- Email: [email protected]
F-48 Liver transplantation for HBV-related liver disease: the experience of Padua Liver Transplant Center
Abstracts of the 46th A.I.S.F. Annual Meeting 2013 / Digestive and Liver Disease 45S (2013), S1–S48 was recorded in 25% C-TACE and 29% DEB-TACE patients; mean survival was 32 months (CI 27–36). Side effects and objective responses were comparable, the DEB-TACE subgroup showing a non-significantly better response rate. VEGF t0 levels were higher in multifocal disease (p=0.015) and nonresponders (p=0.03). At t1 VEGF levels rose significantly overall (p=0.003), in C-TACE (p=0.04) and DEB-TACE (p=0.02). The rise was more significant in partial responders (p=0.005), especially with DEB-TACE (p=0.002); in complete responders the rise was significant only in DEB-TACE subgroup (p=0.05). The percentage of patients with VEGF rising at t1 was higher in DEB-TACE (p=0.007). Tumor size (p=0.0001), t0 vascularization (p=0.003) and t0 VEGF (p=0.009) inversely correlated with survival. A Cox multivariate analysis singled out t0 VEGF, tumor size and vascularization as independent predictors of survival. Conclusions: DEB-TACE and C-TACE provide similar response rate, survival and side effects. DEB-TACE induces more pronounced ischemia, with a sharper rise in t1 VEGF levels and a higher percentage of DEB-TACE patients with VEGF rising at t1. High t0 VEGF levels predict worse response to treatment and survival. Baseline VEGF is as relevant as tumor burden and vascularization in prognosis.
F-46 A novel model of priority assessment for patients with and without hepatocellular carcinoma on a common liver transplant waiting list: a multicentre, cohort study A. Vitale 1 , T. De Feo 2 , P. Burra 1 , A.C. Frigo 1 , R. Ramirez Morales 1 , L. De Carlis 3 , M.F. Donato 4 , S. Fagiuoli 5 , A. Picciotto 6 , P. Toniutto 7 , E. Regalia 8 , U. Cillo 1 , on behalf of the Liver Transplantation NITp Working Group 1 University
Hospital of Padua, Italy; 2 North Italy Transplant program, Fond. IRCCS Ca’ Granda OMP, Milan, Italy; 3 Liver Transplantation, Ospedale Niguarda Ca’ Granda, Milan, Italy; 4 Gastroenterology Unit, Maggiore Hospital Policlinico, Milan, Italy; 5 Gastroenterology and Transplantation Hepatology, Ospedali Riuniti, Bergamo, Italy; 6 IRCCS San Martino,IST Genova, Italy; 7 Medical Liver Transplant Unit, University of Udine, Italy; 8 Liver Transplantation, IRCCS INT, Milan, Italy Background: Liver transplantation (LT) priority assessment strictly based on 3-months dropout estimation creates both an unbalance between patients with and without hepatocellular carcinoma (HCC), and penalizes post LT outcomes. The aim of this study was to describe an alternative model able to re-establish allocation equity between HCC and no-HCC patients using 5-year transplant benefit as the common endpoint. Methods: We enrolled consecutive adult patients with chronic end-stage liver disease entering the waiting list (WL) for LT (WL group = 2697) and undergoing LT (LT group = 1702) during the period 2004–2009 in the North Italian Transplant program area. Two independent multivariable regressions (WL and LT models) were created to measure the prognostic power of model for end stage liver disease (MELD) in patients with and without HCC. The models were also adjusted for the following covariates: recipient age, sex, and aetiology, re-transplant, donor age. For the WL model we used competing risk multivariable analysis. Hazard ratio (HR, 95% confidence intervals) were finally included in a Markov model to calculate 5-year survival benefit in different subgroups. Results: WL competing risk model: MELD significantly predicted survival in both HCC (1.100, 1.081–1.109) and non-HCC (1.070, 1.039–1.101) patients. LT Cox model: MELD significantly predicted patient survival in both HCC (1.042, 1.007–1.075) and non-HCC (1.038, 1.018–1.058) patients. Benefit model: the survival benefit of LT at each MELD point was higher in HCC than non-HCC patients. Using two-way sensitive analysis we calculated the following benefit MELD (bMELD) equation: bMELD=9.16 + 1.32*MELD in HCC patients with MELD score ≤22; bMELD=40 for HCC patients with MELD >22. Conclusion: We obtained a new bMELD score to weigh the priorities of HCC and non-HCC on a common waiting list.
