Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

BACKGROUND Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma(HCC). Modulation of the renin-angiotensin system(RAS) by angiotensin-converting enzyme inhibitors(ACE-Is) and angiotensin receptor blockers(ARBs) seems to be a possible adjuvant therapy for HCC, due to the antiangiogenic and anti-fibrogenic activity of these drugs.AIM To elucidate the role of ARBs and ACE-Is in HCC.METHODS We performed an electronic search of the literature using the most accessed online databases(PubMed, Cochrane library, Scopus and Web of Science),entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma;moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND"hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were:(1)prospective or retrospective clinical studies;(2) epidemiological studies; and(3)experimental studies conducted in vivo or in vitro. Abstracts, conference papers,and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals.RESULTS Thirty-one studies were selected. Three interventional studies showed that ACEIs had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showedconflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1 a,transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs.CONCLUSION In humans, RAS inhibitors-alone or in combination-significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.