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105 Utility of transjugular liver biopsy in the follow-up of liver transplant recipients with HCV disease recurrence
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UTILITY OF T R A N S J U G U L A R LIVER BIOPSY IN THE FOLLOW-UP OF LIVER TRANSPLANT RECIPIENTS WITH HCV DISEASE R E C U R R E N C E
A. Blasco-Pelicano 1 X. Forns 1, M. Garcla-Retortillo 1, J. Tutors I , R. Gilabert2, R. Miquel a, J.C. Garc{a-Pagfin ~, M. Bruguera ~, M. Navasa ~.
ILioer Unit, IMD/Hospital Clinic, University of Barcelona, Barcelona, Spain," 2Radiology Department~Hospital Clinic, University of Barcelona, Barc.elona, Spain," ~Anatomopathology Department~Hospital Clinic, University of Barcelona, Barcelona, Spain Hepatitis C virus (HCV) disease recurrence is a major problem in HCVinfected patients undergoing liver transplantation (LT). Percutaneous liver biopsy (PLB) is part of the routine follow-up of these patients but the usefulness of transjugular liver biopsy (TLB) with measurement of the hepatic venous pressure gradient (HVPG) has not been assessed. The current study prospectively compares the diagnostic accuracy of PLB and TLB in liver transplant recipients with HCV disease recurrence. Patients underwent per protocol PLB and TLB at 3 and 12 months after LT, with HVPG measurements during the TLB procedure. A total of 90 paired biopsies were obtained and the following parameters were blindly assessed by two pathologists: length, thickness and number of tissue samples, number of portal tracts, necrofifftammatory activity (lobulillar, portalperiportal) and fibrosis stage (Scheues classification), cholestasis and steatosis. Among the assessed variables, we found significant differences between PLB and TLB only in the length of the sample (15ram vs 10ram, p < 0.01), the number of portal tracts (9 vs 7, p < 0.01) and the number o f tissue samples (1 vs 2, p <0.01). Among the 51 paired biopsies obtained 3 months after LT, a slightly and non-significant under-estimation of the severity (>1) of necroiitflammatory activity was observed in TLB with respect to PLB (12/51, 24% vs 18/51, 35%; p 0,27), whereas activity was identical in the 39 paired biopsies obtained at 12 months 23 (59%). In the latter biopsies, significant fibrosis (stage >1) was observed in 14 (36%) PLB andin 12 (31%) TLB (ns). However, TLB with HVPG measurement detected 18 patients who had significant fibrosis and/or portal hypertension (HVPG> 6mmHg). Among the 10 patients with HVPG>6mrnHg (two with fibrosis stage 1 in PLB), four developed liver cirrhosis during follow-up (3 with clinical decompensation). The results of the current study suggest that in LT recipients with HCV disease recurrence, the diagnostic accuracy of TLB is similar to that obtained with P LB. However, HVPG measurement adds relevant prognostic information, making TLB an alternative to PLB.
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PORTAL VEIN ARTERIALIZATION INCREASES LIVER REGENERATION IN ACUTE LIVER FAILURE INDUCED BY EXTENDED HEPATECTOMY OR TOXIN ADMINISTRATION IN THE RAT
R Caraceni t,2, B. Nardo 3,2, L. Puviani 3,2, A.M. Pertosa 1,2, M. Domenicali 1,2, A. Principe 1,2, E Trevisani 12, A. Cavallari 3, M. Bemardi 1'2. :Department Internal Medicine, Cardioangiology,
Hepatology, Unioersity of Bologna, Bologna, Italy," 2Center for Applied Biomedical Research (CRBA), S. Orsola University Hospital, Bologna, Italy," SDepartment of Surgery and D'ansplantation, University of Bologna, Bologna, Italy Background and Aim: Optimization of the conditions for regeneration is a major goal in the management of patients with acute liver failure (ALF). Previous observations have suggested that increasing the oxygen delivery to the liver may improve its regenerative capacity. Thus, this study aimed to determine whether an additional supply of oxygenated blood achieved by portal vein arterialization (PVA) is protective in rat ALF caused by hepatectomy or toxin administration. Methods: ALF was induced in Spragne-Dawley rats by performing an extended hepatectomy or by giving i.p. 1 ml&g CC14. Afterwards, rats
