Journal of Hepatology
Volume 53, Issue 2 , Pages 273-282 , August 2010

Renin–angiotensin–aldosterone inhibitors in the reduction of portal pressure: A systematic review and meta-analysis

  • Puneeta Tandon

      Affiliations

    • Hospital Clinic, Liver Unit, Barcelona, Spain
    • University of Alberta, Edmonton, Alberta, Canada
    • ,
  • Juan G. Abraldes

      Affiliations

    • Hospital Clinic, Liver Unit, Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Annalisa Berzigotti

      Affiliations

    • Hospital Clinic, Liver Unit, Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Juan Carlos Garcia-Pagan

      Affiliations

    • Hospital Clinic, Liver Unit, Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Jaime Bosch

      Affiliations

    • Hospital Clinic, Liver Unit, Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • Corresponding Author InformationCorresponding author. Address: Hospital Clinic, University of Barcelona, Calle Villaroel 170, 08036 Barcelona, Spain. Tel.: +34 93227790; fax: +34 932279856.

Received 28 January 2010 ,Revised 3 March 2010 ,Accepted 4 March 2010.

References 

  1. D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. HVPG reduction and prevention of variceal bleeding in cirrhosis. A systematic review. Gastroenterology. 2006;131:1611–1624
  2. Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology. 2003;37:902–908
  3. Turnes J, Garcia-Pagan JC, Abraldes JG, Hernandez-Guerra M, Dell’era A, Bosch J. Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis. Am J Gastroenterol. 2006;101:506–512
  4. Feu F, Garcia-Pagan JC, Bosch J, Luca A, Teres J, Escorsell A, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet. 1995;346:1056–1059
  5. Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 2001;118:1149–1156
  6. Debernardi-Venon W, Martini S, Biasi F, Vizio B, Termine A, Poli G, et al. AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol. 2007;46:1026–1033
  7. Rimola A, Londono MC, Guevara G, Bruguera M, Navasa M, Forns X, et al. Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation. 2004;78:686–691
  8. Yoshiji H, Noguchi R, Kojima H, Ikenaka Y, Kitade M, Kaji K, et al. Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C. World J Gastroenterol. 2006;12:6786–6791
  9. Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–1225
  10. Garcia-Pagan JC, Salmeron JM, Feu F, Luca A, Gines P, Pizcueta P, et al. Effects of low-sodium diet and spironolactone on portal pressure in patients with compensated cirrhosis. Hepatology. 1994;19:1095–1099
  11. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150:776–783
  12. Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology. 1999;29:334–339
  13. De BK, Bandyopadhyay K, Das TK, Das D, Biswas PK, Majumdar D, et al. Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Am J Gastroenterol. 2003;98:1371–1376
  14. Gonzalez-Abraldes J, Albillos A, Banares R, Ruiz del Arbol L, Moitinho E, Rodriguez C, et al. Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Gastroenterology. 2001;121:382–388
  15. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996;17:1–12
  16. Schulz KF, Altman DG, Moher D. Allocation concealment in clinical trials. JAMA. 2002;288:2406–2407
  17. Schulz KF. Subverting randomization in controlled trials. JAMA. 1995;274:1456–1458
  18. Debernardi-Venon W, Barletti C, Alessandria C, Marzano A, Baronio M, Todros L, et al. Efficacy of irbesartan, a receptor selective antagonist of angiotensin II, in reducing portal hypertension. Dig Dis Sci. 2002;47:401–404
  19. Arroyo V, Bosch J, Mauri M, Ribera F, Navarro-Lopez F, Rodes J. Effect of angiotensin-II blockade on systemic and hepatic haemodynamics and on the renin–angiotensin–aldosterone system in cirrhosis with ascites. Eur J Clin Invest. 1981;11:221–229
  20. Yang YY, Lin HC, Lee WC, Hou MC, Lee FY, Chang FY, et al. One-week losartan administration increases sodium excretion in cirrhotic patients with and without ascites. J Gastroenterol. 2002;37:194–199
  21. Pariente EA, Bataille C, Bercoff E, Lebrec D. Acute effects of captopril on systemic and renal hemodynamics and on renal function in cirrhotic patients with ascites. Gastroenterology. 1985;88:1255–1259
  22. Ibarra FR, Afione C, Garzon D, Barontini M, Santos JC, Arrizurieta E. Portal pressure, renal function and hormonal profile after acute and chronic captopril treatment in cirrhosis. Eur J Clin Pharmacol. 1992;43:477–482
