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      Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis

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          Abstract

          Objective

          Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis. Because of their anti-inflammatory and anti-fibrotic effects, angiotensin receptor blockers (ARBs) are potential therapeutic agents for NAFLD. The present systematic review assessed the effectiveness of ARBs in NAFLD management.

          Results

          Accounting for data overlap and exclusion criteria, randomized controlled trial -based and single-arm meta-analyses were conducted for four studies with 362 patients and eight studies with 525 patients, respectively. Although alanine aminotransferase levels were not significantly affected by ARB treatment (standardized mean difference 0.20; 95% confidence interval (CI) [−0.04, 0.44]; P = 0.10), a fixed-effect model revealed a decreasing trend in alanine transaminase levels. Low-density lipoprotein levels were reduced by ARB treatment (MD 5.21; 95% CI [3.01, 7.40]; P < 0.00001), and total cholesterol also decreased in response to ARBs (MD 2.10; 95% CI [−0.37, 4.57]; P = 0.10). However, the fibrosis score and NAFLD activity score were not significantly improved by ARB treatment (MD 0.10; 95% CI [−0.58, 0.78]; P = 0.77) (MD −0.25; 95% CI [−1.05, 0.55]; P = 0.53).

          Materials and Methods

          Keywords were used to identify studies in PubMed, EMBASE, CENTRAL, Web of Science and CNKI published up to July 31, 2017. Single-arm and RCT-based meta-analyses of the available data were performed using RevMan (version 5.3).

          Conclusions

          Although ARBs significantly decreased plasma low-density lipoprotein and total cholesterol levels, the current evidence is insufficient to support the efficacy of ARBs in managing fibrosis in NAFLD patients.

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          Most cited references40

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          Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis.

          The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF-beta1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH.
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            Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II.

            The renin-angiotensin system plays an important role in hepatic fibrogenesis. In other organs, myofibroblasts accumulated in damaged tissues generate angiotensin II, which promotes inflammation and extracellular matrix synthesis. It is unknown whether myofibroblastic hepatic stellate cells, the main hepatic fibrogenic cell type, express the renin-angiotensin system and synthesize angiotensin II. The aim of this study was to investigate whether quiescent and activated human hepatic stellate cells contain the components of the renin-angiotensin system and synthesize angiotensin II. Hepatic stellate cells were freshly isolated from normal human livers (quiescent hepatic stellate cells) and from human cirrhotic livers (in vivo activated hepatic stellate cells). Culture-activated hepatic stellate cells were used after a second passage of quiescent hepatic stellate cells. Angiotensinogen, renin, and angiotensin-converting enzyme were assessed by quantitative polymerase chain reaction. Angiotensin II production was assessed by enzyme-linked immunosorbent assay and immunohistochemistry. Quiescent hepatic stellate cells barely express the renin-angiotensin system components--angiotensinogen, renin, and angiotensin-converting enzyme--and do not secrete angiotensin II. In contrast, both in vivo activated hepatic stellate cells and culture-activated hepatic stellate cells highly express active renin and angiotensin-converting enzyme and secrete angiotensin II to the culture media. Mature angiotensin II protein is also detected in the cytoplasm of in vivo activated and culture-activated hepatic stellate cells. Growth factors (platelet-derived growth factor and epidermal growth factor) and vasoconstrictor substances (endothelin-1 and thrombin) stimulate angiotensin II synthesis, whereas transforming growth factor-beta and proinflammatory cytokines have no effect. Vasodilator substances markedly attenuate the effect of endothelin-1. After activation, human hepatic stellate cells express the components of the renin-angiotensin system and synthesize angiotensin II. These results suggest that locally generated angiotensin II could participate in tissue remodeling in the human liver.
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              Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis.

              Nonalcoholic steatohepatitis (NASH) is now the most frequent cause of chronic liver impairment in developed countries and is a suggested causative factor in the development of cryptogenic cirrhosis and hepatocellular carcinoma. At present there is no effective and accepted therapy for NASH. The renin-angiotensin system is involved in hepatic fibrosis through activation of hepatic stellate cells, major fibrogenic cells in the liver. Hepatic stellate cells are activated by liver injury to express excessive matrix proteins and profibrogenic cytokines such as transforming growth factor-beta 1. Medicines that inhibit this pathway may be of therapeutic potential in NASH. Using a methionine-choline-deficient rat model of NASH, we studied the potential utility of an angiotensin II type 1 receptor blocker (ARB), olmesartan, on biochemical, histologic, and antioxidant measures of disease activity. ARB significantly attenuated increases in aspartate aminotransferase, activation of hepatic stellate cells, oxidative stress, expression of transforming growth factor-beta 1, expression of collagen genes, and liver fibrosis. Our observations strongly suggest a potential preventive role for ARB in the progression of nonalcoholic steatohepatitis.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                8 May 2018
                2 January 2018
                : 9
                : 35
                : 24155-24167
                Affiliations
                1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People’s Republic of China
                2 Department of Orthopaedics, Tianjin Medical University General Hospital, Heping District, Tianjin 300052, People’s Republic of China
                Author notes
                Correspondence to : Lanjuan Li, ljli@ 123456zju.edu.cn
                Article
                23816
                10.18632/oncotarget.23816
                5963622
                29844879
                d4dc1da8-1d5d-40ff-9756-4d5415d9f166
                Copyright: © 2018 Li et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 September 2017
                : 27 October 2017
                Categories
                Meta-Analysis

                Oncology & Radiotherapy
                nafld (non-alcoholic fatty liver disease),arbs (angiotensin receptor blockers),liver fibrosis,liver inflammation,meta-analysis

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