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Analysis of haemodynamic changes related to hepatic cirrhosis by an ultrasound contrast agent
14 pat with HC (clinical and/or histological diagnosis); 17 pat with non-cirrhotic chronic liver disease; 12 patients without liver disease. 4 pat were excluded: 2 pat with HC becausethey are taking vasoactive drugs; 1 pat with non-cirrhotic liver disease and 1 pat without liver diseasefor poor quality of doppler signal. The microbubblecontrast agent usedwas Levovist~ (Schering A.C.), which consists of galactose microparticles and a small admixture of palmitic acid (0.1%). 2.5 or of Levovist~ (concentration of 300 mg/ml) was injected at 1 ml/sec in an antecubital vein. The intensity of the doppler trace of middle hepatic vein was recordered from 10 sec before to 2 rain after Levovist~ injection. To evaluate the liver first-passage of Levovist~, we analyzed: a) arrival time of the contrast; b) time to peak enhancement of dopplersignal; c) absolute peak and d) rise rate of doppler signal. Results: Arrival time and time to peak enhancementwere lower in HC group compared with non-cirrhotic pat (with or without chronic liver disease):(11.54 -+ 4.03 sec vs 26.91 -+ 9.55 sec, p< 0.001) and (41.76 _+17.39 sec vs 69.08 -+ 28.60 sac, p< 0.005) respectively(Tab.l). No significant differences were found betweenpat with or without non-cirrhotic chronic liver disease.For absolute peak and rise rate of doppler signal after bolus injection of Levovist~),no significant differences were found betweenthe three groups. Conclusions:Analysis of liver first-passage of a microbutible contrast agent could be an useful non-invasive tool to evaluate development of HC in pat with chronic liver disease.
6 Regulation of Cholangiocyte Apical Bile Acid Transporter (ABAT) Activity by Biliary Bile Acids: Different Potential CompensatoryChanges for Intrahepafic and Extrahepatic Cholestasis Gianfranco Alpini, The Texas A&M Univ System Health Science Ctr, Temple, iX; Shannon Glaser, Jo Lynne Phinizy, Scott & White Memorial Hosp, Temple, TX; Noriatsu Kanno, The Texas A&M Univ System Health Science Ctr, Temple, TX; Heather Francis, Scott & White Memorial Hosp, Temple, TX; Mikel Ludvik, The Texas A&M Univ System Health Science Ctr, Temple, IX; Gene Lesage,Scott & White Memorial Hosp, Temple, TX We were the first to characterizethe transport activity of the cholangiocyteASAT. Bile acids (BA) accumulation in cholestatic liver diseases may induce liver cell damage and adaptive changes in BA transport that prevent intracellular sequestration of potentially toxic BA. In cholestasis due to extrahepatic obstruction, cholehepatic shunting (initiated by hiliary BA absorption tiy ABAT) could provide a pathway for continued bile acid flux through the liver, thus preventing BA-inducedcellular injury. Alternatively, in intTahepaticchelestasis (e.g. primary hiliary cirrhosis), reducedABATactivity would potentiallyminimize BA-inducedcholangiocyte injury. Alteration of BA transport in cholangiocytes,as secondaryprotectivemechanisms against cholestasisis unknown. OBJECTIVES:To determinein a model of chronic cholestasis, the bile duct ligated (BDL) rat, if ABAT is regulated by biliary BA concentrations and if this regulation is dependenton the structure of BA. METHODS:ABAT protein levels (determined by immunoblots) and transport activity was determined in cholanglocytesfrom normal, BDL, BDL rats with external bile fistula (bile-depleted) and BDL bile-depicted rats which received an infusion of taurocholic acid (TC, 1 /AWmin/kg) to sustain billary BA, and BDL rats fed tauroursodeoxycholicacid (TUDCA) 1% in their diet. RESULTS:ABAT protein and transport activity per cholangiocytewas similar in normal and BOL cholangiocytee,however,total liver ABAT increased 5-fold due to the increase in the number of chofanglocytes in BDL liver. In bile-deplatedBDL rats, ABAT decrease6-fold comparedto BDL control. In bile-depicted BOL rats that received TC infusion, biliary bile acid concentration, ABAT protein and transport activity was restored to values similar to BOL controls. In BDL rats fed TUDCA,ABAT protein and transport activity Jn cholangJocyteswas markedly decreasedcomparedto BDL controls. CONCLUSIONS:We found that ABAT protein and transport activity in BDL rats is directly regulated by biliary BA concentrations. The data are consistent with our hypothesis that with cholestasis due to extrabepaticobstruction, upregulation of ABAT and increased BA uptake from bile ducts provides an adaptive alternative pathway for accumulating BA. Alternatively, in intrahepaticcholestasis TUDCAdown regulation of ABAT has the potential to prevent entry of toxic BA into ctiolangiocytes.