  23. Sookoian S, Castano G, Garcia SI, Viudez P, Gonzalez C, Pirola CJ. A1166C angiotensin II type 1 receptor gene polymorphism may predict hemodynamic response to losartan in patients with cirrhosis and portal hypertension. Am J Gastroenterol. 2005;100:636–642
  24. Chiang HT, Cheng JS, Lin M, Tseng WS, Chang JM, Lai KH. Haemodynamic effects of enalaprilat on portal hypertension in patients with HBsAg-positive cirrhosis. J Gastroenterol Hepatol. 1995;10:256–260
  25. Tripathi D, Therapondos G, Lui HF, Johnston N, Webb DJ, Hayes PC. Chronic administration of losartan, an angiotensin II receptor antagonist, is not effective in reducing portal pressure in patients with preascitic cirrhosis. Am J Gastroenterol. 2004;99:390–394
  26. Terui Y, Saito T, Watanabe H, Togashi H, Kawata S, Kamada Y, et al. Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology. 2002;36:1022
  27. Eriksson LS, Kagedal B, Wahren J. Effects of captopril on hepatic venous pressure and blood flow in patients with liver cirrhosis. Am J Med. 1984;76:66–70
  28. Daskalopoulos G, Pinzani M, Murray N, Hirschberg R, Zipser RD. Effects of captopril on renal function in patients with cirrhosis and ascites. J Hepatol. 1987;4:330–336
  29. 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
  30. Nevens F, Lijnen P, VanBilloen H, Fevery J. The effect of long-term treatment with spironolactone on variceal pressure in patients with portal hypertension without ascites. Hepatology. 1996;23:1047–1052
  31. Nasr AA, el-Hak NG, Settein ME, Khafagy MA, Tadros MT. Effects of angiotensin-converting enzyme inhibitors and sclerotherapy on portal hemodynamics in patients with portal hypertension. Hepatogastroenterology. 2000;47:795–806
  32. Hulagu S, Senturk O, Erdem A, Ozgur O, Celebi A, Karakaya AT, et al. Effects of losartan, somatostatin and losartan plus somatostatin on portal hemodynamics and renal functions in cirrhosis. Hepatogastroenterology. 2002;49:783–787
  33. Girgrah N, Liu P, Collier J, Blendis L, Wong F. Haemodynamic, renal sodium handling, and neurohormonal effects of acute administration of low dose losartan, an angiotensin II receptor antagonist, in preascitic cirrhosis. Gut. 2000;46:114–120
  34. Wagatsuma Y, Naritaka Y, Shimakawa T, Kanako H, Keiichiro I, Shunichi S, et al. Clinical usefulness of the angiotensin II receptor antagonist losartan in patients with portal hypertensive gastropathy. Hepatogastroenterology. 2006;53:171–174
  35. Koda M, Murawaki Y, Kawasaki H, Ikawa S. Effects of canrenoate potassium, an aldosterone antagonist on portal hemodynamics in patients with compensated liver cirrhosis. Hepatogastroenterology. 1996;43:887–892
  36. Vilas-Boas WW, Ribeiro-Oliveira A, Pereira RM, Ribeiro RC, Almeida J, Nadu AP, et al. Relationship between angiotensin-(1–7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis. World J Gastroenterol. 2009;15:2512–2519
  37. Vlachogiannakos J, Tang AK, Patch D, Burroughs AK. Angiotensin converting enzyme inhibitors and angiotensin II antagonists as therapy in chronic liver disease. Gut. 2001;49:303–308
  38. Tox U, Steffen HM. Impact of inhibitors of the renin–angiotensin–aldosterone system on liver fibrosis and portal hypertension. Curr Med Chem. 2006;13:3649–3661
  39. Tsai YT, Lin HC, Lee FY, Hou MC, Wang SS, Lee SD. Effects of captopril on renal functions, renal and portal hemodynamics in patients with cirrhosis. Proc Natl Sci Counc Repub China B. 1996;20:44–50
  40. Okumura H, Aramaki T, Katsuta Y, Satomura K, Akaike M, Sekiyama T, et al. Reduction in hepatic venous pressure gradient as a consequence of volume contraction due to chronic administration of spironolactone in patients with cirrhosis and no ascites. Am J Gastroenterol. 1991;86:46–52
  41. Baik SK, Park DH, Kim MY, Choi YJ, Kim HS, Lee DK, et al. Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol. 2003;38:1150–1154
  42. Svoboda P, Ochmann J, Kantorova I. Effect of enalapril treatment and sclerotherapy of esophageal varices on hepatic hemodynamics in portal hypertension. Hepatogastroenterology. 1992;39:549–552
  43. Schepke M, Werner E, Biecker E, Schiedermaier P, Heller J, Neef M, et al. Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension. Gastroenterology. 2001;121:389–395
  44. Schepke M, Wiest R, Flacke S, Heller J, Stoffel-Wagner B, Herold T, et al. Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: a placebo-controlled, double-blind study. Am J Gastroenterol. 2008;103:1152–1158
  45. Heim MH, Jacob L, Beglinger C. The angiotensin II receptor antagonist candesartan is not effective in reducing portal hypertension in patients with cirrhosis. Digestion. 2007;75:122–123
