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Reversibility of hepatorenal syndrome (HRS) by the administration of terlipressin and albumin. A phase-II study
GENERAL
SESSION
4
mGS4/19 RANDOMIZED STUDY COMPARING THE TRANSJUGULAR INTRAPHEPATIC PORTOSYSTEMIC SHUNT Crrps) WITH PARACENTESIS M. Rijssle’. A. Ochs’. V Gtilbera. V. Sieeerstetter’. J. Holl. P Deibert’, M. Olschewski’. M. Reiser2. A. Gerbes Dpt. of Gastroenterology, Germany. ‘University Hospitals of Freiburg, Munich, Germany. 2Dpt. of Radiology, Germany. Sixty patients with rektory or recidivant ascites (Child-Pugh class B: 42, C: 18) were randomized to receive TIPS (29 pts) or large volume paracentesis (3 1 pts) and followed for 45 It 16 and 44 f 18 months, respectively. In patients in whom pamcentesis failed (i.e., inability to remove the ascites or need for more than 1 large volume paracentesis per week) the TIPS was offered. Re.&s. The shunts were successllly placed in all but one patient. ParacentesisfailedinlOpatientswhorsceivedTIPS5.5f4 months a&r randomization. The 1and Z-year intention-to-treat probability of survival was 69 and 58 percent in the shunted and 52 and 32 percent in the paracentesis patients (P = 0.11). A multivariate &x’s proportional hazard model including relevant pre&eatment covariables showed an independent significant improvement of survival by the TIPS Q = 0.023). Complete response (absence of ascites) was achieved in 87 percent of the shunted and 32 percent of the paracentesis patients (P = 0.006). Both groups had a similar occurrence of hepatic encephalopathy. Conclusions. Our study recommends the use of the transjugular intrahepatic portosystemic shunt for treatment of refractory and recidivant ascites. This treatment prolongs survival and relieves from ascites.
REVERSIBILITY OF HEPATORENAL SYNDROME (HRS) BY THE ADMINISTRATION OF TERLIPRESSIN AND ALBUMIN. A PHASEII STUDY J. Uriz. P Gin&.. P. Sort. A. Cgrdenas. W. Jimbnez. J.M. Salmer6n. V. Arrovo. J. Rod&s Liver Unit, Institut for Digestive Diseases, Hormonal Laboratory, Hospital Clinic, Barcelona, Spain.
In HRS there is an intense stimulation of the sympathetic nervous system (SNS) that plays a major role in the pathogenesis of renal vasoconstriction. It is believed that this effect is due to the action of norepinephrine (NE) released from the sympathetic nerve terminals on the vascular alfa-adrenergic receptors. It is unknown whether this vasoconstriction can also be mediated by vasoconstrictor peptides such as NPY. NPY is costored with NE within the sympathetic nerve terminals and released upon marked stimulations of the SNS and has a marked vasconstrictor potency in several vascular beds, specially the renal circulation. The circulating plasma levels of NPY were determined by RIA in 17 healthy controls, 9 cirrhotic patients without ascites, and 37 cirrhotic patients with ascites of whom 12 had HRS. The NPY levels in cirrhotic patients with ascites were similar to those of patients without ascites and healthy controls (73&4, 76&4 and 68*4 pmol/l, respectively; NS). However, patients with HRS had significantly increased circulating levels of NPY with respect to the other groups (1 IO& pmoi/; pcO.001). NPY levels correlated directly with NE concentration and inversely with renal plasma flow and glomerular filtration rate. These results suggest that the intense hyperstimulation of the SNS in HRS induces a release of NPY that may contribute to the pathogenesis of renal vasoconstriction.