were divided to receive PVA, which was performed by connecting the left renal artery to the splenic vein with a stent following left nephrectemy and splenectomy, or to left nephrectomy and splenectomy only (control rats). Hepatocyte regeneration was assessed by calculating the mitotic index, the brornodeoxyuridine (BrdU) incorporation and the ratio liver/body weights. Liver injury was evaluated by the sermn ALT level and necrotic cell count. The 10-day survival was assessed in separate groups of rats. Results: As expected, the PVA procedure significantly increased pO2 and oxygen saturation in the portal blood compared to controls (pO2: 63:t:1.6 vs 39:t:2.9mmHg; 02 sat.%: 93.1:t=0.7 vs 67.0:t:0.5). PVA significantly improved survival compared to controls in both ALF models (90% hepatectemy: 90 vs 30%; CC14:100 vs 40%). Accordingly, in the toxic ALE serum ALT levels and cell necrosis were significantly reduced by PVA (at 24h: 843:t:344 vs 1493:t:562U/1 and 32:t:7% vs 64:t: 15%). The BrdU staining was significantly greater in PVA than control rats in both experimental models (at 24h, 70% hepatectemy: 2464-22 vs 87± 10 positive cells/mm2; CC14:695±204 vs 49± 10 positive cells/mm2). Similar results were obtained when the mitotic index was measured. The ratio liver/body weight after hepatectorny recovered significantly faster in arterialized rats. Finally, when PVA was performed in healthy rats, all the parameters studied were not significantly affected. Conclusions: These data indicate that the additional supply of arterial oxygenated blood through PVA promotes a rapid and extensive regeneration leading to a faster restoration of liver mass after partial hepatectomy and resolution of toxic-induced massive liver necrosis in rats. Thus, this technique may represent a novel tool for optimizing hepatecyte regeneration during acute liver failure. F10~ EFFICACY AND SAFETY OF ANTIVIRAL T H E R A P Y IN LIVER T R A N S P L A N T RECIPIENTS WITH CHRONIC HEPATITIS C
J.A. Carrion ~. M. Garcla-Retortillo ~, M. Navasa 1, A. Rimola I , J.C. Garcia-Valdecasas2, X. Forns 1. 1Liver Unit, Hospital Clinic,
IDIBAPS, Barcelona, Spain," 2Liver SurgeW and Transplantation Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain Recurrence of hepatitis C after liver transplantation (LT) is a major problenl in transplant programs. The aim of this prospective study was to assess the efficacy and safety ofantiviral therapy in liver transplant recipients with chronic hepatitis C. Fifty-two patients with chronic hepatitis C (diagnosed by liver biopsy after a minimum of 6 months following LT) were randomized to receive: Group A - pegylated interferon o~-2b (I.5 ~tgjkg/w) and ribavirin (800 1000rag/d) for 48 weeks; Group B no treatment. Patients with severe HCV recurrence (Group C: bridging fibrosis or necrosis, cholestatic hepatitis) were treated as group A. Efficacy was evahtated 6 months after treatment discontinuation and was defined as persistent HCV-RNA negativization (SVR). All patients underwent a liver biopsy 6 months after treatment discontinuation. The baseline characteristics of the 52 patients were: age 57 years, 36 (69%) males, 45 (87%) infected with genotype lb, viral load (VL) 3.5× 106 IU[rnl, significant liver fibrosis (F~>2) 15 (29%). From the 37 patients with complete follow-up, 5/12 (42%) of group A, 0/10 of grmtp B and 4/15 (27%) of group C achieved SVR (p < 0.05). An early virological response (EVR: decrease in VL >2 log10 at week 4 of treatment) occurred in 7 (78%) of 9 patients with SVR versus 3 (17%) of 18 non-responders (p=0.004). Althmtgh preliminary data do not demonstrate significant histological improvement in patients achieving SVR, disease progression leading to graft loss occurred only in non-responders from group C (6 of 11, 55%). Severe adverse events were frequent in treated patients: neutropenia and anemia requiring stimulating factors in 11 (41%) and 22 (81%), respectively, depression in 2 (7%) and rejection in 2 (7%). Interferon or ribavirin dose reductions were necessary in 10 (37°/0) and 21 (78°/0) cases, respectively and definitive treatment interruption in 11 (41%). In conclusion, in liver transplant recipients with chronic hepatitis C antiviral treatment is effective in one third of patients. However, tolerance
46
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UTILITY OF T R A N S J U G U L A R LIVER BIOPSY IN THE FOLLOW-UP OF LIVER TRANSPLANT RECIPIENTS WITH HCV DISEASE R E C U R R E N C E
A. Blasco-Pelicano 1 X. Forns 1, M. Garcla-Retortillo 1, J. Tutors I , R. Gilabert2, R. Miquel a, J.C. Garc{a-Pagfin ~, M. Bruguera ~, M. Navasa ~.
