Systematic Reviews
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2019; 25(20): 2524-2538
Published online May 28, 2019. doi: 10.3748/wjg.v25.i20.2524
Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma
Michele Barone, Maria Teresa Viggiani, Giuseppe Losurdo, Mariabeatrice Principi, Alfredo Di Leo
Michele Barone, Maria Teresa Viggiani, Giuseppe Losurdo, Mariabeatrice Principi, Alfredo Di Leo, Gastroenterology Section, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari 70124, Italy
Author contributions: Barone M and Di Leo A conceived and planned the study. Viggiani MT, Barone M, Losurdo G and Principi M collected the data. Barone M and Losurdo G wrote the manuscript. Viggiani MT and Principi M revised the draft. All authors read and approved the final version of the manuscript.
Conflict-of-interest statement: All authors declare no conflict of interest (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants/patents received, or royalties).
PRISMA 2009 Checklist statement: The manuscript was prepared according to the PRISMA 2009 Checklist.
Open-Access: This 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 Non Commercial (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: Michele Barone, MD, PhD, Adjunct Professor, Gastroenterology Section, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Piazza Giulio Cesare 11, Bari 70124, Italy. michele.barone@uniba.it
Telephone: +39-80-5593514 Fax: +39-80-5593177
Received: January 23, 2019
Peer-review started: January 23, 2019
First decision: February 21, 2019
Revised: March 6, 2019
Accepted: March 24, 2019
Article in press: March 25, 2019
Published online: May 28, 2019
Processing time: 125 Days and 16 Hours
ARTICLE HIGHLIGHTS
Research background

Hepatocellular carcinoma (HCC) represents about 90% of primary liver cancers and usually develops in patients with underlying liver cirrhosis. One of the major cancer hallmarks of HCC is the process of neoangiogenesis, which is thought to occur early in the carcinogenetic process. Theoretically, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II type 1 receptor blockers (ARBs) could have a role in HCC primary prevention since they reduce both neovascularization and the development of liver fibrosis.

Research motivation

The possible role of renin-angiotensin system (RAS) inhibitors in the prevention of HCC is still an attractive field of research, as suggested by the recently published experimental and clinical studies.

Research objectives

To elucidate the role of ARBs and ACE-Is in HCC.

Research methods

Literature was selected in August 2018, focusing on studies regarding ACE-Is, ARBs and HCCs. For this purpose, an electronic search of the literature was conducted using the online databases PubMed, Cochrane library, Scopus and Web of Science. Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. We conducted the articles selection using a two-step approach, to evaluate whether they matched the eligibility criteria.

Research results

Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase of overall survival. Among six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in ACE-Is group, whereas the two of them that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either in animals and cell cultures, demonstrated the anti-angiogenetic and anti-fibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or part of these mechanisms were demonstrated in rodents developing less HCC and preneoplastic lesions after receiving such drugs.

Research conclusions

Our systematic analysis of the literature allowed us to partially reinterpret the data supporting the ability of RAS inhibitors to counteract HCC. While there is reasonable research supporting their ability to reduce the HCC recurrence rate, we think that the conclusions of the randomized clinical trials on overall survival underestimated the potential use of these compounds. These conclusions are further supported by the solid experimental data on the anti-angiogenetic activity of RAS inhibitors, which all suggest their clinical use in the prevention of HCC development.

Research perspectives

We also proposed enlarging the future research on the relationship between RAS inhibitors and HCC to other possible anti carcinogenetic mechanisms.