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F-47 Early introduction of everolimus in de novo liver transplantation: a multicenter randomized clinical trial (EPOCAL) U. Cillo 1 , A. Vitale 1 , M. Salizzoni 2 , M. Coledan 3 , G. Rossi 4 , U. Baccarani 5 , L. De Carlis 6 , A. Bertacco 1 , L. Saracino 1 , R. Ramirez Morales 1 , S. Agnes 7 1 Centro
Trapianti di Fegato, Azienda Università di Padova; 2 Azienda Ospedaliero-Universitaria S. Giovanni Battista di Torino Ospedale Molinette; 3 Ospedale Riuniti Bergamo; 4 Ospedale Maggiore Policlinico Milano; 5 Azienda Ospedaliera “S.M. Misericordia” Udine; 6 Ospedale Niguarda- Ca Granda Milano; 7 Policlinico Universitario Agostino Gemelli Roma Introduction: There are no prospective randomized trials analysing safety and efficacy of early introduction of Everolimus in patients undergoing liver transplantation (LT). Methods: We performed a spontaneous, phase 2, multicenter (7 centers), randomized, open label, clinical trial. Inclusion criteria: first LT, acceptable graft function in postoperative day (POD) 7, cold ischemia time <12 hours. Patients were randomized in POD 7 in two possible arms using a 2:1 ratio, the study group (with Everolimus introduction in POD 8 and Tacrolimus reduction/weaning), and a control group (conventional immunosuppression). Primary endpoint: incidence of acute rejection and graft loss in the first 3 months after LT. Secondary endpoints: renal function, suspension of Tacrolimus, incidence of adverse events. Calculated sample size: 117 patients evaluable for the primary endpoint. We present the preliminary results of an interim analysis carried out in October 2012. Results: Up to October 2012, 84 patients were enrolled in the study group and 46 in control group (110 patients evaluable at 3 months for the primary endpoint). We did not find any significant difference between the two groups. The primary endpoint in the study group vs. controls has been so far observed: acute rejection, 17% vs. 7% (p>0.05), graft loss, 2% vs. 8% (p>0.05). The number of adverse events was also comparable between the two groups with the exception of infections having a significantly higher incidence in the controls (20% vs. 1%, p <0.01). The weaning of tacrolimus at 1 month in the study group was successful in 43% of cases. Renal function at 3 months in the two groups was not significantly different. Conclusions: Everolimus seems safe and effective when introduced early after LT.