HEPATITIS C VIRUS (HCV) CORE PROTEIN INHIBITS VLDL LIVER SECRETION: AN IN VZVO MODEL OF VIRUS-LIPID INTERACTION G. Perlemuter’. A. Sabile’. F! Letteror?. K. Koike3. J. Chauman4. D. Pessay&. G. Barba’. C. B&hot’ ‘INSERM U370 and Liver Unit, Necker, Paris, France. 21NSERM U481, Clichy, France. 3Tokyo University of Medicine, Japan. “INSERM U321, Paris, France. Prevalence of fatly liver is high in hepatitis C infection but the mechanisms of steatosis are unknown. We have previously shown in virro the direct role of HCV core in steatosia, its interaction with apolipopmtein AII (ape AD), and mcdulation of HCV core secretion through this interaction. HCV core aansgenic (tg) mice show steatosis and hepatocellular carcinoma; the nlm of the study WBI therefore to analyze in viva the mechanisms of HCV-related steatoais in this model by comparing HCV core and corekpn AR double tg mice. Metbods: 4 tg mice groups wem analyeed: 1) core: 2) spa An: 3) double tg core/ape An; 4) conaol. II-oxidation: CO,* exhalation after force-feeding mice with UC”@nitate( Hepstlc VLDL secretion: a&on WR1339 (which inhibits lipoprotein lipasc) injected lo the mice; aiglycerids (TO) sod apo BlOO measured before and 4 h after injection. PeroxIdation: ethene exhalation and hepstic thioharbituric acid nactsatr (TBARs) levels. Results: 1) No significant difference in B-oxidation (similar CO,* exhalation) in conaol, core. apu AII and double tg core/apoAII mice. 2) T&on injection induced B 16 fold increase of TO in control mice in comparison to 9 (p
INTRAHEPATIC HCV-INFECTION
HCV-SPECIFIC CD4+ ARE MULTISPECIFIC
T CELLS IN CHRONIC AND PRODUCE y-IFN
C.A. Schirren, M.C. June. T. Worzfeld, J.T. Gerlach. N.H. Gruener, H.M. Dieuolder. M. Houghton. G.R. Paoe Med. Dept. II, Klinikum Grosshadern and Inst. f. Imm., Munich, Germany, Chiron, CA, USA.
BACKGROUND: The majority of previous studies of HCV-specific CD4t T cell response has focussed on the peripheral blood and reported that elimination of HCV depends on a strong long-lasting CD4t T cell response. Little is known about the intrahepatic CD4+ T cell response. We therefore studied the intrahepatii CD4t T cell response and compared if to the peripheral T cell response. METHODS: 15 intrahepatic T cell lines were studied in 15 patients with chronic hepatitis C (CH-C) and in 18 patients with HCV-associated liver cirrhosis. Parallelly, blood&&fed T cell lines were grown in all patients. Virus-specific 1”IFN production and phenotyping to various HCV-proteins (core, NSY4, NS5) were determined by ELISPOT and FACS. RESULTS: In 5!15 (33 %) liver tissue-derived T cell lines of patients with CH-C and in lo/l8 (56 %) of patients with cirrhosis a significant number of y-IFN spots to structural and non-structural HCV-proteins were observed. 205 (13 %) of patients with CH-C and 2/18 (11 %) with cirrhosis showed HCV-specifiiity exclusively in the blood; in 3/18 (17 %) patients with cirrhosis virus-specific T cells were observed in both compartments; in 5/15 cases (33 %) with CH-C and in 7/18 (39 %) patients with cirrhosis HCV-specific T cells were exclusively detected in liver tissue. HCVspecificity was significant more often detected in liver tissue than in peripheral blood (p=O.O4). ! ACS-anafysis revealed no statistical significant difference between both groups with regard to expression of surface molecules. All T cell lines were dominated by CD4t T cells. CONCLUSIONS: Our data show that HCVspecific CD4t T cells can be detected in liver tissue and also in peripheral blood of patients with CH-C and HCV-associated cirrhosis. The HCV-specific CD4+ T cell response is multi-specific, characterized by y-IFN production and compartmentalize to the liver. This virus-specific immune response is detected only in a minorii of patients with CH-C and HCV-associated cirrhosis. Our data support the concept that a low frequency of specific T cells is associated with failure to clear the virus and chronic course of disease.
