Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR)

Abstract

Since 1968 the European Liver Transplant Registry (ELTR) collects prospectively the data of liver transplantation (LT) in 145 centers all over Europe. It represents more than 95% of the overall European data compared to the published official figures [[1]International figures on organ donation and transplantation activities 2009. http://www.transplant-observatory.org.Google Scholar]. This collection is made prospectively through a standardized questionnaire. The first part of the questionnaire includes items regarding date and indication for LT, donor and recipient data, surgical technique of LT, and the immediate postoperative immunosuppression therapy. The second part concerns graft and patient outcome, and immunosuppressive regimen follow-up. Participation in the ELTR is voluntary and a standard computerized database is provided to contributing centers with detailed instructions for the collection of accurate and uniform information [[2]Adam R. McMaster P. O’Grady J.G. Castaing D. Klempnauer J.L. Jamieson N. et al.Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry.Liver Transpl. 2003; 9: 1231-1243Crossref PubMed Scopus (492) Google Scholar]. Along with reports concerning LT for specific hepatic diseases [3Mentha G. Giostra E. Majno P.E. Bechstein W.O. Neuhaus P. O’Grady J. et al.Liver transplantation for Budd-Chiari syndrome: a European study on 248 patients from 51 Centres.J Hepatol. 2006; 44: 520-528Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 4Lerut J. Orlando G. Adam R. Sabbà C. Pfitzmann R. Klempnauer J. et al.Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European Liver Transplant Registry.Ann Surg. 2006; 244: 854-862Crossref PubMed Scopus (2) Google Scholar, 5Mutimer D.J. Gunson B. Chen J. Berenguer J. Neuhaus P. 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Seehofer D. et al.Liver transplantation for erythropoietic protoporphyria in Europe.Liver Transpl. 2011; 17: 1021-1026PubMed Google Scholar], ELTR has allowed the development of risk models for liver-transplantation mortality according to the characteristics of the donor and recipient, and of the transplant procedure [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. Quality of the data is assessed routinely. A regular auditing process is conducted each year to ensure the reliability of the scientific analysis of the data, a control of the good adequacy between ELTR questionnaire and patient charts is performed by randomly conducted audit visits. Results of these audit visits have indicated that ELTR data were reliable and the scientific results of ELTR can be considered credible and representative of LT in Europe [15Karam V. Gunson B. Roggen F. Grande L. Wannoff W. Janssen M. et al.Quality control of the European Liver Transplant Registry: Results of audit visits to the contributing Centres.Transplantation. 2003; 75: 2167Crossref PubMed Scopus (48) Google Scholar, 16Morris P. Monaco A. Quality control of transplant registries.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (4) Google Scholar, 17Hanto D. Reliability of voluntary and compulsory databases and registries in the United States.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (20) Google Scholar, 18Van Der Meulen J. Jacob M. Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry.Transplantation. 2003; 75: 2164Crossref PubMed Scopus (24) Google Scholar]. In addition, a control quality program has been developed internally. The data are subjected to checks for completeness, consistency, and range. Comprehensive logical intra- and inter-updates are performed. Moreover, the ELTR has established agreements with the European Organ Sharing Organizations (OSO): United Kingdom Transplant Service Support Authority (UKTransplant), Spanish Organizaciòn Nacional de Transplantes (ONT), Scandinavian Scanditransplant (SKT), Dutch Transplant Foundation (NTS), Eurotransplant (ET), French Agence de la Biomédecine (ABM) to exchange data collected from European Centers and to cross check common data between OSO and ELTR. We have first considered all data since 1968 to show the evolution of results of LT in Europe since its initial development. The rest of the analysis has been undertaken during two different periods: (a) from January 1988 to December 2009 (89,865 LT – 80,347 patients), where the date from January 1988 was chosen as corresponding to the diffusion of cyclosporine-based immunosuppression and to the standardization of the surgical procedure, (b) the last 10-year period data from January 2000 to December 2009 (54,088 LT – 48,218 patients) to give a more recent evaluation of LT results in Europe. Data were analyzed as a whole without distinction of pediatric transplants that represent 10% of LTs in Europe. Data are analyzed with Statistical Analysis System (SAS). The dynamics of data control are continued