  46. Sen S, De BK, Biswas PK, Biswas J, Das D, Maity AK. Hemodynamic effect of spironolactone in liver cirrhosis and propranolol-resistant portal hypertension. Indian J Gastroenterol. 2002;21:145–148
  47. De BK, Dutta D, Som R, Biswas PK, Pal SK, Biswas A. Hemodynamic effects of propranolol with spironolactone in patients with variceal bleeds: a randomized controlled trial. World J Gastroenterol. 2008;14:1908–1913
  48. Abecasis R, Kravetz D, Fassio E, Ameigeiras B, Garcia D, Isla R, et al. Nadolol plus spironolactone in the prophylaxis of first variceal bleed in nonascitic cirrhotic patients: a preliminary study. Hepatology. 2003;37:359–365
  49. Castano G, Viudez P, Riccitelli M, Sookoian S. A randomized study of losartan vs propranolol: effects on hepatic and systemic hemodynamics in cirrhotic patients. Ann Hepatol. 2003;2:36–40
  50. Sugano S, Suzuki T, Nishio M, Makino H, Okajima T. Chronic splanchnic hemodynamic effects of low-dose transdermal nitroglycerin versus low-dose transdermal nitroglycerin plus spironolactone in patients with cirrhosis. Dig Dis Sci. 1997;42:529–535
  51. Sugano S, Kawafune T, Okajima T, Ishii K, Watanabe M, Takamura N. Chronic splanchnic hemodynamic effects of spironolactone with unrestricted sodium diet in patients with compensated cirrhosis. J Hepatol. 1998;43:893–897
  52. Garcia-Tsao G. Angiotensin II receptor antagonists in the pharmacological therapy of portal hypertension: a caution. Gastroenterology. 1999;117:740–742
  53. Groszmann RJ, Bosch J, Grace N, Conn HO, Garcia-Tsao G, Navasa M, et al. Hemodynamic events in a prospective randomized trial of propranolol vs placebo in the prevention of the first variceal hemorrhage. Gastroenterology. 1990;99:1401–1407
  54. Bureau C, Peron JM, Alric L, Morales J, Sanchez J, Barange K, et al. “A La Carte” treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology. 2002;36:1361–1366
  55. Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353:2254–2261
  56. Aracil C, Lopez-Balaguer JM, Monfort D, Piqueras M, Gonzalez B, Minana J, et al. Hemodynamic response to beta-blockers and prediction of clinical efficacy in the primary prophylaxis of variceal bleeding in patients with cirrhosis. Hepatology. 2003;38:296A;[abstract]
  57. Guturu P, Shah V. New insights into the pathobiology of portal hypertension. Hepatol Res. 2009;39:1016–1019
  58. Gupta TK, Chung MK, Toruner M, Groszmann RJ. Endothelial dysfunction in the intrahepatic microcirculation of the cirrhotic rat. Hepatology. 1998;28:926–931
  59. Gracia-Sancho J, Lavina B, Rodriguez-Vilarrupla A, Garcia-Caldero H, Bosch J, Garcia-Pagan JC. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. J Hepatol. 2007;47:220–227
  60. Alam I, Bass NM, Bacchetti P, Gee L, Rockey DC. Hepatic tissue endothelin-1 levels in chronic liver disease correlate with disease severity and ascites. Am J Gastroenterol. 2000;95:199–203
  61. Therapondos G, Hol L, Benjaminov F, Wong F. The effect of single oral low-dose losartan on posture-related sodium handling in post-TIPS ascites-free cirrhosis. Hepatology. 2006;44:640–649
  62. Wong F, Liu P, Blendis L. The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis. Hepatology. 2002;35:1449–1458
  63. Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology. 2001;121:148–155
  64. Paizis G, Gilbert RE, Cooper ME, Murthi P, Schembri JM, Wu LL, et al. Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol. 2001;35:376–385
  65. Zhou X, Jamil A, Nash A, Chan J, Trim N, Iredale JP, et al. Impaired proteolysis of collagen I inhibits proliferation of hepatic stellate cells: implications for regulation of liver fibrosis. J Biol Chem. 2006;281:39757–39765
  66. Yang X, Li X, Wu P, Meng Y, Li S, Lai W. CYP11B2 expression in rat liver and the effect of spironolactone on hepatic fibrogenesis. Horm Res. 2000;53:288–293
  67. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34:745–750
  68. Epstein M. Aldosterone blockade: an emerging strategy for abrogating progressive renal disease. Am J Med. 2006;119:912–919
  69. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol. 1981;91:457–465
  70. Modena MG, Aveta P, Menozzi A, Rossi R. Aldosterone inhibition limits collagen synthesis and progressive left ventricular enlargement after anterior myocardial infarction. Am Heart J. 2001;141:41–46
  71. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–717

PII: S0168-8278(10)00380-6

doi: 10.1016/j.jhep.2010.03.013

Journal of Hepatology
Volume 53, Issue 2 , Pages 273-282 , August 2010

Article Tools

* Image Usage & Resolution