- Email: [email protected]
Liver transplantation for acute hepatic failure
Posters
[
P/C01/O5
]
LIVER TRANSPLANTATION FOR ACUTE HEPATIC FAILURE S. de Rave ~, H.W. Tilanus 2, W.C.J. Hop 3, for the Rotterdam Liver Transplantation Group ~Dept. of Hepatogastroenterology, University Hospital Rotterdam, The Netherlands. 2Dept. of Surgery, University Hospital Rotterdam, The Netherlands. SDept. of Biostatistics, University Hospital Rotterdam, The Netherlands. Acute hepatic failure is defined as severe hepatic dysfunction leading to hepatic encephalopathy in a previously healthy person. There are conlticting reports on the value of the Clichy and the King's College criteria in selecting patients for emergency fiver transplantation. Also, definite proof of a positive effect of transplantation on survival is still lacldng. We studied patient e ~ c s and outcomes in all 75 possible candidates for emergency liver transplantation seen over a 10 year period. We also calculated the impact of transplantation on survival in the 46 patients put on the high urgency wailing list, using a time dependent Cox model. The totai study group consisted of 46 female and 29 male patients with a median age of 39 years. A cause could be determined in two thirds of our patients, viral hepatitis and drug induced liver disease being the most frequent. The patients were grouped according to the Clichy and King's College criteria. In 20 cases neither was fidfilled. In this group 3 of the 5 patients with acute autoimmune hepatitis died, the difference with the other 15 patients being highly significant (P=0.009). Of the other 55 patients all but one did meet the criteri~ This second category was subdivided in 9 patients with absolute contraindications for transplar~31ion, all of whom died, and 46 that were enlisted, 7 of whom died on the waiting list. The one year survival of transplanted patients was 69% (58% when calculated on an intention to treat basis). Liver transplantation resulted in a 78% mortality reduction (P--~).069). We conclude that beth the C/icily and King's College criteria reliably predict who will survive without transplantation,except in patientspresenting with acute autoimmune hepatitis.Our study shows a strong trend towards a positive effect of emergency liver transplantation on survival in patients with acute hepatic failure.
I
P/C01/06
I
RIBAVIRIN DECREASES INTERFERON-? PRODUCTION IN LIVER TRANSPLANT RECIPIENTS WITH RECURRENT HCV INFECTION E Bolacchi l, A. Bergamini l, G. Tisone2, M. Cepparulo l, G. Iario 2, E. Torri 2, B. Bon~iovanni l, I. Uccella 1, M. Canozzi a, G. Rocchi 1, M. Angelicol ~Dept. of Public Health, University of Rome "Tor Vergata", Italy. 2Dept. of Surgery, University of Rome "Tor Vergata", Italy. Background & aims. Ribavirin has been proposed for the treatment of patients with recurrent HCV infection after liver transplantation. Ribavirin may normalize aminotransferase levels but it has limited effect on HCV replication. This raises the possibility that the main effect of ribavirin may be immunomodulatory rather than strictly antiviral. The aim of this study was to investigate the effect of ribavirin on cytokine production in patients with recurrent HCV infection after liver transplantation. Materials and methods. Cytokine production by activated circulating T cells was prospectively studied by FACS analysis and ELISA testing before and alter 6 months of treatment with 200-400 rag/daily of ribavirin in liver transplant recipients with persistent HCV infection, (n=7, mean age 56 yrs). Patients had been transplanted from 13 to 80 months earlier and were receiving oral cyclosporin as maintenance immunosuppression. Results. Treatment with ribavirin was associated with a significant reduction of ALT levels, but no changes in HCV-RNA levels. Ribavirin caused a significant suppression of the production of interferon-7(IFN-7) by T cells, with respect to basal values. The analysis of the "naive" and "memory" T cell subsets also demonstrated a reduction of IFN-7 production in either cell subsets after ribavirin treatment. In contrast, the expression of interleukin IL-2, IL-4 and 1L-10 was not different between the two groups. Conclusions. We conclude that ribavirin down-modulates IFN-T production in patients with recurrent HCV infection after liver transplantation. This may favour an anti-inflammatory effect and help reducing HCV-related T cell activation and associated liver damage.
