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A prospective randomized trial between the prophylactic endoscopicvariceal ligation and propranolol administration for prevention offirst bleeding in cirrhotic patients with high-risk esophageal varices
WORKING PARTY 3: Complications of cirrhosis I
WP3/19
I
OVEREXPRESSION OF ENDOTHELIN-1 DIRECTLY CORRE LATES WITH ACTIVATION OF HEPATIC STELLATE CELLS AND PORTAL PRESSURE IN BILE DUCT LIGATED RATS
SODIUM RETENTION IN PARTIAL PORTAL VEIN LIGATED (PPVL) RATS IN MEDIATED BY METABOLIC LIVER FUNCTION, NCYT BY PERIPHERAL ARTERIAL VASODILATATION
A. De Gottardi’. S. Tibhe’. A. Kaooeler’. S. Shaw3. H. S&esser’. A. Zimmermam?. J. Reichen’ ‘Dept. of Clinical Pharmacology, University of Berne, Switzerland. *Dept. of Pathology, University of &me, Switzerland. 3Dept. of Clinical Research, University of Berne, Switzerland.
0. Distler, A. Galler. W.E. Fleia. E.G. Hahn.
BackgroundAims: Hepatic stellate cells (HSCs) are involved in cirrhogenesis and the regulation of hepatic blood flow. Although endothelin-1 (ET-l) is increased in cirrhosis, data concerning its pathogenetic role are conflicting. The aim of this study was to correlate portal pressure with changes occurring in ET-1 expression and HSC activation. Methods: Studies were performed 3,7,14 and 28 days after bile duct ligation. Sham operated animals (n=6) served as controls. PreproET-1 mRNA was measured by quantitative real time PCR; its corresponding peptide was quantified by a specific radioimmunoassay. Morphometric studies were carried out on sections by the point counting procedure after immunostaining using a-smooth muscle actin. Results: The increase in ET-1 mRNA was already evident in the early course of obstructive jaundice (5.8f2.5 SD fold, 9.7i4.8, 17.7f 11.2’, 35.OS.4’, 3,7,14,28 days after BDL, respectively, compared to controls, pc.05). ET-l peptide increased significantly only in the late phase (l.liO.7 pg/lOOmg in controls, 1.8k0.4, 3.8k1.6, 4.9i1.8, 26.1ilO.O’, 3,7,14,28 days after BDL, respectively). The corresponding actin positive cell averaged 0.3*0.1%, 0.9kO.3, 2.ofO.7, 2.4f 1.1, 4.0f 1.3 in controls and after 3,7,14.28 days. There was a linear correlation between portal pressure and portal vein ET-1 (r=O.66; p=O.O03),and portal pressure and activated HSCs (r-0.80, p
LACK OF AN ANTIFIBROTIC EFFECT THELIN A/B RECEPTOR ANTAGONIST ONDARY BILIARY FIBROSIS IN RATS
OF THE MIXED ENDOLU 420627 ON RAT SEC-
J.J. Cho’s2. M. Kraiewska’. M. Raschack3. H. Herbst4. M. Ruehl’, E.G. Hahn*. E.O. Riecken’. D. Schuuuan* ‘Dept. of Gastroenterology, Univ. Hosp. B. Franklin, Free Univ. of Berlin, Germany. *Dept. of Gastroenterology, Univ. of Erlangen Nuernberg, Germany. 3BASF-Pharma Knoll AG, Univ. of Muenster, Germany. 41nst. of Pathology, Univ. of Muenster, Germany. Backgmun& Endothelin-1 (ET-l) is a potent hepatic vasoconstrictor, Furthermore, it induces proliferation and collagen synthesis of hepatic stellate cells in vitro. There is controversy if either ETA or ETB receptors are mediator of hepatic fibrogenesis. Therefore, we investigated the antifibrotic effect of the orally active non-selevtive ETA/B receptor antagonist LU 420627 (selectivity for the ETA recqtor is only 2.8 fold higher than for the ETB recepbiliary with secondary fibrosis. tor) in rats Methodsz Rats were subjected to bile duct occlwion (BDO) by retrognule injection of the sclerosant ethibloc and treated with LU 420627 at 30,lO and 3 mg/kg/d from we& 1-6 (30 and 3 mg: each n==lO,10 mg: n=20), or week 4-6 (10 mg: n=20). Animals with BDO alone (n=20) and sham-operated rats without (n=lO) or with LU 420627 at 10 mgikg/d over 6 weeks (n=lO) served as conlxols. After 6 weeks parameters of fibrogenesis were determined. Re-
sults: Liver and spleen weights were 2.8- and 3-fold increased aBer BDO, rasp.. The non-selective ETA/B R antagonist did not change body and organ weights. Total and relative liver hydnxypmline content, as a measure of the hcpatic collagen, was increased almost 7-fold after BDO (BDO vs control, 880 vs 130 mg/g liver) (p
inbiiits fibrogenesis in the progressive, non-inflammatory model of BDO and sin- a mixed ETA/B receptor antagonist is ineffective, the ETA receptor is target for an antifibrotic the therapy.