F-48 Liver transplantation for HBV-related liver disease: the experience of Padua Liver Transplant Center I. Bortoluzzi 1 , M. Gambato 1 , G. Germani 1 , E. Nadal 1 , M. Senzolo 1 , G. Zanus 2 , P. Boccagni 2 , U. Cillo 2 , P. Burra 1 , F.P. Russo 1 1 Multivisceral Transplant Unit- Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University Hospital Padova, Padua, Italy; 2 Hepatobiliary Surgery and Liver Transplantation, Department of Surgical, Oncological and Gastroenterological Sciences, University Hospital Padova, Padua, Italy
HBV- related liver disease is a frequent indication to liver transplantation (LT) in Europe (15–25%) and prophylaxis after LT has drastically reduced HBV recurrence (<5%). The aim of the study is to evaluate results of LT for HBVrelated disease in the Liver Transplant Center of Padua. Materials and methods: All patients who had undergone LT in our Centre for HBV-related liver disease were included. At yearly intervals we analyzed: HBsAg, anti-HBs titer, HBV-DNA, liver biopsies, prophylaxis received. Results: From November 1990 to September 2011 189/1010 (18.7%) LT have been performed for HBV-related liver disease. Etiology of liver disease was: 83/189 (44%) HBV infection, 49/189 (26%) HBV/HDV, 47/189 (24.8%) HBV/HCV and 10/189 (5.2%) HBV/alcohol. Indication to LT was: fulminant hepatic failure in 11/189 patients (5.8%), decompensated cirrhosis in 121/189 patients (64%), hepatocellular carcinoma (HCC) on cirrhosis in 57/189 patients (30.2%). 6/189 of these patients received a HBsAg and antiHBc positive graft, 25/189 from a HBsAg negative/anti-HBc positive one. All
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Abstracts of the 46th A.I.S.F. Annual Meeting 2013 / Digestive and Liver Disease 45S (2013), S1–S48
patients received prophylaxis after LT. No statistically significant difference has been observed analyzing patient and organ survival in relation to etiology of liver disease, presence or not of HCC, viral load at LT and HBV serology of the donor. No statistically significant difference on histology has been observed in relation to HBV-DNA levels at LT and prophylaxis after LT. After LT 13/189 (6.8%) patients had HBsAg reactivation and 7/189 (3.7%) histological demonstration of recurrent cirrhosis. 2/189 (1.05%) patients underwent retransplantation for recurrence of liver disease. Conclusions: LT is the best treatment option for advanced HBV-related disease. Prophylaxis is effective to prevent HBV recurrence after LT and can ensure good survival both of the patients and of organ. The use of anti-HBc and HBsAg positive donors can be considered a safe way to expand the donor pool for patients transplanted for HBV-related liver disease.
F-49 International benchmarking in liver transplantation in Europe M. Carbone 1,2 , A. Gimson 1 , A. Nardi 2 , T. Marianelli 2 , K. Barber 1 , A. Hudson 1 , D. Collett 1 , J.M. Neuberger 1 , M. Angelico 2 1 Organ
Donation and Transplantation, NHS Blood and Transplant, Bristol, United Kingdom; 2 Tor Vergata University, Rome, Italy and Italian Association for the Study of the Liver (AISF) Background: Differences in donor quality and recipient selection for liver transplantation (LT) in European countries may lead to differences in outcome. Comparing outcomes after LT internationally might stimulate cross-national learning. Aim of this study was to compare outcomes in LT recipients in the United Kingdom (UK) and in Italy. Patients and methods: Data on 2,339 deceased donor LTs performed in adult recipients (01.06.2007–31.05.2009) were obtained from the UK Transplant Registry (n=859) and the Italian “Liver Match” database (n=1480). Results: Hepatitis C (HCV) and hepatocellular carcinoma (HCC) were more common as primary indications for LT in Italy compared to the UK (HCV: 22.8% vs.16.1%; HCC: 42.4% vs. 5.8%). Compared with their UK counterparts, Italian recipients had lower MELD (median: 15 vs.16, p<0.0001), lower BMI (median: 25.1 vs. 26, p=0.0001), were more likely to receive grafts from older donors (median: 56 vs.47 years, p<0.0001) who died for trauma (25.8% vs. 13.1, p<0.0001). Risk factors for graft loss at Cox multivariate regression were different: in Italy, these were donor age (HR=1.007), donor HBcAb status (HR=1.5), aetiology (HR for HCV=2.2), bilirubin (HR=1.18), creatinine (HR=1.3), portal vein thrombosis (HR=2.03); in the UK, risk factors were national vs. local allocation (HR=1.5), creatinine (HR=1.6) and donor BMI (HR=1.03). Ninety-day unadjusted graft survival was similar. Differences were observed at 3-years (78% in Italy vs. 84.4% in UK, p=0.0001). However, after adjusting for donor, graft and recipient significant factors, disease-specific survival was significantly different only in alcoholic liver disease (ALD) (HR=3.95; 95% CI, 1.8–5). Conclusions: Risk adjusted-survival analysis provides similar results in both countries, except for those transplanted for ALD; this requires further exploration. Given significant differences in aetiology, donor, recipient characteristics and risk factors, international comparison of LT outcomes must be approached with caution. These data suggest that predictive models developed in one country may not be valid in another.