during the statistical analyzes. Calculation of survival rates are determined by the actuarial method. From May 1968 to December 2009, the ELTR collected data concerning 93,634 liver transplantations (LTs) in 83,816 patients from 145 centers of 26 countries (Fig. 1). These data give a comprehensive overview of the status and evolution of LT in Europe. Both the number of transplant centers and the annual number of LTs performed in Europe have gradually increased since the creation of ELTR (Fig. 2). However, after an exponential increase from the eighties, a plateau has become to be reached in recent years with about 5800 LTs performed all over Europe.Fig. 2Evolution of 93,634 LTs performed in Europe since May 1968. Arrows indicate the year the first LT was performed in indicated countries. ∗This decrease is owed to the fact that some centers did not yet send their updating further to the recent changes of the questionnaire.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Main indications for LT in Europe with the corresponding graft and patient survival rates at 1, 5 and 10 years are listed in Table 1. Cirrhosis is the most frequent indication (52%), mainly related to either viral infection (21% with 13% of hepatitis C virus infection (HCV) and 7% of hepatitis B virus infection (HBV)), or alcohol abuse (19%). Combined viral and alcoholic (ALD) cirrhosis represents 3% of cases, with 2% of HCV–ALD. Cirrhosis is followed by three major indications: primary liver tumors (14% with 12.1% of hepatocellular carcinoma), cholestatic disease (11%), and acute hepatic failure (8%, 2% of which are virus-related). Cholestatic disease includes primary biliary cirrhosis (6%) and extra-hepatic biliary atresia (4%). Primary sclerosing cholangitis represents 4% of cases. Biliary atresia is the most frequent indication (57%) in the pediatric population, followed by metabolic disease (19%). Metabolic disease represents 6% of indications with familial amyloïdotic polyneuropathy as the major indication (2%), followed by three indications of equal frequency (1%): Wilson disease, alpha-1-antitrypsin deficiency and hemochromatosis. Secondary tumors (mainly carcinoid), Budd Chiari and benign liver tumors (mainly polycystic disease) represent only 1% of indications in Europe.Table 1Primary indications for LT in Europe and the corresponding survival. Open table in a new tab The percentage of main indications for LT has significantly changed with time. While cancers represented 50% of indications before 1980, they dramatically decreased during the nineties (10%) before resuming a linear increase since 2000, to currently represent more than 20%. Conversely, acute hepatic failure that led anecdotally to LT before 1986 has since become a recognized indication for LT. (Fig. 3). In the 10 recent years, two groups of indication have shown an increase: primary liver tumors (16%), mainly related to HCC, and cirrhosis (53%), mainly alcoholic (20%). Drug-related fulminant hepatitis is henceforth the leading disease in the group of acute hepatic failures. In the same way, primary sclerosing cholangitis is the main indication in the group of cholestatic diseases. Patient and graft survival of this 10-recent-year population are summarized in Table 1. One, 3 and 6-month patient’s survivals were 90%, 85% and 82% before 2000. Survival rates dramatically increased to reach 94%, 91% and 88%, respectively. The critical period for post-LT outcome is the first 6 months: 46% of deaths and 65% of re-LT occurs within 6 months after LT (Fig. 4). In 49% of cases, re-LT is indicated in the month after primary LT, and one quarter of deaths occurs within the first month after LT. Data represented in Table 2, Table 3 correspond to main cause of death or graft failure. Main causes of death in the 18,186 patients (about 23%) who died after primary LT or re-LT were, by decreasing order: (1) general causes as multiple organ failure and cerebrovascular, cardiovascular, pulmonary, and renal complications (29%); (2) recurrence of primary disease (20%), mostly cancer (11%); (3) sepsis (18%) mostly bacterial (9%); (4) technical complications (5%), mostly hemorrhage and vascular (3%); and (5) rejection (4%) mostly chronic (3%) (Table 2). Intra-operative deaths and primary non-function represented 3% of all deaths. When we consider only the patients who survive beyond 6 months (Fig. 5), there are less technical complications, infection and general complications (cerebrovascular, cardiovascular, pulmonary, and renal), but more tumoral and non-tumoral recurrences, de novo tumor and rejection.Table 2Post-LT mortality after first LT in Europe. Complications correspond to first declared cause of death according to date of occurrence. Open table in a new tab Table 3Recipient graft survival according to the type of LT in Europe. Open table in a new tab The data of the last 10 years show a