Tab. 1 - Paranletersof time~ntesitycurveof dopplersignal.(Mean+ SD)
69 60 54 42
67 59 53 43
p
Ardvat time (sec) 'rkne to peak (sec)
11.54_+4.03 41 76 + 17.39
26.91 + 9.55 69.08 + 28.60
<0.001 <0.005
10 lladoloi M u Spironolactone vs Nadolol Alone in the Prophylaxis of the First Vodceal Bleeding in Non-Ascific Cirrhotic Patients.A Prospective, MulUcenter, Double Blind and RandomizedTrial. Raquel G. Abecasis, David Kravetz, Eduardo Fassio, BeatrizAmeigeiras, Daniel Garcia, Rogelio Isla, Graciela Landeira, Gustavo A. Romero, Ruben A. Terg, Hosp Dr C B Udaondo, Hosp Posadas, Hosp Ramos Mejia, Hosp Municipal, and Hosp Israel, Buenos Aires Argentina Beta--Blockers fail to decreaseportal pressurein nearly40% of cirrhotic patients(pts).Recent studies have suggestedthat spironolactone(Spi) reduces pressure and flow in the portal and variceal systems. Aim:to assess if nadolol(Nad)plusSpi is more effective than Ned alone to prevent the first variceal bleeding. Materials and Methods:100 pts, with medium and large esophagealvarices who had never bled, without ascites and no diuretic treatment for at least 30 days, were included. Pts were randomized in 2 groups. Gh(n =51)was treated with Ned to reduce heart rate by 25% plus placebo and GIl:(n =49) received Nad as GI plus Spi 100 mg/day. All pts were under a unrestricted sodium diet. Portal pressure estimated from the hepatic venous pressure gradient (HVPG)and the activity of the renin-aldosterone system (PRA-PA) ware measured in 12 pts of each group, before and after 2 and 18 months of treatment, respectively. Results: At baseline both groups were similar in age, sex, etiology, Child-Pugh score, variceal size, previous ascites, PRA-PA,HVPG, liver and renal function tests.The efficacy of both treatments is summarized in the table. The mean nadolol dose was similar( GI 81_+60 and GII 76_+62 rag/d). Six pts (3 in each group) were lost of follow-up, The rate of complications that required withdrawal from the study was 10% in GI and 12% in GII (9 pts due to Nad and 2 pts due to Spi). The actuarial percentageof pts free of bleeding and ascites after 48 months were 73 and 57% in GI and 79 and 73% in GII respectively(ns). Cumulative survival was also similar (85% in GI and 96% in GII). Conclusions: These results suggest that the association of spironolactone and nadolol did not significantly increasethe efficacy of nadolol alone in the prophylaxis of the first variceal bleeding nor in the prevention of ascites development.
Actual Survival (%) TIPS HGPCS 83 76 65 49
Non4iver cirrhosis (with or without liver disease)
The llddenco Of Esophageal Varices In Cirrhosis Gennaro D'Nnico, Linda Pasta, Salvatore Madonia, Hosp V Cervello, Palermo Italy; Ilaria G. Tarantino, Andrea Mancuso, Univ of Palermo, Palermo Italy; Giuseppe Malizia, Gandoifo C. Glannooli, Divisione di Medicine, Hosp V Cervello, Palermo Italy; Luigi Pagliaro, Clin Medica-University of Palermo, Palermo Italy Background.The incidenceof esophagealvarices in cirrhosis is still poorly defined. Therefore it is not known which is the best time interval for repeat endoscopywhen screening patients at risk of bleeding.Methods. We assessedthe incidenceof esophagealvarices in a prospective study of the natural history of liver cirrhosis. Results. Among the 494 consecutive patients with newly diagnosed cirrhosis enrolled in this study between 1981 and 1984, there were 225 without varices at inclusion in the study (124 males, mean age 48 yrs, anti-HCV 201, ascites 11, Child-PnghNB/C 165/57/3). The mean follow-up of these 225 patients is 131 _+48 mos (5 lost to follow-up). The study is still in progress. All patients underwent endoscopy at 1-3 yr intervals or at bleeding. After 10 yrs, varices were detected in 93/225 pts (41%). At that time, the cumulative proportion of patients free of varices was 55% (CI 49-62%). Platelets and HBsAg (p<0.00001) at diagnosis were the only significant predictors of the development of varices, out of ten candidate variables (Cox model). Thirty patients bled (cumulative proportion free of bleeding 85%, CI 80-89%) and 66 died (cumulative proportion surviving 70%, CI 64-76%).Thirtysix had no varices when died (9 for liver failure, 3 sepsis, 12 HCC, 11 other, 1 unknown). Thirty died after development of varices (9 for bleeding, 9 liver lallure, 1 sepsis, 5 HCC,6 other). Conclusions.The incidenceof varicesin newlydiagnosed compensatedcirrhosis is near 4.5% per year, mortality in patientswithout varicesat diagnosis is near 3% per year and mortality from bleeding near 0.5% per year.