F-50 Obstructive cholestasis induces a lobe-specific matrix metalloproteinase activation in rat livers G. Palladini 1 , A. Bianchi 1 , A. Ferrigno 1 , V. Rizzo 2 , S. Perlini 1 , P. Richelmi 1 , M. Vairetti 1 1 Department of Internal Medicine and Therapeutics, Fondazione IRCCS Policlinico S. Matteo and University of Pavia; 2 Department of Biochemistry, Fondazione IRCCS Policlinico S. Matteo and University of Pavia, Pavia, Italy
Introduction: Matrix metalloproteinases (MMPs) are a large family of calcium-dependent, zinc-containing endopeptidases, which are responsible for the degradation of extracellular matrix proteins. Recent studies report an
induction of MMPs in the progression of liver damage such as I/R injury, acute allograft rejection and chronic viral hepatitis. Aim: This study investigated whether in a obstructive model of cholestasis the activation of MMPs occur and equally/likewise affect the different lobes. Materials and methods: Fourteen male Sprague-Dawley rats underwent to 3-days obstructive cholestasis by common bile duct ligation (BDL) or sham operation. Blood samples and hepatic biopsies from left-lobe (LL), medianlobe (ML) and right-lobe (RL) were collected. Serum levels of hepatic enzymes (AST, ALT and g-GT), bilirubin (direct and total), and Ca2+ were evaluated. Tissue matrix metalloproteinases (MMP-2, MMP-9) and protein of the hepatic lobes were monitored. Results: Cholestasis injury was confirmed by altered serum levels of hepatic enzymes and bilirubin as compared with the sham group. A significant increase in serum Ca2+ levels was also found. After 3 days BDL a concomitant increase in MMP-2 and MMP-9 occurred in RL as compared with ML and LL. Higher tissue protein levels were found in ML and RL as compared with LL. Conclusions:This study indicates that already after 3-days cholestasis an increase in MMP-2 and MMP-9 activity occur and this event is lobe specific and associated to the RL. There is increasing evidence of a functional heterogeneity between the liver lobes as confirmed and supported by the present study: a heterogeneous damage distribution in the different lobes during obstructive cholestasis occurs in rat livers. Supported by FAR-UniPV.
F-51 Berberine ameliorates hepatic injury in mice acting on the NALP3 inflammasome pathway E. Vivoli 1 , S. Milani 2 , A. Provenzano 1 , S. Madiai 1 , E. Novo 4 , C.P.M.S. Oliveira 5 , G. Moneti 3 , N. Pecora 1 , M. Parola 3 , F. Marra 1 1 Dipartimento
di Medicina Interna; 2 Dipartimento di Fisiopatologia Clinica; Interdipartimentale di Spettrometria di Massa, Università di Firenze; 4 Dipartimento di Medicina e Oncologia Sperimentali, Università di Torino; 5 Universidade de Sao Paulo, Brazil 3 Centro
Background/Aims: The natural alkaloid berberine has a wide range of pharmacological and biochemical effects, including protection against liver injury. Aim of this study was to analyze the effects of BRB in two unrelated murine models of liver injury and to investigate the underlying mechanism of action. Materials/methods: BRB was tested in steatohepatitis induced by MCD diet and in acute acetaminophen (APAP) intoxication. BRB was administered at 5 mg/kg i.p in both models. Intrahepatic gene expression was assayed by quantitative real time PCR. The effects of BRB were further investigated in the murine macrophage cell line, RAW 264.7. Results: BRB markedly suppressed ALT serum levels in mice fed a MCD diet for 4 weeks. In addition, the necroinflammatory score was dramatically reduced. In MCD-fed, BRB-treated mice the intrahepatic gene expression of CD11b, CCL2, TGF-beta, type I collagen and TNF was significantly downregulated. MCD diet has been previously found to activate the NALP3 inflammasome pathway. BRB limited gene expression of all components of this pathway, including NALP3, ASC, caspase-1 and IL-1beta. In addition, IL-1beta protein levels in hepatic homogenates were significantly lower in mice treated with MCD and BRB than MCD alone. BRB also reduced the expression of TLR-4. APAP toxicity is another condition associated with inflammasome activation. In mice administered a toxic dose of APAP, BRB administration was associated with significantly lower ALT levels. APAPinduced increase in all components of the NALP3 inflammasome was limited by BRB. In murine macrophages stimulated with LPS, BRB significantly decreased NALP3 inflammasome activation, indicating a direct interference with this pathway. Conclusions: BRB administration ameliorates necroinflammation and liver injury in experimental steatohepatitis and in APAP intoxication. These effects are associated with inhibition of the inflammasome pathway in vivo and in cultured macrophages, identifying a novel mechanism of action for BRB.