decrease in overall mortality (16%) with the same distribution of the causes of death observed in the population from 1988. When all indications are considered during the entire study period, patient survival rates are 82% at 1 year, 71% at 5 years, 61% at 10 years, 51% at 15 years and 43% at 20 years. When we consider only the patients who survive beyond 6 months, patient survival rates are dramatically higher (96% at 1 year, 83% at 5 years, 71% at 10 years, 61% at 15 years and 52% at 20 years). After an improvement between 1988 and 2000, the survival of these patients appears to be relatively steady since 2000 (Fig. 6). Survival has improved regularly year after year, reaching 85% at 1 year after 2004 compared with 76% in 1990–1994 and only 33% before 1985 (Fig. 7). The improvement concerns all the indications but particularly LT for cancers (Fig. 8).Fig. 8Patient survival according to indication for and year of LT.View Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, survival of patients transplanted in the recent 10 years has improved to reach 85% at 1 year and 73% at 5 years. Ten percent of LTs have been performed in pediatric patients (<15 with of than years. survival in is significantly than in adults In the pediatric population, survival is for years and for 3 to 15 years In the 10 last years, the of pediatric LT has decreased to and the corresponding 5 is than in adults The patient survival is significantly for cirrhosis than for primary liver tumors and acute hepatic failure In viral and have a survival than with or The survival rates in metabolic diseases cholestatic disease and biliary disease of the percentage of in these of survival rates at 1, 5 and 15 and 20 years according to the primary indication are listed in Table 1. survival in the last 10-year population was improved in all the most in survival was observed in LTs for primary liver which is liver and acute hepatic failure The of were percent were than years, were than years. percentage of are from than years in in and in in to the between a and a relatively donor (Fig. survival were from than years was significantly higher than that with from than years at 5 years, 71% at and 50% graft there is to among without risk (Fig. graft survival according to donor Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, graft survival was with than years and with donor than years. However, are more transplanted to of than years were in than years, and only were in than years, at in the in survival. In to the survival of pediatric LT an of recipient age is observed for Survival rates are for adults years, for years, and for than years. However, age of transplanted has increased during the last and patients than years, who represented less than in the represented of transplant in 2009 (Fig. When we consider the last 10-year period, survival has increased in all the of to reach for adults of years, 73% for years and over years. percent of LTs were and were were and to In and LTs have survival. In LTs have a survival than LTs LTs have a decreased graft survival as compared to and LTs However, of these in indications 50% survival in patients to a 5 in the last 10-year population was improved in all the groups of type the most in survival was observed in However, only of LTs were than LTs were and of were to LTs have been in recent years before 2000 after In the were represented by (2%), (6%) and transplants 1, 15 and graft survivals of each type of graft are summarized in Table Survival at 5 years was between liver and but than that of and higher than that of and and represented of overall LTs with a graft survival as compared to in indications survival and in indications survival was was less than and of was for When we consider the last 10-year period, graft survival has increased in all of graft to reach for for and for The ELTR has data concerning related LTs performed in centers from 20 countries from to December 2009 (Fig. 1). The results of this technique be published In adults represented 65% of Since pediatric The donor surgical mortality was graft survival of was for than for adults graft survival of was than LT for was for adults graft more technical complications more infection more rejection more tumor recurrence but less general complications and less disease recurrence after than after LT was indicated in mainly for technical complications vascular and biliary for primary non-function and for rejection mainly chronic of primary disease was in only of (Table of re-LT after the first LT in Europe. The complications correspond to the first cause of failure declared according to of occurrence. Open table in a new tab graft survival rates for the second and LTs were and significantly than for primary LT – (Fig. The data of the last 10 years show a decrease in the of re-LT with an increase of technical complications and a decrease of rejection Moreover, graft survival was increased in all the of re-LT and the between primary LT and LT has been more than the ELTR is a to the evolution and results of LT in Europe. It is representative of LT in Europe of LTs to a control of data audit visits to randomly its scientific has been [15Karam V. Gunson B. Roggen F. Grande L. Wannoff W. Janssen M. et al.Quality control of the European Liver Transplant Registry: Results of audit visits to the contributing Centres.Transplantation. 