ILioer Unit, IMD/Hospital Clinic, University of Barcelona, Barcelona, Spain," 2Radiology Department~Hospital Clinic, University of Barcelona, Barc.elona, Spain," ~Anatomopathology Department~Hospital Clinic, University of Barcelona, Barcelona, Spain Hepatitis C virus (HCV) disease recurrence is a major problem in HCVinfected patients undergoing liver transplantation (LT). Percutaneous liver biopsy (PLB) is part of the routine follow-up of these patients but the usefulness of transjugular liver biopsy (TLB) with measurement of the hepatic venous pressure gradient (HVPG) has not been assessed. The current study prospectively compares the diagnostic accuracy of PLB and TLB in liver transplant recipients with HCV disease recurrence. Patients underwent per protocol PLB and TLB at 3 and 12 months after LT, with HVPG measurements during the TLB procedure. A total of 90 paired biopsies were obtained and the following parameters were blindly assessed by two pathologists: length, thickness and number of tissue samples, number of portal tracts, necrofifftammatory activity (lobulillar, portalperiportal) and fibrosis stage (Scheues classification), cholestasis and steatosis. Among the assessed variables, we found significant differences between PLB and TLB only in the length of the sample (15ram vs 10ram, p < 0.01), the number of portal tracts (9 vs 7, p < 0.01) and the number o f tissue samples (1 vs 2, p <0.01). Among the 51 paired biopsies obtained 3 months after LT, a slightly and non-significant under-estimation of the severity (>1) of necroiitflammatory activity was observed in TLB with respect to PLB (12/51, 24% vs 18/51, 35%; p 0,27), whereas activity was identical in the 39 paired biopsies obtained at 12 months 23 (59%). In the latter biopsies, significant fibrosis (stage >1) was observed in 14 (36%) PLB andin 12 (31%) TLB (ns). However, TLB with HVPG measurement detected 18 patients who had significant fibrosis and/or portal hypertension (HVPG> 6mmHg). Among the 10 patients with HVPG>6mrnHg (two with fibrosis stage 1 in PLB), four developed liver cirrhosis during follow-up (3 with clinical decompensation). The results of the current study suggest that in LT recipients with HCV disease recurrence, the diagnostic accuracy of TLB is similar to that obtained with P LB. However, HVPG measurement adds relevant prognostic information, making TLB an alternative to PLB.
Fi•
PORTAL VEIN ARTERIALIZATION INCREASES LIVER REGENERATION IN ACUTE LIVER FAILURE INDUCED BY EXTENDED HEPATECTOMY OR TOXIN ADMINISTRATION IN THE RAT
R Caraceni t,2, B. Nardo 3,2, L. Puviani 3,2, A.M. Pertosa 1,2, M. Domenicali 1,2, A. Principe 1,2, E Trevisani 12, A. Cavallari 3, M. Bemardi 1'2. :Department Internal Medicine, Cardioangiology,
Hepatology, Unioersity of Bologna, Bologna, Italy," 2Center for Applied Biomedical Research (CRBA), S. Orsola University Hospital, Bologna, Italy," SDepartment of Surgery and D'ansplantation, University of Bologna, Bologna, Italy Background and Aim: Optimization of the conditions for regeneration is a major goal in the management of patients with acute liver failure (ALF). Previous observations have suggested that increasing the oxygen delivery to the liver may improve its regenerative capacity. Thus, this study aimed to determine whether an additional supply of oxygenated blood achieved by portal vein arterialization (PVA) is protective in rat ALF caused by hepatectomy or toxin administration. Methods: ALF was induced in Spragne-Dawley rats by performing an extended hepatectomy or by giving i.p. 1 ml&g CC14. Afterwards, rats