50
PIC01107 I ENHANCED INTRAHEPATIC CHEMOKINE EXPRESSION AS A POSSIBLE MEDIATOR OF FULMINANT HEPATIC FAILURE L. Leifeld, I. Purr, K. Janberg, EL. Dumoulin, C. Trautwein, T. Sauerbruch, I5. Spengler Dpt. of Medicine I, University of Bonn, Germany.
In fulminant hepatic failure [FHF] massive infiltrates of macrophages and lymphocytes lead to tissue damage and might be a result of chemokine upregulation. Therefore, we analysed the intrahepatic expression of macrophage and lymphocyte attracting chemokines MCP1-3, MIPla, MIPlf~ and Rantes by immunohistochemistry and by competitive RT-PCR. Explant livers of 24 patients with FHF, 41 patients with chronic liver disease [CLD] and 10 normal controls [NC] were included. Furthermore, we performed a quantitative real time PCR to analyse the time course of chemokine expression in the Con A and GalN/LPS mice models of fulminant hepatitis. Results: Kupffer cells/macrophages were the predominant type of cells with chemokine expression but all chemokines were also expressed by sinusoidal endothelie! ceils, vascular endothelial cells and bile ducts in CLD and FHF. Hepatocytes in CI.D and FHF expressed MCP1, MIPli2, and Rantes. The total number of chemokine expressing cells was significantly (p<0.001) enhanced in FHF compared to CLD and NC. Competitive RT-PCR confirmed massive upregulation of chemokine mRNA levels. Interestingly, chemokine expression was significantly correlated to the number of infiltrating intrahepatic macmphages and CD8+ lymphocytes (r=0,7-0.92; p< 0.001) but not to the number of CD20+ lymphocytes. In both mice models we found strong chemokine induction beginning one hour after application of the toxin. Discussion: Abundant chemokine production may be a pivotal step, which occurs early in the pathogenesis of FHF.
I P/COllO8 I SHORT- AND LONG-TERM CHANGES IN SPLANCHNIC HEMODYNAMICS AFTER LIVER TRANSPLANTATION (OLT) M. Boloanesi. D. Sacerdoti, G.C. Bombonato, A. Gatta Department of Clinical and Experimental Medicine, University of Padua, Italy. Duplex Doppler parameters, i.e., portal flow mean velocity (PFMV) and volume (PFV), superior mesenteric artery (SMA) flow and arterial resistance indices (pulsatility indices (PI): (Vmax-Vmin)Nmean) in the liver (L), SMA and the kidneys (K), were recorded in 180 OLT performed in 166 cirrhotic patients. When possible, patients were evaluated before, and 1, 3, 7 days, 1, 3, 6, 9, 12 months after, and every year after OLT up to 6 years (mean follow-up 2.2_+2.1 years). The same parameters were also evaluated in 30 normal subjects. The first day after OLT, PFMV and PFV dramatically increased (p<0.001) (from 10.4_+4.3 cm/s to 39.6_+16.8 and from 948_+553 ml/min to 2362-+1242 respectively). L-PI increased too (from 1.31_+0.34 to 2.63_+1.50, p<0.001), probably as a consequence of heparle buffer response. These parameters contemporaneously decreased by 22% after 3 days and by 36-45% after 7 days. L-PI decreased to values not different from normal subjects after 3 months and then remained stable. PFV returned to normal range (to 919_+424 ml/min) only after 2 years, and remained normal for the subsequent 4 years. SMA parameters normalized after 3-9 months (p<0.01) (SMA-PI from 2.09_+0.63 to 2.82_+0.56 and 3.13_+1.01 respectively; SMA flow from 723_+286 ml/min to 418_+189 and to 334_+172 respectively). The persistence of a high PFV even after normalization of mesenteric flow suggests a lasting elevated splenic blood flow, confirmed by the persistence of splenomegaly even after 6 years (form 17.3_+3.5 cm before OLT, to 14.6_+2.2 after 6 years). K-PI values improved after OLT, but did not return to normal values (from 1.26-+0.33 before OLT, to 1.11_+0.26 after 3 months, 1.08_+0.20 after 2 years and 1.23_+0.15 after 6 years), probably because of concomitant therapy. In conclusion, L- and SMA-PI values return to normal range 3-9 months after OLT, while an increase in PFV persists for 2 years, probably because of the persistence of splenomegaly. A dramatic increase in hepatic resistance indices can be considered a normal finding the day after OLT.