Predicted vs Actual Survival Following TIPS vs H-Graff Poftacaval Shunt Alexander S. Rosemurgy, Mark Bloomsotn, Shelby Blank, Francesco Scrafioi, Univ of South Florida, Tampa, FL Background: From 1993-1998, patients were prospectively randomizedto undergo TIPS or small diameter prosthetic H-graft portacavalshunt (HGPCS)as definitive therapy of bleeding varices. This study was undertakento compare predictedsurvival, actual vs predicted survival, and actual survival/failure in patients undergoing TIPS vs HGPCS.Methods: Using a formula to predict survival after TIPS (Hepatology2000;31:864), 3, 6,12, and 24 month survival was predicted for patients undergoing TIPS and HGPCS.Predicted survivals were compared and then comparedto actual survivals using ManteI-Haenszei7.2analysis.Curvesof actual survival or failure (death,irreversibleshunt occlusion, unexpectedtransplantation,or varicealrehemorrhage) after TIPS or HGPCSwere compared using ManteI-HaenszelLife Table tests. Results: Data used to calculate predicted survival were available for 126 (95%) of 132 patients (64 TIPS, 62 HGPCS). Patients undergoing TIPS or HGPCSware similar by age, gender, Child's class, cause of cirrhosis, and urgency of shunting and had needy identical predicted survival (p=0.88) (Table). After TIPS, patients had better survival than predicted (p =O.O04)(Tabla), as after HGPCS (p
3 months 8 mo.ths 12 months 24 months
Liver ciwhosis
9
7
P~dicted Survival (%) TIPS HGPCS
PanmMm~
79 77 72 64
8 Analysis Of Haemodynamic Changes Related To Hepatic Cirdiosis By An Ultrasound Contrast Agent Giuseppe Feiiciangeli, Giullo Argalia, Laura Belngnini, Teresa Abhattista, Martina Urhani, Univ of Ancona, Ancona Italy; PasqualeRusso, Antonio Benedetti, Univ of Ancona, Ancona Italy Background:Hepatic cirrhosis(HC) is accompained by hyperdynamic circulatory state and portal hypertension. Developmentof ultrasound microbubble contrast agents provided new diagnostic tool for the evaluationof patients (pat) with chronic liver disease. Aim: To assess whether quantitative dynamic uitrasonography of hepatic veins after an intravenous bolus injection of a microhubble contrast agent can he used to analyzedhaemodynamic changes in patients (pat) with HC. Methods: 43 pat (27 males, mean age 54.5 years) were enrolled:
A-2
6 Regulation of Cholangiocyte Apical Bile Acid Transporter (ABAT) Activity by Biliary Bile Acids: Different Potential CompensatoryChanges for Intrahepafic and Extrahepatic Cholestasis Gianfranco Alpini, The Texas A&M Univ System Health Science Ctr, Temple, iX; Shannon Glaser, Jo Lynne Phinizy, Scott & White Memorial Hosp, Temple, TX; Noriatsu Kanno, The Texas A&M Univ System Health Science Ctr, Temple, TX; Heather Francis, Scott & White Memorial Hosp, Temple, TX; Mikel Ludvik, The Texas A&M Univ System Health Science Ctr, Temple, IX; Gene Lesage,Scott & White Memorial Hosp, Temple, TX We were the first to characterizethe transport activity of the cholangiocyteASAT. Bile acids (BA) accumulation in cholestatic liver diseases may induce liver cell damage and adaptive changes in BA transport that prevent intracellular sequestration of potentially toxic BA. In cholestasis due to extrahepatic obstruction, cholehepatic shunting (initiated by hiliary BA absorption tiy ABAT) could provide a pathway for continued bile acid flux through the liver, thus preventing BA-inducedcellular injury. Alternatively, in intTahepaticchelestasis (e.g. primary hiliary cirrhosis), reducedABATactivity would potentiallyminimize BA-inducedcholangiocyte injury. Alteration of BA transport in cholangiocytes,as secondaryprotectivemechanisms against cholestasisis unknown. OBJECTIVES:To determinein a model of chronic cholestasis, the bile duct ligated (BDL) rat, if ABAT is regulated by biliary BA concentrations and if this regulation is dependenton the structure of BA. METHODS:ABAT protein levels (determined by immunoblots) and transport activity was determined in cholanglocytesfrom normal, BDL, BDL rats with external bile fistula (bile-depleted) and BDL bile-depicted rats which received an infusion of taurocholic acid (TC, 1 /AWmin/kg) to sustain billary BA, and BDL rats fed tauroursodeoxycholicacid (TUDCA) 1% in their diet. RESULTS:ABAT protein and transport activity per cholangiocytewas similar in normal and BOL cholangiocytee,however,total liver ABAT increased 5-fold due to the increase in the number of chofanglocytes in BDL liver. In bile-deplatedBDL rats, ABAT decrease6-fold comparedto BDL control. In bile-depicted BOL rats that received TC infusion, biliary bile acid concentration, ABAT protein and transport activity was restored to values similar to BOL controls. In BDL rats fed TUDCA,ABAT protein and transport activity Jn cholangJocyteswas markedly decreasedcomparedto BDL controls. CONCLUSIONS:We found that ABAT protein and transport activity in BDL rats is directly regulated by biliary BA concentrations. The data are consistent with our hypothesis that with cholestasis due to extrabepaticobstruction, upregulation of ABAT and increased BA uptake from bile ducts provides an adaptive alternative pathway for accumulating BA. Alternatively, in intrahepaticcholestasis TUDCAdown regulation of ABAT has the potential to prevent entry of toxic BA into ctiolangiocytes.
Tab. 1 - Paranletersof time~ntesitycurveof dopplersignal.(Mean+ SD)
69 60 54 42
67 59 53 43
p
Ardvat time (sec) 'rkne to peak (sec)
11.54_+4.03 41 76 + 17.39
26.91 + 9.55 69.08 + 28.60
<0.001 <0.005
10 lladoloi M u Spironolactone vs Nadolol Alone in the Prophylaxis of the First Vodceal Bleeding in Non-Ascific Cirrhotic Patients.A Prospective, MulUcenter, Double Blind and RandomizedTrial. Raquel G. Abecasis, David Kravetz, Eduardo Fassio, BeatrizAmeigeiras, Daniel Garcia, Rogelio Isla, Graciela Landeira, Gustavo A. Romero, Ruben A. Terg, Hosp Dr C B Udaondo, Hosp Posadas, Hosp Ramos Mejia, Hosp Municipal, and Hosp Israel, Buenos Aires Argentina Beta--Blockers fail to decreaseportal pressurein nearly40% of cirrhotic patients(pts).Recent studies have suggestedthat spironolactone(Spi) reduces pressure and flow in the portal and variceal systems. Aim:to assess if nadolol(Nad)plusSpi is more effective than Ned alone to prevent the first variceal bleeding. Materials and Methods:100 pts, with medium and large esophagealvarices who had never bled, without ascites and no diuretic treatment for at least 30 days, were included. Pts were randomized in 2 groups. Gh(n =51)was treated with Ned to reduce heart rate by 25% plus placebo and GIl:(n =49) received Nad as GI plus Spi 100 mg/day. All pts were under a unrestricted sodium diet. Portal pressure estimated from the hepatic venous pressure gradient (HVPG)and the activity of the renin-aldosterone system (PRA-PA) ware measured in 12 pts of each group, before and after 2 and 18 months of treatment, respectively. Results: At baseline both groups were similar in age, sex, etiology, Child-Pugh score, variceal size, previous ascites, PRA-PA,HVPG, liver and renal function tests.The efficacy of both treatments is summarized in the table. The mean nadolol dose was similar( GI 81_+60 and GII 76_+62 rag/d). Six pts (3 in each group) were lost of follow-up, The rate of complications that required withdrawal from the study was 10% in GI and 12% in GII (9 pts due to Nad and 2 pts due to Spi). The actuarial percentageof pts free of bleeding and ascites after 48 months were 73 and 57% in GI and 79 and 73% in GII respectively(ns). Cumulative survival was also similar (85% in GI and 96% in GII). Conclusions: These results suggest that the association of spironolactone and nadolol did not significantly increasethe efficacy of nadolol alone in the prophylaxis of the first variceal bleeding nor in the prevention of ascites development.