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SESSION
4
mGS4/19 RANDOMIZED STUDY COMPARING THE TRANSJUGULAR INTRAPHEPATIC PORTOSYSTEMIC SHUNT Crrps) WITH PARACENTESIS M. Rijssle’. A. Ochs’. V Gtilbera. V. Sieeerstetter’. J. Holl. P Deibert’, M. Olschewski’. M. Reiser2. A. Gerbes Dpt. of Gastroenterology, Germany. ‘University Hospitals of Freiburg, Munich, Germany. 2Dpt. of Radiology, Germany. Sixty patients with rektory or recidivant ascites (Child-Pugh class B: 42, C: 18) were randomized to receive TIPS (29 pts) or large volume paracentesis (3 1 pts) and followed for 45 It 16 and 44 f 18 months, respectively. In patients in whom pamcentesis failed (i.e., inability to remove the ascites or need for more than 1 large volume paracentesis per week) the TIPS was offered. Re.&s. The shunts were successllly placed in all but one patient. ParacentesisfailedinlOpatientswhorsceivedTIPS5.5f4 months a&r randomization. The 1and Z-year intention-to-treat probability of survival was 69 and 58 percent in the shunted and 52 and 32 percent in the paracentesis patients (P = 0.11). A multivariate &x’s proportional hazard model including relevant pre&eatment covariables showed an independent significant improvement of survival by the TIPS Q = 0.023). Complete response (absence of ascites) was achieved in 87 percent of the shunted and 32 percent of the paracentesis patients (P = 0.006). Both groups had a similar occurrence of hepatic encephalopathy. Conclusions. Our study recommends the use of the transjugular intrahepatic portosystemic shunt for treatment of refractory and recidivant ascites. This treatment prolongs survival and relieves from ascites.
REVERSIBILITY OF HEPATORENAL SYNDROME (HRS) BY THE ADMINISTRATION OF TERLIPRESSIN AND ALBUMIN. A PHASEII STUDY J. Uriz. P Gin&.. P. Sort. A. Cgrdenas. W. Jimbnez. J.M. Salmer6n. V. Arrovo. J. Rod&s Liver Unit, Institut for Digestive Diseases, Hormonal Laboratory, Hospital Clinic, Barcelona, Spain.
In HRS there is an intense stimulation of the sympathetic nervous system (SNS) that plays a major role in the pathogenesis of renal vasoconstriction. It is believed that this effect is due to the action of norepinephrine (NE) released from the sympathetic nerve terminals on the vascular alfa-adrenergic receptors. It is unknown whether this vasoconstriction can also be mediated by vasoconstrictor peptides such as NPY. NPY is costored with NE within the sympathetic nerve terminals and released upon marked stimulations of the SNS and has a marked vasconstrictor potency in several vascular beds, specially the renal circulation. The circulating plasma levels of NPY were determined by RIA in 17 healthy controls, 9 cirrhotic patients without ascites, and 37 cirrhotic patients with ascites of whom 12 had HRS. The NPY levels in cirrhotic patients with ascites were similar to those of patients without ascites and healthy controls (73&4, 76&4 and 68*4 pmol/l, respectively; NS). However, patients with HRS had significantly increased circulating levels of NPY with respect to the other groups (1 IO& pmoi/; pcO.001). NPY levels correlated directly with NE concentration and inversely with renal plasma flow and glomerular filtration rate. These results suggest that the intense hyperstimulation of the SNS in HRS induces a release of NPY that may contribute to the pathogenesis of renal vasoconstriction.