[
P/C01/O5
]
LIVER TRANSPLANTATION FOR ACUTE HEPATIC FAILURE S. de Rave ~, H.W. Tilanus 2, W.C.J. Hop 3, for the Rotterdam Liver Transplantation Group ~Dept. of Hepatogastroenterology, University Hospital Rotterdam, The Netherlands. 2Dept. of Surgery, University Hospital Rotterdam, The Netherlands. SDept. of Biostatistics, University Hospital Rotterdam, The Netherlands. Acute hepatic failure is defined as severe hepatic dysfunction leading to hepatic encephalopathy in a previously healthy person. There are conlticting reports on the value of the Clichy and the King's College criteria in selecting patients for emergency fiver transplantation. Also, definite proof of a positive effect of transplantation on survival is still lacldng. We studied patient e ~ c s and outcomes in all 75 possible candidates for emergency liver transplantation seen over a 10 year period. We also calculated the impact of transplantation on survival in the 46 patients put on the high urgency wailing list, using a time dependent Cox model. The totai study group consisted of 46 female and 29 male patients with a median age of 39 years. A cause could be determined in two thirds of our patients, viral hepatitis and drug induced liver disease being the most frequent. The patients were grouped according to the Clichy and King's College criteria. In 20 cases neither was fidfilled. In this group 3 of the 5 patients with acute autoimmune hepatitis died, the difference with the other 15 patients being highly significant (P=0.009). Of the other 55 patients all but one did meet the criteri~ This second category was subdivided in 9 patients with absolute contraindications for transplar~31ion, all of whom died, and 46 that were enlisted, 7 of whom died on the waiting list. The one year survival of transplanted patients was 69% (58% when calculated on an intention to treat basis). Liver transplantation resulted in a 78% mortality reduction (P--~).069). We conclude that beth the C/icily and King's College criteria reliably predict who will survive without transplantation,except in patientspresenting with acute autoimmune hepatitis.Our study shows a strong trend towards a positive effect of emergency liver transplantation on survival in patients with acute hepatic failure.
I
P/C01/06
I
RIBAVIRIN DECREASES INTERFERON-? PRODUCTION IN LIVER TRANSPLANT RECIPIENTS WITH RECURRENT HCV INFECTION E Bolacchi l, A. Bergamini l, G. Tisone2, M. Cepparulo l, G. Iario 2, E. Torri 2, B. Bon~iovanni l, I. Uccella 1, M. Canozzi a, G. Rocchi 1, M. Angelicol ~Dept. of Public Health, University of Rome "Tor Vergata", Italy. 2Dept. of Surgery, University of Rome "Tor Vergata", Italy. Background & aims. Ribavirin has been proposed for the treatment of patients with recurrent HCV infection after liver transplantation. Ribavirin may normalize aminotransferase levels but it has limited effect on HCV replication. This raises the possibility that the main effect of ribavirin may be immunomodulatory rather than strictly antiviral. The aim of this study was to investigate the effect of ribavirin on cytokine production in patients with recurrent HCV infection after liver transplantation. Materials and methods. Cytokine production by activated circulating T cells was prospectively studied by FACS analysis and ELISA testing before and alter 6 months of treatment with 200-400 rag/daily of ribavirin in liver transplant recipients with persistent HCV infection, (n=7, mean age 56 yrs). Patients had been transplanted from 13 to 80 months earlier and were receiving oral cyclosporin as maintenance immunosuppression. Results. Treatment with ribavirin was associated with a significant reduction of ALT levels, but no changes in HCV-RNA levels. Ribavirin caused a significant suppression of the production of interferon-7(IFN-7) by T cells, with respect to basal values. The analysis of the "naive" and "memory" T cell subsets also demonstrated a reduction of IFN-7 production in either cell subsets after ribavirin treatment. In contrast, the expression of interleukin IL-2, IL-4 and 1L-10 was not different between the two groups. Conclusions. We conclude that ribavirin down-modulates IFN-T production in patients with recurrent HCV infection after liver transplantation. This may favour an anti-inflammatory effect and help reducing HCV-related T cell activation and associated liver damage.
