronic HCV infection)

  • Targeted genetic manipulation of certain metabolic or stress-response pathways causes NAFLD and liver cancer in experimental animal models

  • A subset of human liver cancers has a gene expression profile indicative of defective intermediary metabolism

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Figure 1: Overview of pathways that regulate NAFLD-mediated carcinogenesis.

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  1. Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 595 LaSalle Street, Snyderman Building, Suite 1073, Durham, 27710, NC, USA

    Gregory A. Michelotti, Mariana V. Machado & Anna Mae Diehl

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  1. Gregory A. Michelotti
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All authors contributed equally to all aspects of this manuscript.

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Correspondence to Anna Mae Diehl.

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Michelotti, G., Machado, M. & Diehl, A. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 10, 656–665 (2013). https://doi.org/10.1038/nrgastro.2013.183

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