were divided to receive PVA, which was performed by connecting the left renal artery to the splenic vein with a stent following left nephrectemy and splenectomy, or to left nephrectomy and splenectomy only (control rats). Hepatocyte regeneration was assessed by calculating the mitotic index, the brornodeoxyuridine (BrdU) incorporation and the ratio liver/body weights. Liver injury was evaluated by the sermn ALT level and necrotic cell count. The 10-day survival was assessed in separate groups of rats. Results: As expected, the PVA procedure significantly increased pO2 and oxygen saturation in the portal blood compared to controls (pO2: 63:t:1.6 vs 39:t:2.9mmHg; 02 sat.%: 93.1:t=0.7 vs 67.0:t:0.5). PVA significantly improved survival compared to controls in both ALF models (90% hepatectemy: 90 vs 30%; CC14:100 vs 40%). Accordingly, in the toxic ALE serum ALT levels and cell necrosis were significantly reduced by PVA (at 24h: 843:t:344 vs 1493:t:562U/1 and 32:t:7% vs 64:t: 15%). The BrdU staining was significantly greater in PVA than control rats in both experimental models (at 24h, 70% hepatectemy: 2464-22 vs 87± 10 positive cells/mm2; CC14:695±204 vs 49± 10 positive cells/mm2). Similar results were obtained when the mitotic index was measured. The ratio liver/body weight after hepatectorny recovered significantly faster in arterialized rats. Finally, when PVA was performed in healthy rats, all the parameters studied were not significantly affected. Conclusions: These data indicate that the additional supply of arterial oxygenated blood through PVA promotes a rapid and extensive regeneration leading to a faster restoration of liver mass after partial hepatectomy and resolution of toxic-induced massive liver necrosis in rats. Thus, this technique may represent a novel tool for optimizing hepatecyte regeneration during acute liver failure. F10~ EFFICACY AND SAFETY OF ANTIVIRAL T H E R A P Y IN LIVER T R A N S P L A N T RECIPIENTS WITH CHRONIC HEPATITIS C
J.A. Carrion ~. M. Garcla-Retortillo ~, M. Navasa 1, A. Rimola I , J.C. Garcia-Valdecasas2, X. Forns 1. 1Liver Unit, Hospital Clinic,
IDIBAPS, Barcelona, Spain," 2Liver SurgeW and Transplantation Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain Recurrence of hepatitis C after liver transplantation (LT) is a major problenl in transplant programs. The aim of this prospective study was to assess the efficacy and safety ofantiviral therapy in liver transplant recipients with chronic hepatitis C. Fifty-two patients with chronic hepatitis C (diagnosed by liver biopsy after a minimum of 6 months following LT) were randomized to receive: Group A - pegylated interferon o~-2b (I.5 ~tgjkg/w) and ribavirin (800 1000rag/d) for 48 weeks; Group B no treatment. Patients with severe HCV recurrence (Group C: bridging fibrosis or necrosis, cholestatic hepatitis) were treated as group A. Efficacy was evahtated 6 months after treatment discontinuation and was defined as persistent HCV-RNA negativization (SVR). All patients underwent a liver biopsy 6 months after treatment discontinuation. The baseline characteristics of the 52 patients were: age 57 years, 36 (69%) males, 45 (87%) infected with genotype lb, viral load (VL) 3.5× 106 IU[rnl, significant liver fibrosis (F~>2) 15 (29%). From the 37 patients with complete follow-up, 5/12 (42%) of group A, 0/10 of grmtp B and 4/15 (27%) of group C achieved SVR (p < 0.05). An early virological response (EVR: decrease in VL >2 log10 at week 4 of treatment) occurred in 7 (78%) of 9 patients with SVR versus 3 (17%) of 18 non-responders (p=0.004). Althmtgh preliminary data do not demonstrate significant histological improvement in patients achieving SVR, disease progression leading to graft loss occurred only in non-responders from group C (6 of 11, 55%). Severe adverse events were frequent in treated patients: neutropenia and anemia requiring stimulating factors in 11 (41%) and 22 (81%), respectively, depression in 2 (7%) and rejection in 2 (7%). Interferon or ribavirin dose reductions were necessary in 10 (37°/0) and 21 (78°/0) cases, respectively and definitive treatment interruption in 11 (41%). In conclusion, in liver transplant recipients with chronic hepatitis C antiviral treatment is effective in one third of patients. However, tolerance