Renin–angiotensin system inhibitors and fibrosis in chronic liver disease: a systematic review
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Background and aims
The renin–angiotensin system (RAS) has an important role in hepatic fibrosis and portal hypertension. RAS inhibitors are already accepted in clinical fields for antihypertensive management, but their effects on hepatic fibrosis are controversial. The aim of this study was to systematically review the effects of RAS inhibitors on hepatic fibrosis based on histological assessment.
We performed a systematic review and meta-analysis (MA) of the literature using the Ovid-MEDLINE, EMBASE, and Cochrane Library databases (up to January 2015) to identify clinical studies evaluating the effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on hepatic fibrosis or cirrhosis patients based on histological assessment. Of the 455 studies identified, we analyzed 7, including a total of 1066 patients, which met our selection criteria.
According to the MA, patients treated with RAS inhibitors had significantly lower fibrosis scores (SMD −0.68, 95 % CI −1.03, −0.34, I 2 = 0 %, p < 0.0001) and smaller fibrosis areas (SMD −0.80, 95 % CI −1.18, −0.41, I 2 = 0 %, p < 0.0001) than controls. Serum fibrosis markers such as TGF-β1, collagen I, IV, TIMP-1, and MMP2 were significantly reduced in the intervention group. In two studies, mean arterial pressures were significantly decreased in RAS inhibitor users, but there were no reports about symptoms related to decreased blood pressure. No significant difference was found in serum creatinine levels between the intervention and control groups, and significant renal dysfunction was not observed after administration of RAS inhibitors.
RAS inhibitors are potential therapeutic agents for hepatic fibrosis, which can be safely used in patients with chronic liver disease.
KeywordsRenin–angiotensin system Hepatic fibrosis Systematic review Meta-analysis
Angiotensin receptor blocker
Angiotensin II type 1 receptor
Hepatitis C virus
Randomized controlled trial
Reactive oxygen stress
Standardized mean difference
Compliance with ethical standards
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2364), and also by the Yonsei University Future-Leading Research Initiative of 2014.
Conflict of interest
Gaeun Kim, Juyoung Kim, Yoo Li Lim, Moon Young Kim, and Soon Koo Baik declare that there are no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 1.Moreno M, Gonzalo T, Kok RJ, et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 2010;51(3):942–952Google Scholar
- 2.Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med 2015;30(5):580–589Google Scholar
- 3.Kim G, Lee SS, Baik SK, et al. The need for histological subclassification of cirrhosis: a systematic review and meta-analysis. Liver Int 2015. doi: 10.1111/liv.12923. [Epub ahead of print]
- 4.Kim G, Cho YZ, Baik SK. Assessment for risk of bias in systematic reviews and meta-analyses in the field of hepatology. Gut Liver 2015;9(6):701–706Google Scholar
- 5.Kim G, Eom YW, Baik SK, et al. Therapeutic effects of mesenchymal stem cells for patients with chronic liver diseases: systematic review and meta-analysis. J Korean Med Sci 2015;30(10):1405–1415Google Scholar
- 6.Kim G, Cho YZ, Baik SK, Kim MY, Hong WK, Kwon SO. The accuracy of ultrasonography for the evaluation of portal hypertension in patients with cirrhosis: a systematic review. Korean J Radiol 2015;16(2):314–324Google Scholar
- 7.Kim G, Baik SK. Overview and recent trends of systematic reviews and meta-analyses in hepatology. Clin Mol Hepatol 2014;20(2):137–150Google Scholar
- 8.Hong WK, Shim KY, Baik SK, et al. Relationship between tetrahydrobiopterin and portal hypertension in patients with chronic liver disease. J Korean Med Sci 2014;29(3):392–399Google Scholar
- 9.Kim MY, Baik SK, Park DH, et al. Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model. J Gastroenterol 2008;43(11):889–896Google Scholar
- 10.Rockey DC. Antifibrotic therapy in chronic liver disease. Clin Gastroenterol Hepatol 2005;3(2):95–107Google Scholar
- 11.Pereira RM, dos Santos RA, da Costa Dias FL, Teixeira MM, Simoes e Silva AC. Renin-angiotensin system in the pathogenesis of liver fibrosis. World J Gastroenterol 2009;15(21):2579–2586Google Scholar
- 12.Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol 2005;289(6):H2281–H2290Google Scholar
- 13.Kim JH, Kim JM, Cho YZ, et al. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension. Clin Mol Hepatol 2014;20(4):376–383Google Scholar
- 14.Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol 2003;35(6):881–900Google Scholar
- 15.Munshi MK, Uddin MN, Glaser SS. The role of the renin–angiotensin system in liver fibrosis. Exp Biol Med (Maywood) 2011;236(5):557–566Google Scholar
- 16.Tox U, Steffen HM. Impact of inhibitors of the renin–angiotensin–aldosterone system on liver fibrosis and portal hypertension. Curr Med Chem 2006;13(30):3649–3661Google Scholar
- 17.Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin–angiotensin–aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol 2010;53(2):273–282Google Scholar
- 18.Kim MY, Jeong WK, Baik SK. Invasive and non-invasive diagnosis of cirrhosis and portal hypertension. World J Gastroenterol 2014;20(15):4300–4315Google Scholar
- 19.Mohamadnejad M, Tavangar SM, Sotoudeh M, et al. Histopathological Study of Chronic Hepatitis B: A Comparative Study of Ishak and METAVIR Scoring Systems. Int J Organ Transplant Med 2010;1(4):171–176Google Scholar
- 20.Abu Dayyeh BK, Yang M, Dienstag JL, Chung RT. The effects of angiotensin blocking agents on the progression of liver fibrosis in the HALT-C Trial cohort. Dig Dis Sci 2011;56(2):564–568Google Scholar
- 21.Corey KE, Shah N, Misdraji J, et al. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int 2009;29(5):748–753Google Scholar
- 22.Guillaud O, Gurram KC, Puglia M, et al. Angiotensin blockade does not affect fibrosis progression in recurrent hepatitis C after liver transplantation. Transplant Proc 2013;45(6):2331–2336Google Scholar
- 23.Kim MY, Cho MY, Baik SK, et al. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis—a randomized open-label controlled study. Liver Int 2012;32(6):977–987Google Scholar
- 24.Rimola A, Londono MC, Guevara G, et al. Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation 2004;78(5):686–691Google Scholar
- 25.Sookoian S, Fernandez MA, Castano G. Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: a pilot study. World J Gastroenterol 2005;11(48):7560–7563Google Scholar
- 26.Terui Y, Saito T, Watanabe H, et al. Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology 2002;36(4 Pt 1):1022Google Scholar
- 27.Liu T, Wang X, Karsdal MA, Leeming DJ, Genovese F. Molecular serum markers of liver fibrosis. Biomark Insights 2012;7:105–117Google Scholar