F-46 A novel model of priority assessment for patients with and without hepatocellular carcinoma on a common liver transplant waiting list: a multicentre, cohort study A. Vitale 1 , T. De Feo 2 , P. Burra 1 , A.C. Frigo 1 , R. Ramirez Morales 1 , L. De Carlis 3 , M.F. Donato 4 , S. Fagiuoli 5 , A. Picciotto 6 , P. Toniutto 7 , E. Regalia 8 , U. Cillo 1 , on behalf of the Liver Transplantation NITp Working Group 1 University
Hospital of Padua, Italy; 2 North Italy Transplant program, Fond. IRCCS Ca’ Granda OMP, Milan, Italy; 3 Liver Transplantation, Ospedale Niguarda Ca’ Granda, Milan, Italy; 4 Gastroenterology Unit, Maggiore Hospital Policlinico, Milan, Italy; 5 Gastroenterology and Transplantation Hepatology, Ospedali Riuniti, Bergamo, Italy; 6 IRCCS San Martino,IST Genova, Italy; 7 Medical Liver Transplant Unit, University of Udine, Italy; 8 Liver Transplantation, IRCCS INT, Milan, Italy Background: Liver transplantation (LT) priority assessment strictly based on 3-months dropout estimation creates both an unbalance between patients with and without hepatocellular carcinoma (HCC), and penalizes post LT outcomes. The aim of this study was to describe an alternative model able to re-establish allocation equity between HCC and no-HCC patients using 5-year transplant benefit as the common endpoint. Methods: We enrolled consecutive adult patients with chronic end-stage liver disease entering the waiting list (WL) for LT (WL group = 2697) and undergoing LT (LT group = 1702) during the period 2004–2009 in the North Italian Transplant program area. Two independent multivariable regressions (WL and LT models) were created to measure the prognostic power of model for end stage liver disease (MELD) in patients with and without HCC. The models were also adjusted for the following covariates: recipient age, sex, and aetiology, re-transplant, donor age. For the WL model we used competing risk multivariable analysis. Hazard ratio (HR, 95% confidence intervals) were finally included in a Markov model to calculate 5-year survival benefit in different subgroups. Results: WL competing risk model: MELD significantly predicted survival in both HCC (1.100, 1.081–1.109) and non-HCC (1.070, 1.039–1.101) patients. LT Cox model: MELD significantly predicted patient survival in both HCC (1.042, 1.007–1.075) and non-HCC (1.038, 1.018–1.058) patients. Benefit model: the survival benefit of LT at each MELD point was higher in HCC than non-HCC patients. Using two-way sensitive analysis we calculated the following benefit MELD (bMELD) equation: bMELD=9.16 + 1.32*MELD in HCC patients with MELD score ≤22; bMELD=40 for HCC patients with MELD >22. Conclusion: We obtained a new bMELD score to weigh the priorities of HCC and non-HCC on a common waiting list.
