( accepted December 10th, 2001 )
Vojislav N. Perisic
University Children , s Hospital, Belgrade
University Children , s Hospital
YU-11000 Belgrade, Serbia, Yugoslavia
E-mail: [email protected]
……………………………… ………………………………………
Gastroesophageal variceal haemorrhage, a major complication of portal hypertension resulting from cirrhosis, accounts for 10-30% of all cases of bleeding from the upper GI tract (1). In patients with cirrhosis variceal haemorrhage occurs in 25-35% of cases within 2 years after the documentation of varices (2). Initial bleeding episode is fatal in up to 30% of cases; bleeding recur in up to 70% (3). Treatment of patients with varices includes the prevention of the initial bleeding espisode (primary prophylaxis), and the prevention of recurrent bleeding after a first episode (secondary prophylaxis).
Standard protocol of primary prophylaxis consists of beta-blockers alone or in combination with isosorbide mononitrate as first-line therapy (1,4). In advanced (Child-Pugh C) liver disease, variceal band ligation in combination with beta-blockers or liver transplantation is indicated (1). Secondary prophylaxis encompasses the combination of variceal band ligation and beta-blockers (1). This combination is more effective than either alone. The addition of isosorbid mononitrate appears to enhance the protective effect beta-blockers (5). Secondary prophylaxis with decompressive (selective) shunt surgery is more effective than medical or endoscopic treatment in patients with Child-Pugh class A or B cirrhosis with more or less preserved hepatic synthetic function (6).
In this issue of the Archives of Gastroenterohepatology, Erdem Aysun et al from Istambul, Turkey reported the beneficial effects of losartan (angiotensin-II receptor antagonist) and somatostatin on hepatic haemodynamics in patients with chronic liver disease (13). A significant increase of portal blood flow was recorded (13). This prompted us to briefly review this topic.
In portal hypertension the goals of pharmacological treatment is to reduce portal and variceal pressure. This may be achieved by decreasing portal blood flow or intrahepatic vascular resistance or both. The drug of choice among portal hypotensive drug is beta-blocker, propranolol. Propranolol has proved effective in reducing portal pressure by lowering splanchnic blood inflow and therefore is used in primary and secondary prevention of variceal bleeding (7,8,9,10) However, the mean decrease in portal pressure in response to propranolol is averaging approximately 15% and 1/3 of cirrhotic patients do not respond despite adequate blockade (10). Furthermore beta-blockers did not show any beneficial effect in preventing variceal enlargement, so this type of drug cannot be recommended in patients with small or no varices (11,12). When nitrovasodilatator, isosorbide mononitrate is added to beta-blockers their effect is enhanced for about 10%. This drug reduce intrahepatic vascular resistance and decrease portal blood flow by splanchnic vasoconstriction induced by venous blood pooling and reduction of arterial pressure (barroreceptor mediated paradoxical splanchnic vasoconstriction) (7,14,25). Decrease of hepatic vascular resistance is consequence of amelioration of intrahepatic, sinusoidal contraction partly because of deficient intrahepatic nitric oxide production (14,15). Therefore, the new pharmacological target in portal hypertension is activated and contracted stellate cells (myofibroblasts) which are in the perisinoidal space of Disse, and regulate sinusoidal blood flow via sinusoidal contraction (15,24,25). These cells are activated during liver injury (15).
The renin-angiotensin-aldosteron system is activated in portal hypertension due to peripheral vasodilatation, arterial hypotension, and renal hypoperfusion (16). In cirrhosis plasma renin acivity is increased and correlates with hepatic venous pressure gradient (17). Angiotensin-II is potentially mediator of increased intrahepatic vascular resistance. Its plasma activity is increased in cirrhosis. Infusion of angiotrensin-II rises portal pressure (7,17). This is induced by potentiating the adrenergic vasoconstrictor influence on the portal system, stimulating contraction of activated stellate cells in the perisinusoidal space of Disse, and retaining Na+ and fluid by stimulation of aldosteron secretion (19,25). This was the theoretical basis of the supposition that blockade of renin-angiotensin-aldosterone system by angiotensin converting enzyme (ACE) inhibitors/angiotensin-II receptor antagonist may reduce portal pressure, and improve H20and Na+ excretion. But their application was of great concern due to possibility of further deterioration of renal function and worsening of Na+ excretion in cirrhotics due to their hypotensive effect and action on abnormal renal Na+ handling (16,25).
ACE inhibitors, captopril and enalapril,, were investigated in liver cirrhosis. It was demonstrated that captopril did not induce significant change in portal pressure (20). Only in two small studies enalapril was effective in reducing portal pressure in patients with less severe liver impairment (21,25). But significant changes in mean arterial pressure after enalapril were of great concern due to the potential adverse effect on renal function (21). Further on, prolonged ACE inhibition may led to activation of the alternative enzyme systems (trypsin, cathepsin) in converting angiotensin-I to angiotensin-II what abolish ACE inhibitory effect (21). Moreover, ACE inhibition of bradykinin conversion to inactive peptides may led to bradykinin accumulation, and potentiation of the systemic hyperdynamic circulation in cirrhosis (25). This led to the abolishment of potential beneficial effects of ACE inhibitors on portal pressure.