HEPATITIS C VIRUS (HCV) CORE PROTEIN INHIBITS VLDL LIVER SECRETION: AN IN VZVO MODEL OF VIRUS-LIPID INTERACTION G. Perlemuter’. A. Sabile’. F! Letteror?. K. Koike3. J. Chauman4. D. Pessay&. G. Barba’. C. B&hot’ ‘INSERM U370 and Liver Unit, Necker, Paris, France. 21NSERM U481, Clichy, France. 3Tokyo University of Medicine, Japan. “INSERM U321, Paris, France. Prevalence of fatly liver is high in hepatitis C infection but the mechanisms of steatosis are unknown. We have previously shown in virro the direct role of HCV core in steatosia, its interaction with apolipopmtein AII (ape AD), and mcdulation of HCV core secretion through this interaction. HCV core aansgenic (tg) mice show steatosis and hepatocellular carcinoma; the nlm of the study WBI therefore to analyze in viva the mechanisms of HCV-related steatoais in this model by comparing HCV core and corekpn AR double tg mice. Metbods: 4 tg mice groups wem analyeed: 1) core: 2) spa An: 3) double tg core/ape An; 4) conaol. II-oxidation: CO,* exhalation after force-feeding mice with UC”@nitate( Hepstlc VLDL secretion: a&on WR1339 (which inhibits lipoprotein lipasc) injected lo the mice; aiglycerids (TO) sod apo BlOO measured before and 4 h after injection. PeroxIdation: ethene exhalation and hepstic thioharbituric acid nactsatr (TBARs) levels. Results: 1) No significant difference in B-oxidation (similar CO,* exhalation) in conaol, core. apu AII and double tg core/apoAII mice. 2) T&on injection induced B 16 fold increase of TO in control mice in comparison to 9 (p
INTRAHEPATIC HCV-INFECTION
HCV-SPECIFIC CD4+ ARE MULTISPECIFIC
T CELLS IN CHRONIC AND PRODUCE y-IFN
C.A. Schirren, M.C. June. T. Worzfeld, J.T. Gerlach. N.H. Gruener, H.M. Dieuolder. M. Houghton. G.R. Paoe Med. Dept. II, Klinikum Grosshadern and Inst. f. Imm., Munich, Germany, Chiron, CA, USA.
BACKGROUND: The majority of previous studies of HCV-specific CD4t T cell response has focussed on the peripheral blood and reported that elimination of HCV depends on a strong long-lasting CD4t T cell response. Little is known about the intrahepatic CD4+ T cell response. We therefore studied the intrahepatii CD4t T cell response and compared if to the peripheral T cell response. METHODS: 15 intrahepatic T cell lines were studied in 15 patients with chronic hepatitis C (CH-C) and in 18 patients with HCV-associated liver cirrhosis. Parallelly, blood&&fed T cell lines were grown in all patients. Virus-specific 1”IFN production and phenotyping to various HCV-proteins (core, NSY4, NS5) were determined by ELISPOT and FACS. RESULTS: In 5!15 (33 %) liver tissue-derived T cell lines of patients with CH-C and in lo/l8 (56 %) of patients with cirrhosis a significant number of y-IFN spots to structural and non-structural HCV-proteins were observed. 205 (13 %) of patients with CH-C and 2/18 (11 %) with cirrhosis showed HCV-specifiiity exclusively in the blood; in 3/18 (17 %) patients with cirrhosis virus-specific T cells were observed in both compartments; in 5/15 cases (33 %) with CH-C and in 7/18 (39 %) patients with cirrhosis HCV-specific T cells were exclusively detected in liver tissue. HCVspecificity was significant more often detected in liver tissue than in peripheral blood (p=O.O4). ! ACS-anafysis revealed no statistical significant difference between both groups with regard to expression of surface molecules. All T cell lines were dominated by CD4t T cells. CONCLUSIONS: Our data show that HCVspecific CD4t T cells can be detected in liver tissue and also in peripheral blood of patients with CH-C and HCV-associated cirrhosis. The HCV-specific CD4+ T cell response is multi-specific, characterized by y-IFN production and compartmentalize to the liver. This virus-specific immune response is detected only in a minorii of patients with CH-C and HCV-associated cirrhosis. Our data support the concept that a low frequency of specific T cells is associated with failure to clear the virus and chronic course of disease.
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