S45
F-47 Early introduction of everolimus in de novo liver transplantation: a multicenter randomized clinical trial (EPOCAL) U. Cillo 1 , A. Vitale 1 , M. Salizzoni 2 , M. Coledan 3 , G. Rossi 4 , U. Baccarani 5 , L. De Carlis 6 , A. Bertacco 1 , L. Saracino 1 , R. Ramirez Morales 1 , S. Agnes 7 1 Centro
Trapianti di Fegato, Azienda Università di Padova; 2 Azienda Ospedaliero-Universitaria S. Giovanni Battista di Torino Ospedale Molinette; 3 Ospedale Riuniti Bergamo; 4 Ospedale Maggiore Policlinico Milano; 5 Azienda Ospedaliera “S.M. Misericordia” Udine; 6 Ospedale Niguarda- Ca Granda Milano; 7 Policlinico Universitario Agostino Gemelli Roma Introduction: There are no prospective randomized trials analysing safety and efficacy of early introduction of Everolimus in patients undergoing liver transplantation (LT). Methods: We performed a spontaneous, phase 2, multicenter (7 centers), randomized, open label, clinical trial. Inclusion criteria: first LT, acceptable graft function in postoperative day (POD) 7, cold ischemia time <12 hours. Patients were randomized in POD 7 in two possible arms using a 2:1 ratio, the study group (with Everolimus introduction in POD 8 and Tacrolimus reduction/weaning), and a control group (conventional immunosuppression). Primary endpoint: incidence of acute rejection and graft loss in the first 3 months after LT. Secondary endpoints: renal function, suspension of Tacrolimus, incidence of adverse events. Calculated sample size: 117 patients evaluable for the primary endpoint. We present the preliminary results of an interim analysis carried out in October 2012. Results: Up to October 2012, 84 patients were enrolled in the study group and 46 in control group (110 patients evaluable at 3 months for the primary endpoint). We did not find any significant difference between the two groups. The primary endpoint in the study group vs. controls has been so far observed: acute rejection, 17% vs. 7% (p>0.05), graft loss, 2% vs. 8% (p>0.05). The number of adverse events was also comparable between the two groups with the exception of infections having a significantly higher incidence in the controls (20% vs. 1%, p <0.01). The weaning of tacrolimus at 1 month in the study group was successful in 43% of cases. Renal function at 3 months in the two groups was not significantly different. Conclusions: Everolimus seems safe and effective when introduced early after LT.
F-48 Liver transplantation for HBV-related liver disease: the experience of Padua Liver Transplant Center I. Bortoluzzi 1 , M. Gambato 1 , G. Germani 1 , E. Nadal 1 , M. Senzolo 1 , G. Zanus 2 , P. Boccagni 2 , U. Cillo 2 , P. Burra 1 , F.P. Russo 1 1 Multivisceral Transplant Unit- Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University Hospital Padova, Padua, Italy; 2 Hepatobiliary Surgery and Liver Transplantation, Department of Surgical, Oncological and Gastroenterological Sciences, University Hospital Padova, Padua, Italy
HBV- related liver disease is a frequent indication to liver transplantation (LT) in Europe (15–25%) and prophylaxis after LT has drastically reduced HBV recurrence (<5%). The aim of the study is to evaluate results of LT for HBVrelated disease in the Liver Transplant Center of Padua. Materials and methods: All patients who had undergone LT in our Centre for HBV-related liver disease were included. At yearly intervals we analyzed: HBsAg, anti-HBs titer, HBV-DNA, liver biopsies, prophylaxis received. Results: From November 1990 to September 2011 189/1010 (18.7%) LT have been performed for HBV-related liver disease. Etiology of liver disease was: 83/189 (44%) HBV infection, 49/189 (26%) HBV/HDV, 47/189 (24.8%) HBV/HCV and 10/189 (5.2%) HBV/alcohol. Indication to LT was: fulminant hepatic failure in 11/189 patients (5.8%), decompensated cirrhosis in 121/189 patients (64%), hepatocellular carcinoma (HCC) on cirrhosis in 57/189 patients (30.2%). 6/189 of these patients received a HBsAg and antiHBc positive graft, 25/189 from a HBsAg negative/anti-HBc positive one. All
S46
Abstracts of the 46th A.I.S.F. Annual Meeting 2013 / Digestive and Liver Disease 45S (2013), S1–S48
patients received prophylaxis after LT. No statistically significant difference has been observed analyzing patient and organ survival in relation to etiology of liver disease, presence or not of HCC, viral load at LT and HBV serology of the donor. No statistically significant difference on histology has been observed in relation to HBV-DNA levels at LT and prophylaxis after LT. After LT 13/189 (6.8%) patients had HBsAg reactivation and 7/189 (3.7%) histological demonstration of recurrent cirrhosis. 2/189 (1.05%) patients underwent retransplantation for recurrence of liver disease. Conclusions: LT is the best treatment option for advanced HBV-related disease. Prophylaxis is effective to prevent HBV recurrence after LT and can ensure good survival both of the patients and of organ. The use of anti-HBc and HBsAg positive donors can be considered a safe way to expand the donor pool for patients transplanted for HBV-related liver disease.