50
PIC01107 I ENHANCED INTRAHEPATIC CHEMOKINE EXPRESSION AS A POSSIBLE MEDIATOR OF FULMINANT HEPATIC FAILURE L. Leifeld, I. Purr, K. Janberg, EL. Dumoulin, C. Trautwein, T. Sauerbruch, I5. Spengler Dpt. of Medicine I, University of Bonn, Germany.
In fulminant hepatic failure [FHF] massive infiltrates of macrophages and lymphocytes lead to tissue damage and might be a result of chemokine upregulation. Therefore, we analysed the intrahepatic expression of macrophage and lymphocyte attracting chemokines MCP1-3, MIPla, MIPlf~ and Rantes by immunohistochemistry and by competitive RT-PCR. Explant livers of 24 patients with FHF, 41 patients with chronic liver disease [CLD] and 10 normal controls [NC] were included. Furthermore, we performed a quantitative real time PCR to analyse the time course of chemokine expression in the Con A and GalN/LPS mice models of fulminant hepatitis. Results: Kupffer cells/macrophages were the predominant type of cells with chemokine expression but all chemokines were also expressed by sinusoidal endothelie! ceils, vascular endothelial cells and bile ducts in CLD and FHF. Hepatocytes in CI.D and FHF expressed MCP1, MIPli2, and Rantes. The total number of chemokine expressing cells was significantly (p<0.001) enhanced in FHF compared to CLD and NC. Competitive RT-PCR confirmed massive upregulation of chemokine mRNA levels. Interestingly, chemokine expression was significantly correlated to the number of infiltrating intrahepatic macmphages and CD8+ lymphocytes (r=0,7-0.92; p< 0.001) but not to the number of CD20+ lymphocytes. In both mice models we found strong chemokine induction beginning one hour after application of the toxin. Discussion: Abundant chemokine production may be a pivotal step, which occurs early in the pathogenesis of FHF.
I P/COllO8 I SHORT- AND LONG-TERM CHANGES IN SPLANCHNIC HEMODYNAMICS AFTER LIVER TRANSPLANTATION (OLT) M. Boloanesi. D. Sacerdoti, G.C. Bombonato, A. Gatta Department of Clinical and Experimental Medicine, University of Padua, Italy. Duplex Doppler parameters, i.e., portal flow mean velocity (PFMV) and volume (PFV), superior mesenteric artery (SMA) flow and arterial resistance indices (pulsatility indices (PI): (Vmax-Vmin)Nmean) in the liver (L), SMA and the kidneys (K), were recorded in 180 OLT performed in 166 cirrhotic patients. When possible, patients were evaluated before, and 1, 3, 7 days, 1, 3, 6, 9, 12 months after, and every year after OLT up to 6 years (mean follow-up 2.2_+2.1 years). The same parameters were also evaluated in 30 normal subjects. The first day after OLT, PFMV and PFV dramatically increased (p<0.001) (from 10.4_+4.3 cm/s to 39.6_+16.8 and from 948_+553 ml/min to 2362-+1242 respectively). L-PI increased too (from 1.31_+0.34 to 2.63_+1.50, p<0.001), probably as a consequence of heparle buffer response. These parameters contemporaneously decreased by 22% after 3 days and by 36-45% after 7 days. L-PI decreased to values not different from normal subjects after 3 months and then remained stable. PFV returned to normal range (to 919_+424 ml/min) only after 2 years, and remained normal for the subsequent 4 years. SMA parameters normalized after 3-9 months (p<0.01) (SMA-PI from 2.09_+0.63 to 2.82_+0.56 and 3.13_+1.01 respectively; SMA flow from 723_+286 ml/min to 418_+189 and to 334_+172 respectively). The persistence of a high PFV even after normalization of mesenteric flow suggests a lasting elevated splenic blood flow, confirmed by the persistence of splenomegaly even after 6 years (form 17.3_+3.5 cm before OLT, to 14.6_+2.2 after 6 years). K-PI values improved after OLT, but did not return to normal values (from 1.26-+0.33 before OLT, to 1.11_+0.26 after 3 months, 1.08_+0.20 after 2 years and 1.23_+0.15 after 6 years), probably because of concomitant therapy. In conclusion, L- and SMA-PI values return to normal range 3-9 months after OLT, while an increase in PFV persists for 2 years, probably because of the persistence of splenomegaly. A dramatic increase in hepatic resistance indices can be considered a normal finding the day after OLT.