G. Wensing Med. Klinik I, University or Erlangen-Ntirnberg, Germany. Background: The role of the liver in the development of sodium and water retention and functional renal failure in liver disease is controversially discussed. Many investigations focused a peripheral arterial vasodilatation as the primary event, whde other postulate a critical role of the reduction of metabolic liver function. The aim of this study was to differentiate between these possibilities by investigating the effect of hepatic enzyme induction on sodium balance, renal function and hemodynamics in PPVL rats. Material & Methods: 4 groups of rats (n=31) were studied. I7 rats
underwent partial Portal vein ligation (PPVL), 7 of them were additionally treated with Phenobarbital (PhB) during the study. 6 untreated and 8 PhB sham-operated (SH) rats served as controls. 14C-Aminopyrine breath test (ABT) and sodium balance was determined before and after surgery. Mean arterial pressure (MAP), portal venous pressure (PVP) and renal function, measured by glomerular tiltration rate (GFR) and renal plasma flow (RPF) were studied in anaesthetized animals at the time of sodium retention. Results: Sodium retention (>0,7 mmol124h) occurred mostly at the 3rd day abler PPVL in untreated rats and was associated with a significant decrease in ABT by 45%. None of the SH-rats, nor one of the PhB-treated animals developed sodium retention. In PhB-treated rats the ABT after PPVL was significantly higher (0,02lmin~’ vs. 0,OlOmin”) than in untreated PPVL rats. MAP lacks a difference between PPVL groups (67,s vs. 67,lmmHg) and was lower than in SH rats (94.3 vs87,2mmHg; p
PPVL groups, irrespective of treatment with PhB suggests. rhat peripheral arterial vasodilatation is not the main cause for induction of sodium retention. both
The ABT discriminates between PPVL rats with and without sodium retention. Our results strongly suppon the concept of metabolic liver capacity in the pathogenesis of renal sodium and water metabolism in liver diseases.
A PROSPECTIVE RANDOMIZED TRIAL BETWEEN THE PROPHYLACTIC ENDOSCOPIC VARICEAL LIGATION AND PROPRANOLOL ADMINISTRATION FOR PREVENTION OF FIRST BLEEDING IN CIRRHOTIC PATIENTS WITH HIGH-RISK ESOPHAGEAL VARICRS
I.H. Sona. J.W. Shin. I.H. Kim. J. Choi. C.Y. Lim. J.W. Kim. I.H. Roe Division of Hepatology, Department of Internal Medicine, Dankook Univerity College of Medicine, Cheonan, Korea. Background and Aims : The prophylactic management for first bleeding in cirrhotic patients with esophageal varices is still debated. The aim of present study was to compare the outcomes between the prophylactic endoscopic variceal ligation (EVL) and propranolol admmlstration for prevention of first bleeding in cirrhotic patients with high-risk esophageal varices. Methods : We performed a propective, randomized trial in 61 cirrhotic patients with high-risk esophageal varices. The criteria used for high-risk esophageal varix were based on the endoscopic findings that showed blue colored, more than enlarged tortuous vaix with red color signs. Patients with history of esophageal variceal bleeding, hepatocellular carcinoma, cardiopulmonary diseases were excluded in this study. Endpoint of the present stady during followup were death, eradication of varices and gastrointestinal bleeding Including esophageal variceal bleemg. Results : 6 (19.4%) and 7 (23.3%) gastrointestinal bleeding occurred during follow-up in EVL and propranolol group, respectively. The cumulative varlceal bleedmg rate m EVL group at 2 weeks, 6 months, 1 year was 3.2, 3.2, 9.7%, while that in propranolol group was 0, 10, 20%. The cumulative survival rate in EVL group at 6, 12, 18 months was 93.5, 90.3, 83.9%. while that in propranolol group was 90, 83.3, 73.3%. The mortality rate during follow-up was 16.1% and 26.6% in prophylactic EVL and propranolol group, respectively. Conclusion : In cirrhotic patients with high-risk esophageal -blocker varices, the prophylactic EVL, compared with the administratlon, tends to decrease the incidence of first variceal bleeding and death in the present study, but the statistic significance for outcomes between the both treatment modalities should be assessed through the long term follow-up.