Actual Survival (%) TIPS HGPCS 83 76 65 49
Non4iver cirrhosis (with or without liver disease)
The llddenco Of Esophageal Varices In Cirrhosis Gennaro D'Nnico, Linda Pasta, Salvatore Madonia, Hosp V Cervello, Palermo Italy; Ilaria G. Tarantino, Andrea Mancuso, Univ of Palermo, Palermo Italy; Giuseppe Malizia, Gandoifo C. Glannooli, Divisione di Medicine, Hosp V Cervello, Palermo Italy; Luigi Pagliaro, Clin Medica-University of Palermo, Palermo Italy Background.The incidenceof esophagealvarices in cirrhosis is still poorly defined. Therefore it is not known which is the best time interval for repeat endoscopywhen screening patients at risk of bleeding.Methods. We assessedthe incidenceof esophagealvarices in a prospective study of the natural history of liver cirrhosis. Results. Among the 494 consecutive patients with newly diagnosed cirrhosis enrolled in this study between 1981 and 1984, there were 225 without varices at inclusion in the study (124 males, mean age 48 yrs, anti-HCV 201, ascites 11, Child-PnghNB/C 165/57/3). The mean follow-up of these 225 patients is 131 _+48 mos (5 lost to follow-up). The study is still in progress. All patients underwent endoscopy at 1-3 yr intervals or at bleeding. After 10 yrs, varices were detected in 93/225 pts (41%). At that time, the cumulative proportion of patients free of varices was 55% (CI 49-62%). Platelets and HBsAg (p<0.00001) at diagnosis were the only significant predictors of the development of varices, out of ten candidate variables (Cox model). Thirty patients bled (cumulative proportion free of bleeding 85%, CI 80-89%) and 66 died (cumulative proportion surviving 70%, CI 64-76%).Thirtysix had no varices when died (9 for liver failure, 3 sepsis, 12 HCC, 11 other, 1 unknown). Thirty died after development of varices (9 for bleeding, 9 liver lallure, 1 sepsis, 5 HCC,6 other). Conclusions.The incidenceof varicesin newlydiagnosed compensatedcirrhosis is near 4.5% per year, mortality in patientswithout varicesat diagnosis is near 3% per year and mortality from bleeding near 0.5% per year.
Predicted vs Actual Survival Following TIPS vs H-Graff Poftacaval Shunt Alexander S. Rosemurgy, Mark Bloomsotn, Shelby Blank, Francesco Scrafioi, Univ of South Florida, Tampa, FL Background: From 1993-1998, patients were prospectively randomizedto undergo TIPS or small diameter prosthetic H-graft portacavalshunt (HGPCS)as definitive therapy of bleeding varices. This study was undertakento compare predictedsurvival, actual vs predicted survival, and actual survival/failure in patients undergoing TIPS vs HGPCS.Methods: Using a formula to predict survival after TIPS (Hepatology2000;31:864), 3, 6,12, and 24 month survival was predicted for patients undergoing TIPS and HGPCS.Predicted survivals were compared and then comparedto actual survivals using ManteI-Haenszei7.2analysis.Curvesof actual survival or failure (death,irreversibleshunt occlusion, unexpectedtransplantation,or varicealrehemorrhage) after TIPS or HGPCSwere compared using ManteI-HaenszelLife Table tests. Results: Data used to calculate predicted survival were available for 126 (95%) of 132 patients (64 TIPS, 62 HGPCS). Patients undergoing TIPS or HGPCSware similar by age, gender, Child's class, cause of cirrhosis, and urgency of shunting and had needy identical predicted survival (p=0.88) (Table). After TIPS, patients had better survival than predicted (p =O.O04)(Tabla), as after HGPCS (p
3 months 8 mo.ths 12 months 24 months
Liver ciwhosis
9
7
P~dicted Survival (%) TIPS HGPCS
PanmMm~
79 77 72 64
8 Analysis Of Haemodynamic Changes Related To Hepatic Cirdiosis By An Ultrasound Contrast Agent Giuseppe Feiiciangeli, Giullo Argalia, Laura Belngnini, Teresa Abhattista, Martina Urhani, Univ of Ancona, Ancona Italy; PasqualeRusso, Antonio Benedetti, Univ of Ancona, Ancona Italy Background:Hepatic cirrhosis(HC) is accompained by hyperdynamic circulatory state and portal hypertension. Developmentof ultrasound microbubble contrast agents provided new diagnostic tool for the evaluationof patients (pat) with chronic liver disease. Aim: To assess whether quantitative dynamic uitrasonography of hepatic veins after an intravenous bolus injection of a microhubble contrast agent can he used to analyzedhaemodynamic changes in patients (pat) with HC. Methods: 43 pat (27 males, mean age 54.5 years) were enrolled:
A-2