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World J Hepatol. Sep 27, 2021; 13(9): 1107-1121
Published online Sep 27, 2021. doi: 10.4254/wjh.v13.i9.1107
Hepatocellular carcinoma in nonalcoholic fatty liver disease: A growing challenge
Ângelo Z Mattos, Jose D Debes, Renu Dhanasekaran, Jihane N Benhammou, Marco Arrese, André Luiz V Patrício, Amanda C Zilio, Angelo A Mattos
Ângelo Z Mattos, Angelo A Mattos, Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
Ângelo Z Mattos, André Luiz V Patrício, Amanda C Zilio, Angelo A Mattos, Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
Jose D Debes, Department of Medicine, Division of Infectious Diseases and of Gastroenterology, University of Minnesota, Minneapolis, MN 55455, United States
Jose D Debes, Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam 3015 CN, South Holland, Netherlands
Renu Dhanasekaran, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, United States
Jihane N Benhammou, The Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles, CA 90095, United States
Marco Arrese, Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
Author contributions: Mattos AZ and Debes JD were involved in the manuscript conceptualization; Mattos AZ, Debes JD, Dhanasekaran R, Benhammou JN, Arrese M, Patrício ALV, Zilio AC, and Mattos AA were involved in literature review and writing of the original draft; Dhanasekaran R and Benhammou JN were involved in figure design; All authors have read and approved the final manuscript.
Supported by the European-South American Consortium to Assess Liver-Originated Neoplasia (the ESCALON consortium), the European Union’s Horizon 2020 program, No. 825510; Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Program (to Debes JD); and Fondo Nacional de Ciencia y Tecnología de Chile, No. 1191145 (to Arrese M).
Conflict-of-interest statement: Dr. Mattos reports grants from EU Horizon 2020 program, grants from Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Program (to Debes JD) , grants from Fondo Nacional de Ciencia y Tecnología de Chile and Comisión Nacional de Investigación, Ciencia y Tecnología (to Arrese M), during the conduct of the study.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ângelo Z Mattos, MD, MSc, Professor, Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, 154, Professor Annes Dias St., office 1103, Porto Alegre 90020-090, Rio Grande do Sul, Brazil. angmattos@hotmail.com
Received: March 14, 2021
Peer-review started: March 14, 2021
First decision: April 6, 2021
Revised: April 21, 2021
Accepted: July 26, 2021
Article in press: July 26, 2021
Published online: September 27, 2021
Processing time: 191 Days and 15.9 Hours
Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, and its prevalence increases continuously. As it predisposes to hepatocellular carcinoma both in the presence and in the absence of cirrhosis, it is not surprising that the incidence of NAFLD-related hepatocellular carcinoma would also rise. Some of the mechanisms involved in hepatocarcinogenesis are particular to individuals with fatty liver, and they help explain why liver cancer develops even in patients without cirrhosis. Genetic and immune-mediated mechanisms seem to play an important role in the development of hepatocellular carcinoma in this population. Currently, it is consensual that patients with NAFLD-related cirrhosis should be surveilled with ultrasonography every 6 mo (with or without alpha-fetoprotein), but it is known that they are less likely to follow this recommendation than individuals with other kinds of liver disease. Moreover, the performance of the methods of surveillance are lower in NAFLD than they are in other liver diseases. Furthermore, it is not clear which subgroups of patients without cirrhosis should undergo surveillance. Understanding the mechanisms of hepatocarcinogenesis in NAFLD could hopefully lead to the identification of biomarkers to be used in the surveillance for liver cancer in these individuals. By improving surveillance, tumors could be detected in earlier stages, amenable to curative treatments.

Keywords: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Hepatocellular carcinoma; Hepatocarcinogenesis; Surveillance

Core Tip: Nonalcoholic fatty liver disease (NAFLD) is a growing cause of hepatocellular carcinoma, and liver cancer is one of the leading causes of cancer-related death worldwide. There are particular genetic and immune-mediated mechanisms for hepatocarcinogenesis in NAFLD. Moreover, hepatocellular carcinoma can develop in NAFLD in the absence of cirrhosis. Finally, the characteristics of NAFLD and its high prevalence lead to important challenges regarding surveillance for liver cancer in this population. This review will approach the most important issues concerning NAFLD-related hepatocellular carcinoma.