Effect of Candesartan and Ramipril on Liver Fibrosis in Patients with Chronic Hepatitis C Viral Infection: A Randomized Controlled Prospective Study

Tarek M Mostafa, Gamal A El-Azab, Gamal A Badra, Alyaa S Abdelwahed, Abeer A Elsayed, Tarek M Mostafa, Gamal A El-Azab, Gamal A Badra, Alyaa S Abdelwahed, Abeer A Elsayed

Abstract

Objective: This study aimed at evaluating the effects of candesartan and ramipril on liver fibrosis in patients with chronic hepatitis C. Methods: This randomized controlled prospective study involved 64 patients with chronic hepatitis C and liver fibrosis. Participants were randomized into 3 groups: group I (control group; n = 21), members of which received traditional therapy only; group 2 (ramipril group; n = 21), members of which received traditional therapy plus 1.25 mg/d oral ramipril; and group 3 (candesartan group; n = 22), members of which received traditional therapy plus 8 mg/d oral candesartan. Patients were assessed at baseline and 6 months after intervention through measuring of liver stiffness (Fibro-Scan; Echosens, Paris, France); evaluation of the serum levels of hyaluronic acid and transforming growth factor beta-1; and calculation of indices of liver fibrosis, including fibrosis index based on the 4 factors and aspartate transaminase-to-platelet-ratio index. Data were analyzed using paired t test and 1-way ANOVA followed by Tukey's honest significant difference test for multiple pairwise comparisons. Results: At baseline, the 3 study groups were statistically similar in demographic and laboratory data. After treatment, the 3 study groups showed significant decrease in liver stiffness, serum levels of hyaluronic acid and transforming growth factor beta-1, and indices of liver fibrosis compared with baseline data (P < 0.001). Six months after treatment, patients taking ramipril and candesartan showed significant improvement in all measured parameters compared with the control group. Additionally, the candesartan-treated group showed significant decrease in liver stiffness, biomarkers, and indices of liver fibrosis compared with ramipril recipients. Conclusions: The administration of ramipril and candesartan in patients with chronic hepatitis C with hepatic fibrosis was well tolerated and effective in improving liver fibrosis. angiotensin II receptor 1 (AT1) antagonist candesartan maintained antifibrotic effects more effectively than ramipril and may represent a safe and effective therapeutic strategy for liver fibrosis in patients with chronic liver diseases. ClinicalTrials.gov identifier: NCT03770936. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX) © 2022 Elsevier HS Journals, Inc.

Keywords: candesartan; hyaluronic acid; liver fibrosis; liver stiffness; ramipril; transforming growth factor-beta 1.

© 2021 The Author(s).

Figures

Figure 1
Figure 1
Flowchart illustrating the participants’ screening, enrollment, and randomization. GIT = gastrointestinal.
Figure 2
Figure 2
Changes in liver stiffness in the 3 studied groups before treatment and 6 months after treatment. Liver stiffness in both ramipril and candesartan groups decreased significantly (P < 0.001) 6 months after treatment in comparison with its baseline. Values are presented as mean (SD). *Significant difference.
Figure 3
Figure 3
Changes in hyaluronic acid (HA) serum level in the 3 studied groups before treatment and 6 months after treatment. HA level in both ramipril and candesartan groups decrease significantly (P < 0.001) 6 months after treatment in comparison with its baseline level. Values are presented s mean (SD). *Significant difference.
Figure 4
Figure 4
Changes in transforming growth factor-beta 1 (TGF-β1) serum level in the 3 studied groups before treatment and 6 months after treatment. TGF-β1 level in ramipril and candesartan groups decreased significantly (P < 0.001) 6 months after treatment in comparison with its baseline level. Values are presented as mean ± SD. *Significant difference.
Figure 5
Figure 5
Liver stiffness of the 3 studied groups after treatment. Values are presented a mean (SD). *Significant difference from control group. ⁎⁎Significant difference from control and ramipril groups
Figure 6
Figure 6
The Pearson correlation analysis between the measured variables. APRI = aspartate transaminase-to-platelet ratio index; FIB-4 = fibrosis index based on the 4 factors; HA = hyaluronic acid; TGF-β1 = transforming growth factor-beta 1.