2003; 75: 2167Crossref PubMed Scopus (48) Google Scholar, 16Morris P. Monaco A. Quality control of transplant registries.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (4) Google Scholar, 17Hanto D. Reliability of voluntary and compulsory databases and registries in the United States.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (20) Google Scholar, 18Van Der Meulen J. Jacob M. Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry.Transplantation. 2003; 75: 2164Crossref PubMed Scopus (24) Google Scholar]. LTs year are currently performed in a number to that of the United However, donation rates in Europe more than in United for Organ Sharing has by the donation in Europe in followed by most of the European countries with a of organ donation between 20 and to that of in the and which has the donation in figures on donation and European for the Quality of Transplant Scholar]. with a donor that represents the most of LT, to LT as or related LTs are for of all more these give results to that for LT and a number of patients to LT. they from the centers [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. This is to the risk for in of has been between the and the of the risk of donor mortality and In of two main from the European (1) as cirrhosis to represent the main indication of LT with more than of the and a within this group of patients with alcoholic and virus C related (2) the major is for mainly HCC, which represents currently of all after a decrease from 50% in the to only 10% in the The of patients within the V. E. R. S. A. F. et al.Liver transplantation for the treatment of hepatocellular in patients with J PubMed Scopus Google with results of survival between and benign hepatic disease this of the most in the evolution of LT is the improvement of results with leading to a survival of all indications This results from a surgical a of patients and an improved post-LT of complications and immunosuppressive therapy. The improvement is particularly for mainly hepatocellular carcinoma as with a of in survival rates from to This was with the data of the last 10 years with an improved survival of and recipient age the quality of the as shown by a analysis of ELTR data on mortality after LT [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. However, they are not of the fact that donor age has been as an risk of outcome R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar], the evolution that are to the donor recipient age has been considered as with higher the but LT to improved results and of has not changed with is the critical period of the first 6 months more the first year to the outcome of the transplanted than a of the deaths and three of within the first year after LT. that patients have reached the first year after LT, they have an to survive at When 7% of patients), re-LT is with less results than the first LT. However, there is that consider this a to a new LT that a of with the in to of the of the of survival is observed between first and second LT and LTs are not with results than of second of the of recent years has been the development of performed by of the centers. with LT, to more patients with but with to decrease as as for the to be of for mortality and for postoperative However, has to decrease in recent years in Europe the in the where has decreased in liver Full Text Full Text PDF PubMed Scopus Google Scholar]. liver are by accurate information about donor to data is and these from liver donor registries and of donor an for centers with deaths to these to the liver transplantation liver donor where we J 2006; PubMed Scopus Google Scholar, Adam R. J. deaths of hepatic for donor liver Transpl. 2006; PubMed Scopus Google Scholar]. In LT is a of liver disease, acute liver failure and It is relatively as compared to the initial years. are to more of the donor Survival is gradually in to in the surgical procedure and of immunosuppressive therapy. to of liver are to the organ This development the of the evaluation of the in the of countries represent a in the increase the donor to patient death on the and to equal to good indications of LT have become the main of a treatment that of patients to survive at 5 years. The declared that they not have to regarding or of with to this The are to all the 145 contributing centers listed at the following The is by a from and a of the – de ELTR is a of the European Liver and Transplant