Angiotensin-II receptor antagonist represents the most advanced group of drugs affecting renin-angiotensin system. However, unlike ACE inhibitors, they do not inhibit the breakdown bradykinin and other kinins whish causes dry cough commonly accompanying ACE inhibitor therapy. In very frequently quoted report from from Heinz Kalk-Hospital, Bad Kissingen, Germany it is demonstrated that orally active antiotensin-II receptor antagonist losartan (25mg/daily) may cause significant decrease of portal pressure (in severe and moderate portal hypertension; cut-off value 20mmHg)) while no significant reduction was found in controls (23). Liver and renal function deterioration was not recorded (23). Interestingly, despite the average hepatic venous pressure gradient decrease of 45%, there was no effect on systemic pressure (23). The authors suggested that the reduction in portal pressure with losartan was due to decreased intrahepatic vascular resistance without major effect on systemic haemodynamics (23). This observation is in concordance with the fact that the activated hepatic stilette cells express antiotensin-II receptors and that binding of angiotensin-II induces their contraction and proliferation (24). In this issue of the Archives of Gastroenterohepatology Erdem A et al. further demonstrated the beneficial effect of losartan on hepatic haemodynamic in 7 patients with chronic liver disease and portal hypertension (13). They noted that the addition of somatostatin further improves portal blood flow volume and velocity in portal hypertension. All the above mentioned findings may indicate that at least in compensated liver cirrhosis angiotensin-II receptor inhibitor losartan may exhibit the positive effect by postponing the progression of portal hypertension. Suppressing the perisinusoidal stellate cell proliferation, angiotensin-II receptor antagonist, e.g. losartan may suppress hepatic fibrogenesis. This rises the possibility of the new effective treatments in the early stages of portal hypertension in chronic liver diseases.
REFERENCES:
1.Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001; 345: 669-80.
2.Gores GJ, Wiesner RH, Dickson ER, Zinmeister AR, Jorgensen RA, Langworthy A. Prospective evaluation of esophageal varices in primary biliary cirrhosis: development, natural history, and influence on survival. Gastroenterology 1989; 96: 1552-9.
3.Graham DY, Smith H. The course of patients after variceal hemorrhage. Gastroenterology 1981: 80: 800-9.
4.Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. Comparison of endoscopic ligation and propranolol for the primary prevention of varical bleeding. N Engl J Med 1999; 340: 988-93.
5.Gouirnay J, Masliah C, Martin T. Perrin D, Galmiche JP. Isosorbide mononitrate and propranolol cmmpared with propranolol alone for the prevention of variceal rebleeding. Hepatology 2000; 31: 1239-45.
6.Radevic B. Dekompresivni sant. U: Radevic B, Perisic VN, Sagic D, eds. Portna hipertenzija. Beograd: Zavet, 1999; 221-36
7.Reichen J. Liver function and pharmacological considerations in pathogenesis and treatment of portal hypertension. Hepatology 1990; 11: 1066-78
8.Vlachogiannacos J, Goulis J, Patch D et al. Primary prophylaxis for portal hypertensive bleeding in cirrhosis. Aliment Pharmacol Ther 2000; 14: 851-60.
9.Lebrec D, Poynard T, Bernuau J et al. A randomized controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhoisis; a final report. Hepatology 1984; 4: 355-8.
10. Groszman RJ, Bosch J, Grace ND et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990; 99: 1401-7.
11.Cales P, Oberti F, Payen JL et al. Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. Eur J Gastroenterol Hepatol 1999; 11: 741-5.
12.lebrec D. Drug therapy for portal hypertension. Gut 2001; 49: 441-2.
13.Erdem A, Gundogdu TT, Seyhogullari M, Ozgur S, Erdem I, Hulagu S. Arch Gastroenbterohepatol 2001; 20:
14 Ferayoni L, Polio J, Groszmann RJ. Drug therapy for portal hypertension. In: Franchis R,ed. Portal hypertension II. Second Baveno International Consensus Workshop of definitions, methodology, and therapeutic strategies. Oxford: Blackwell, 1996; 68-100.
15.Rockey D. The cellular pathogenesis of portal hypertension: stellate cells contractility, endothelin, and nitric oxide. Hepatology 1997; 25: 2-5.
16.Bosh J, Pagain-Gascia JC. Patophysiology of portal hypertension. In: Bircher J, Benhamou JP, McIntyre N, Rizzeto M, Rodes J,eds. Oxford Textbook of Hepatology. Oxford: Oxford Medical Publications, 1999; 653-60.
17.Arroyo V, Bosch J, Mauri M et al. Renin, aldosterone and renal haemodynamics in cirrhosis with ascited. Eur J Clin Invest 1979; 9: 69-73.
18.Ballet F, Chretien Y, Rey C et al. Differential response of normal and cirrhotic liver to vasoactive agents. A study in the isolated perfussed rat liver. J Pharmacol Exp Ther 1988; 244: 233-5.
19.Pinzani M, Falli P, Ruocco C et al. Fat-storing cells as liver specific perycites. Spatial dynamics of agonist-stimulated itracellular calcium tranmsients. J Clin Invest 1992; 9); 642-6.
20.Eriksson LS, Kagedal B, Wahren J. Effect of captopril on hepatic venous pressure and blood flow in patients with cirrhosis. Am J Med 1984; 76: 66-70.
21.Atlas Sam Case DB, Yu ZY et al. Hormonal and metabolic effects of angiotensin converting enzymes inhibitors. Possible differences between enalapril and captopril. Am J Med 1984; 77: 13-7.
22.Burnier M, Brunner HR. Angiotensin-II receptor antagonists. Lancet 200; 355: 637-45.
23.Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist on the portal pressure in cirrhosis. Hepatology 1999; 29: 334-9.
24.Bataller R, Gines P, Nicolas JM et al. Angiotensin-II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000; 118: 1149-56.
25.Vlachogiannakos J, Tang AKW, Patch D, Burroughs AK. Angiotensin converting enzyme inhibitors and angiotensin II antagonists as therapy in chronic liver disease. Gut 2001; 49: 303-8.