F-49 International benchmarking in liver transplantation in Europe M. Carbone 1,2 , A. Gimson 1 , A. Nardi 2 , T. Marianelli 2 , K. Barber 1 , A. Hudson 1 , D. Collett 1 , J.M. Neuberger 1 , M. Angelico 2 1 Organ
Donation and Transplantation, NHS Blood and Transplant, Bristol, United Kingdom; 2 Tor Vergata University, Rome, Italy and Italian Association for the Study of the Liver (AISF) Background: Differences in donor quality and recipient selection for liver transplantation (LT) in European countries may lead to differences in outcome. Comparing outcomes after LT internationally might stimulate cross-national learning. Aim of this study was to compare outcomes in LT recipients in the United Kingdom (UK) and in Italy. Patients and methods: Data on 2,339 deceased donor LTs performed in adult recipients (01.06.2007–31.05.2009) were obtained from the UK Transplant Registry (n=859) and the Italian “Liver Match” database (n=1480). Results: Hepatitis C (HCV) and hepatocellular carcinoma (HCC) were more common as primary indications for LT in Italy compared to the UK (HCV: 22.8% vs.16.1%; HCC: 42.4% vs. 5.8%). Compared with their UK counterparts, Italian recipients had lower MELD (median: 15 vs.16, p<0.0001), lower BMI (median: 25.1 vs. 26, p=0.0001), were more likely to receive grafts from older donors (median: 56 vs.47 years, p<0.0001) who died for trauma (25.8% vs. 13.1, p<0.0001). Risk factors for graft loss at Cox multivariate regression were different: in Italy, these were donor age (HR=1.007), donor HBcAb status (HR=1.5), aetiology (HR for HCV=2.2), bilirubin (HR=1.18), creatinine (HR=1.3), portal vein thrombosis (HR=2.03); in the UK, risk factors were national vs. local allocation (HR=1.5), creatinine (HR=1.6) and donor BMI (HR=1.03). Ninety-day unadjusted graft survival was similar. Differences were observed at 3-years (78% in Italy vs. 84.4% in UK, p=0.0001). However, after adjusting for donor, graft and recipient significant factors, disease-specific survival was significantly different only in alcoholic liver disease (ALD) (HR=3.95; 95% CI, 1.8–5). Conclusions: Risk adjusted-survival analysis provides similar results in both countries, except for those transplanted for ALD; this requires further exploration. Given significant differences in aetiology, donor, recipient characteristics and risk factors, international comparison of LT outcomes must be approached with caution. These data suggest that predictive models developed in one country may not be valid in another.