References

    1. Kouyoumjian SP, Chemaitelly H, Abu-Raddad LJ. Characterizing hepatitis C virus epidemiology in Egypt: systematic reviews, meta-analyses, and meta-regressions. Sci Rep. 2018;8(1):1661.
    1. Abbas G, Silveira MG, Lindor KD. Hepatic fibrosis and the renin-angiotensin system. Am J Ther. 2011;18:e202–e208.
    1. Shim KY, Eom YW, Kim MY, Kang SH, Baik SK. Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension. Korean J Intern Med. 2018;33(3):453–461.
    1. Saber S. Angiotensin II: a key mediator in the development of liver fibrosis and cancer. Bull Natl Res Cent. 2018;42:18.
    1. Salama ZA, Sadek A, Abdelhady AM, Darweesh SK, Morsy SA, Esmat G. Losartan may inhibit the progression of liver fibrosis in chronic HCV patients. Hepatobiliary Surg Nutr. 2016;5:249–255.
    1. Ogata H, Noguch H, Ohtsubo T, Liao J, Kohara H, Yamada K, et al. Angiotensin II type I receptor blocker, Losartan, inhibits fibrosis in liver by suppressing TGF-beta1 production. Integr Mol Med. 2016;3(1):520–523.
    1. Reza HM, Tabassum N, Sagor MA, Chowdhury MR, Rahman M, Jain P, et al. Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride-treated rat liver. Toxicol Mech Methods. 2016;26:46–53.
    1. Tuncer I, Ozbek H, Ugras S, Bayram I. Anti-fibrogenic effects of captopril and candesartan cilexetil on the hepatic fibrosis development in rat. The effect of AT1-R blocker on the hepatic fibrosis. Exp Toxicol Pathol. 2003;55:159–166.
    1. Zhu Q, Li N, Li F, Zhou Z, Han Q, Lv Y, et al. Therapeutic effect of renin angiotensin system inhibitors on liver fibrosis. J Renin Angiotensin Aldosterone Syst. 2016;17(1)
    1. McPherson S, Wilkinson N, Tiniakos D, Wilkinson J, Burt AD, McColl E, et al. A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis. PLoS One. 2017;12
    1. Li Y, Xu H, Wu W, et al. Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Oncotarget. 2018;9:24155–24167.
    1. Bergmeyer HU, Horder M, Rej R. International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase (L-alanine: 2-oxoglutarate aminotransferase, EC 2.6.1.2) J Clin Chem Clin Biochem. 1986;24:481–495.
    1. Doumas BT, Kwok-Cheung PP, Perry BW, et al. Candidate reference method for determination of total bilirubin in serum: development and validation. Clin Chem. 1985;31:1779–1789.
    1. Dumas BT, Watson WA, Biggs HG. Albumin standards and the measurement of serum albumin with bromcresol green. Clin Chim Acta. 1971;258:21–30. 1997.
    1. Fung J, Lai CL, Fong DY, Yuen JC, Wong DK, Yuen MF. Correlation of liver biochemistry with liver stiffness in chronic hepatitis B and development of a predictive model for liver fibrosis. Liver Int. 2008;28:1408–1416.
    1. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325.
    1. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–526.
    1. Kim G, Kim J, Lim YL, Kim MY, Baik SK. Renin-angiotensin system inhibitors and fibrosis in chronic liver disease: a systematic review. Hepatol Int. 2016;10:819–828.
    1. Ziada DH, El Sadany S, Soliman H, et al. Prevalence of hepatocellular carcinoma in chronic hepatitis C patients in Mid Delta, Egypt: a single center study. J Egypt Natl Canc Inst. 2016;28:257–262.
    1. 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;11:7560–7563.
    1. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97(10):2614–2618.
    1. Abd El Rihim AY, Omar RF, Fathalah W, El Attar I, Hafez HA, Ibrahim W. Role of fibroscan and APRI in detection of liver fibrosis: a systematic review and meta-analysis. Arab J Gastroenterol. 2013;14:44–50.
    1. Orasan OH, Ciulei G, Cozma A, Sava M, Dumitrascu DL. Hyaluronic acid as a biomarker of fibrosis in chronic liver diseases of different etiologies. Clujul Med. 2016;89(1):24–31.
    1. Rodart IF, Pares MM, Mendes A, Accardo CM, Martins JRM, Silva CB, et al. Diagnostic accuracy of serum hyaluronan for detecting HCV infection and liver fibrosis in asymptomatic blood donors. Molecules. 2021;26(13):3892.