41
WP3/19
I
OVEREXPRESSION OF ENDOTHELIN-1 DIRECTLY CORRE LATES WITH ACTIVATION OF HEPATIC STELLATE CELLS AND PORTAL PRESSURE IN BILE DUCT LIGATED RATS
SODIUM RETENTION IN PARTIAL PORTAL VEIN LIGATED (PPVL) RATS IN MEDIATED BY METABOLIC LIVER FUNCTION, NCYT BY PERIPHERAL ARTERIAL VASODILATATION
A. De Gottardi’. S. Tibhe’. A. Kaooeler’. S. Shaw3. H. S&esser’. A. Zimmermam?. J. Reichen’ ‘Dept. of Clinical Pharmacology, University of Berne, Switzerland. *Dept. of Pathology, University of &me, Switzerland. 3Dept. of Clinical Research, University of Berne, Switzerland.
0. Distler, A. Galler. W.E. Fleia. E.G. Hahn.
BackgroundAims: Hepatic stellate cells (HSCs) are involved in cirrhogenesis and the regulation of hepatic blood flow. Although endothelin-1 (ET-l) is increased in cirrhosis, data concerning its pathogenetic role are conflicting. The aim of this study was to correlate portal pressure with changes occurring in ET-1 expression and HSC activation. Methods: Studies were performed 3,7,14 and 28 days after bile duct ligation. Sham operated animals (n=6) served as controls. PreproET-1 mRNA was measured by quantitative real time PCR; its corresponding peptide was quantified by a specific radioimmunoassay. Morphometric studies were carried out on sections by the point counting procedure after immunostaining using a-smooth muscle actin. Results: The increase in ET-1 mRNA was already evident in the early course of obstructive jaundice (5.8f2.5 SD fold, 9.7i4.8, 17.7f 11.2’, 35.OS.4’, 3,7,14,28 days after BDL, respectively, compared to controls, pc.05). ET-l peptide increased significantly only in the late phase (l.liO.7 pg/lOOmg in controls, 1.8k0.4, 3.8k1.6, 4.9i1.8, 26.1ilO.O’, 3,7,14,28 days after BDL, respectively). The corresponding actin positive cell averaged 0.3*0.1%, 0.9kO.3, 2.ofO.7, 2.4f 1.1, 4.0f 1.3 in controls and after 3,7,14.28 days. There was a linear correlation between portal pressure and portal vein ET-1 (r=O.66; p=O.O03),and portal pressure and activated HSCs (r-0.80, p
LACK OF AN ANTIFIBROTIC EFFECT THELIN A/B RECEPTOR ANTAGONIST ONDARY BILIARY FIBROSIS IN RATS
OF THE MIXED ENDOLU 420627 ON RAT SEC-
J.J. Cho’s2. M. Kraiewska’. M. Raschack3. H. Herbst4. M. Ruehl’, E.G. Hahn*. E.O. Riecken’. D. Schuuuan* ‘Dept. of Gastroenterology, Univ. Hosp. B. Franklin, Free Univ. of Berlin, Germany. *Dept. of Gastroenterology, Univ. of Erlangen Nuernberg, Germany. 3BASF-Pharma Knoll AG, Univ. of Muenster, Germany. 41nst. of Pathology, Univ. of Muenster, Germany. Backgmun& Endothelin-1 (ET-l) is a potent hepatic vasoconstrictor, Furthermore, it induces proliferation and collagen synthesis of hepatic stellate cells in vitro. There is controversy if either ETA or ETB receptors are mediator of hepatic fibrogenesis. Therefore, we investigated the antifibrotic effect of the orally active non-selevtive ETA/B receptor antagonist LU 420627 (selectivity for the ETA recqtor is only 2.8 fold higher than for the ETB recepbiliary with secondary fibrosis. tor) in rats Methodsz Rats were subjected to bile duct occlwion (BDO) by retrognule injection of the sclerosant ethibloc and treated with LU 420627 at 30,lO and 3 mg/kg/d from we& 1-6 (30 and 3 mg: each n==lO,10 mg: n=20), or week 4-6 (10 mg: n=20). Animals with BDO alone (n=20) and sham-operated rats without (n=lO) or with LU 420627 at 10 mgikg/d over 6 weeks (n=lO) served as conlxols. After 6 weeks parameters of fibrogenesis were determined. Re-
sults: Liver and spleen weights were 2.8- and 3-fold increased aBer BDO, rasp.. The non-selective ETA/B R antagonist did not change body and organ weights. Total and relative liver hydnxypmline content, as a measure of the hcpatic collagen, was increased almost 7-fold after BDO (BDO vs control, 880 vs 130 mg/g liver) (p
inbiiits fibrogenesis in the progressive, non-inflammatory model of BDO and sin- a mixed ETA/B receptor antagonist is ineffective, the ETA receptor is target for an antifibrotic the therapy.