F-50 Obstructive cholestasis induces a lobe-specific matrix metalloproteinase activation in rat livers G. Palladini 1 , A. Bianchi 1 , A. Ferrigno 1 , V. Rizzo 2 , S. Perlini 1 , P. Richelmi 1 , M. Vairetti 1 1 Department of Internal Medicine and Therapeutics, Fondazione IRCCS Policlinico S. Matteo and University of Pavia; 2 Department of Biochemistry, Fondazione IRCCS Policlinico S. Matteo and University of Pavia, Pavia, Italy
Introduction: Matrix metalloproteinases (MMPs) are a large family of calcium-dependent, zinc-containing endopeptidases, which are responsible for the degradation of extracellular matrix proteins. Recent studies report an
induction of MMPs in the progression of liver damage such as I/R injury, acute allograft rejection and chronic viral hepatitis. Aim: This study investigated whether in a obstructive model of cholestasis the activation of MMPs occur and equally/likewise affect the different lobes. Materials and methods: Fourteen male Sprague-Dawley rats underwent to 3-days obstructive cholestasis by common bile duct ligation (BDL) or sham operation. Blood samples and hepatic biopsies from left-lobe (LL), medianlobe (ML) and right-lobe (RL) were collected. Serum levels of hepatic enzymes (AST, ALT and g-GT), bilirubin (direct and total), and Ca2+ were evaluated. Tissue matrix metalloproteinases (MMP-2, MMP-9) and protein of the hepatic lobes were monitored. Results: Cholestasis injury was confirmed by altered serum levels of hepatic enzymes and bilirubin as compared with the sham group. A significant increase in serum Ca2+ levels was also found. After 3 days BDL a concomitant increase in MMP-2 and MMP-9 occurred in RL as compared with ML and LL. Higher tissue protein levels were found in ML and RL as compared with LL. Conclusions:This study indicates that already after 3-days cholestasis an increase in MMP-2 and MMP-9 activity occur and this event is lobe specific and associated to the RL. There is increasing evidence of a functional heterogeneity between the liver lobes as confirmed and supported by the present study: a heterogeneous damage distribution in the different lobes during obstructive cholestasis occurs in rat livers. Supported by FAR-UniPV.
F-51 Berberine ameliorates hepatic injury in mice acting on the NALP3 inflammasome pathway E. Vivoli 1 , S. Milani 2 , A. Provenzano 1 , S. Madiai 1 , E. Novo 4 , C.P.M.S. Oliveira 5 , G. Moneti 3 , N. Pecora 1 , M. Parola 3 , F. Marra 1 1 Dipartimento
di Medicina Interna; 2 Dipartimento di Fisiopatologia Clinica; Interdipartimentale di Spettrometria di Massa, Università di Firenze; 4 Dipartimento di Medicina e Oncologia Sperimentali, Università di Torino; 5 Universidade de Sao Paulo, Brazil 3 Centro
Background/Aims: The natural alkaloid berberine has a wide range of pharmacological and biochemical effects, including protection against liver injury. Aim of this study was to analyze the effects of BRB in two unrelated murine models of liver injury and to investigate the underlying mechanism of action. Materials/methods: BRB was tested in steatohepatitis induced by MCD diet and in acute acetaminophen (APAP) intoxication. BRB was administered at 5 mg/kg i.p in both models. Intrahepatic gene expression was assayed by quantitative real time PCR. The effects of BRB were further investigated in the murine macrophage cell line, RAW 264.7. Results: BRB markedly suppressed ALT serum levels in mice fed a MCD diet for 4 weeks. In addition, the necroinflammatory score was dramatically reduced. In MCD-fed, BRB-treated mice the intrahepatic gene expression of CD11b, CCL2, TGF-beta, type I collagen and TNF was significantly downregulated. MCD diet has been previously found to activate the NALP3 inflammasome pathway. BRB limited gene expression of all components of this pathway, including NALP3, ASC, caspase-1 and IL-1beta. In addition, IL-1beta protein levels in hepatic homogenates were significantly lower in mice treated with MCD and BRB than MCD alone. BRB also reduced the expression of TLR-4. APAP toxicity is another condition associated with inflammasome activation. In mice administered a toxic dose of APAP, BRB administration was associated with significantly lower ALT levels. APAPinduced increase in all components of the NALP3 inflammasome was limited by BRB. In murine macrophages stimulated with LPS, BRB significantly decreased NALP3 inflammasome activation, indicating a direct interference with this pathway. Conclusions: BRB administration ameliorates necroinflammation and liver injury in experimental steatohepatitis and in APAP intoxication. These effects are associated with inhibition of the inflammasome pathway in vivo and in cultured macrophages, identifying a novel mechanism of action for BRB.