    1. Yen YH, Kuo FY, Kee KM, et al. APRI and FIB-4 in the evaluation of liver fibrosis in chronic hepatitis C patients stratified by AST level. PLoS One. 2018;13
    1. Saber S, Goda R, El-Tanbouly GS, Ezzat D. Lisinopril inhibits nuclear transcription factor kappa B and augments sensitivity to silymarin in experimental liver fibrosis. Int Immunopharmacol. 2018;64:340–349.
    1. Zhang L, Bansal MB. Role of Kupffer cells in driving hepatic inflammation and fibrosis in HIV infection. Front Immunol. 2020;16(11):1086.
    1. van der Heide D, Weiskirchen R, Bansal R. Therapeutic targeting of hepatic macrophages for the treatment of liver diseases. Front Immunol. 2019;10:2852.
    1. Wengrower D, Zanninelli G, Latella G, et al. Losartan reduces trinitrobenzenesulphonic acid-induced colorectal fibrosis in rats. Can J Gastroenterol. 2012;26:33–39.
    1. Wei G-W, Li K-Y, Tang K-L, Sh C-X. Tanshinone IIA alters the transforming growth factor-β1/Smads pathway in angiotensin II-treated rat hepatic stellate cells. J Int Med Res. 2020;48(6)
    1. Dewidar B, Soukupova J, Fabregat I, Dooley S. TGF-β in hepatic stellate cell activation and liver fibrogenesis: updated. Curr Pathobiol Rep. 2015;3:291–305.
    1. Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-β in hepatic stellate cell activation and liver fibrogenesis—updated 2019. Cells. 2019;8(11):1419.
    1. Iwanami J, Mogi M, Iwai M, Horiuchi M. Inhibition of the renin-angiotensin system and target organ protection. Hypertens Res. 2009;32:229–237.
    1. Pereira RM1, 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;15:2579–2586.
    1. de Oliveira da Silva B, Ramos LF, Moraes KC. Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis. Cell Biol Int. 2017;41(9):946–959.
    1. 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;29:748–753.
    1. Fujinaga Y, Kawaratani H, Kaya D, Tsuji Y, Ozutsumi T, Furukawa M, et al. Effective combination therapy of angiotensin-II receptor blocker and rifaximin for hepatic fibrosis in rat model of nonalcoholic steatohepatitis. Int J Mol Sci. 2020;21(15):5589.
    1. 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;56:564–568.
    1. Reese LJ, Tider DS, Stivala AC, Fishbein DA. Effects of angiotensin converting enzyme inhibitors on liver fibrosis in HIV and hepatitis C coinfection. AIDS Res Treat. 2012:978–990.
    1. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1):47–64. Suppl.
    1. Michel MC, Brunner HR, Foster C, Huo Y. Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease. Pharmacol Ther. 2016;164:1–81.
    1. El-Dahr SS, Dipp S, Yosipiv IV, Baricos WH. Bradykinin stimulates c-fos expression, AP-1-DNA binding activity and proliferation of rat glomerular mesangial cells. Kidney Int. 1996;50:1850–1855.
    1. Zhang J, Li N, Yang L, Xie H, Yang Y, Wang H, et al. Bradykinin contributes to immune liver injury via B2R receptor-mediated pathways in trichloroethylene sensitized mice: a role in Kupffer cell activation. Toxicology. 2019;415:37–48.
    1. Zhang J, Li N, Yang L, Zang D, Yang P, Wang H, et al. Role of selective blocking of bradykinin b1 receptor in attenuating immune liver injury in trichloroethylene-sensitized mice. Cytokine. 2018;108:71–81.
    1. 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;43:889–896.
    1. Abbass S, Hendawy G, Mahmoud ES, Younis F, ST Ali, Zalam S, et al. Role of hepatic transforming growth factor-Β1 (TGF- Β1) and serum hyaluronic acid in the pathogenesis of liver fibrosis in chronic HCV patients. AAMJ. 2011;9(1):1–12.
    1. Kempinski R, Neubauer K, Poniewierka E, Kaczorowski M, Halon A. The immunoreactivity of TGF-b1 in non-alcoholic fatty liver disease. Folia Histochem Cytobiol. 2019;57(2):74–83.
    1. Tian F, Liu Y, Gao J, Yang N, Shang X, Lv J, et al. Study on the association between TGF-β1 and liver fibrosis in patients with hepatic cystic echinococcosis. Exp Ther Med. 2020;19(2):1275–1280.

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