G. Wensing Med. Klinik I, University or Erlangen-Ntirnberg, Germany. Background: The role of the liver in the development of sodium and water retention and functional renal failure in liver disease is controversially discussed. Many investigations focused a peripheral arterial vasodilatation as the primary event, whde other postulate a critical role of the reduction of metabolic liver function. The aim of this study was to differentiate between these possibilities by investigating the effect of hepatic enzyme induction on sodium balance, renal function and hemodynamics in PPVL rats. Material & Methods: 4 groups of rats (n=31) were studied. I7 rats
underwent partial Portal vein ligation (PPVL), 7 of them were additionally treated with Phenobarbital (PhB) during the study. 6 untreated and 8 PhB sham-operated (SH) rats served as controls. 14C-Aminopyrine breath test (ABT) and sodium balance was determined before and after surgery. Mean arterial pressure (MAP), portal venous pressure (PVP) and renal function, measured by glomerular tiltration rate (GFR) and renal plasma flow (RPF) were studied in anaesthetized animals at the time of sodium retention. Results: Sodium retention (>0,7 mmol124h) occurred mostly at the 3rd day abler PPVL in untreated rats and was associated with a significant decrease in ABT by 45%. None of the SH-rats, nor one of the PhB-treated animals developed sodium retention. In PhB-treated rats the ABT after PPVL was significantly higher (0,02lmin~’ vs. 0,OlOmin”) than in untreated PPVL rats. MAP lacks a difference between PPVL groups (67,s vs. 67,lmmHg) and was lower than in SH rats (94.3 vs87,2mmHg; p
PPVL groups, irrespective of treatment with PhB suggests. rhat peripheral arterial vasodilatation is not the main cause for induction of sodium retention. both
The ABT discriminates between PPVL rats with and without sodium retention. Our results strongly suppon the concept of metabolic liver capacity in the pathogenesis of renal sodium and water metabolism in liver diseases.
A PROSPECTIVE RANDOMIZED TRIAL BETWEEN THE PROPHYLACTIC ENDOSCOPIC VARICEAL LIGATION AND PROPRANOLOL ADMINISTRATION FOR PREVENTION OF FIRST BLEEDING IN CIRRHOTIC PATIENTS WITH HIGH-RISK ESOPHAGEAL VARICRS
I.H. Sona. J.W. Shin. I.H. Kim. J. Choi. C.Y. Lim. J.W. Kim. I.H. Roe Division of Hepatology, Department of Internal Medicine, Dankook Univerity College of Medicine, Cheonan, Korea. Background and Aims : The prophylactic management for first bleeding in cirrhotic patients with esophageal varices is still debated. The aim of present study was to compare the outcomes between the prophylactic endoscopic variceal ligation (EVL) and propranolol admmlstration for prevention of first bleeding in cirrhotic patients with high-risk esophageal varices. Methods : We performed a propective, randomized trial in 61 cirrhotic patients with high-risk esophageal varices. The criteria used for high-risk esophageal varix were based on the endoscopic findings that showed blue colored, more than enlarged tortuous vaix with red color signs. Patients with history of esophageal variceal bleeding, hepatocellular carcinoma, cardiopulmonary diseases were excluded in this study. Endpoint of the present stady during followup were death, eradication of varices and gastrointestinal bleeding Including esophageal variceal bleemg. Results : 6 (19.4%) and 7 (23.3%) gastrointestinal bleeding occurred during follow-up in EVL and propranolol group, respectively. The cumulative varlceal bleedmg rate m EVL group at 2 weeks, 6 months, 1 year was 3.2, 3.2, 9.7%, while that in propranolol group was 0, 10, 20%. The cumulative survival rate in EVL group at 6, 12, 18 months was 93.5, 90.3, 83.9%. while that in propranolol group was 90, 83.3, 73.3%. The mortality rate during follow-up was 16.1% and 26.6% in prophylactic EVL and propranolol group, respectively. Conclusion : In cirrhotic patients with high-risk esophageal -blocker varices, the prophylactic EVL, compared with the administratlon, tends to decrease the incidence of first variceal bleeding and death in the present study, but the statistic significance for outcomes between the both treatment modalities should be assessed through the long term follow-up.
41