Vincent Karam

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

Royal Free Hospital, London, UKIntroductionBackground of the European Liver Transplant RegistrySince 1968 the European Liver Transplant Registry (ELTR) collectsprospectively the data of liver transplantation (LT) in 145 centersall over Europe. It represents more than 95% of the overallEuropean data compared to the published official figures [1]. Thiscollectionismadeprospectivelythroughastandardizedquestion-naire. The first part of the questionnaire includes items regardingdate andindicationfor LT,donor andrecipientdata, surgical tech-niqueofLT,andtheimmediatepostoperativeimmunosuppressiontherapy. The second part concerns graft and patient outcome, andimmunosuppressive regimen follow-up. Participation in the ELTRis voluntary and a standard computerized database is provided tocontributing centers with detailed instructions for the collectionof accurate and uniform information [2].Along with reports concerning LT for specific hepatic diseases[3–12],ELTRhasallowedthedevelopmentofriskmodelsforliver-transplantation mortality according to the characteristics of thedonor and recipient, and of the transplant procedure [13,14].Qualityofthedataisassessedroutinely.Aregularauditingpro-cessisconductedeachyeartoensurethereliabilityofthescientificanalysis of the data, a control of the good adequacy between ELTRquestionnaire and patient charts is performed by randomly con-ductedauditvisits.ResultsoftheseauditvisitshaveindicatedthatELTR data were reliable and the scientific results of ELTR can beconsidered credible and representative of LT in Europe [15–18].In addition, a control quality program has been developed inter-nally. The data are subjected to checks for completeness, consis-tency, and range. Comprehensive logical intra- and inter-updatesare performed. Moreover, the ELTR has established agreementswith the European Organ Sharing Organizations (OSO): UnitedKingdom Transplant Service Support Authority (UKTransplant),Spanish Organizacion Nacional de Transplantes (ONT), Scandina-vian Scanditransplant (SKT), Dutch Transplant Foundation (NTS),Eurotransplant (ET), French Agence de la Biomedecine (ABM) toexchangedatacollectedfromEuropeanCentersandtocrosscheckcommon data between OSO and ELTR.Patients and methodsWe have first considered all data since 1968 to show the evolu-tion of results of LT in Europe since its initial development. Therest of the analysis has been undertaken during two differentperiods: (a) from January 1988 to December 2009 (89,865 LT –80,347 patients), where the date from January 1988 was chosenJournal of Hepatology 2012 vol. 57

3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome

BACKGROUND Mortality after liver transplantation depends on heterogeneous recipient and donor factors. Our aim was to assess risk of death and to develop models to help predict mortality after liver transplantation. METHODS We analysed data from 34,664 first adult liver transplants from the European Liver Transplant Registry to identify factors associated with mortality at 3-months (n=21,605 in training dataset) and 12-months (n=18,852 in training dataset) after transplantation. We used multivariable logistic regression models to generate mortality scores for each individual, and assessed model discrimination and calibration on an independent validation dataset (n=9489 for 3-month model and n=8313 for 12-month model). FINDINGS 2540 of 21,605 (12%) individuals in the 3-month training sample had died by 3 months. Compared with those transplanted in 2000-03, those transplanted earlier had a higher risk of death. Increased mortality at 3-months post-transplantation was associated with acute liver failure (adjusted odds ratio 1.61), donor age older than 60 years (1.16), compatible (1.22) or incompatible (2.07) donor-recipient blood group, older recipient age (1.12 per 5 years), split or reduced graft (1.96), total ischaemia time of longer than 13 h (1.38), and low United Network for Organ Sharing score (score 1: 2.43; score 2: 1.67). However, cirrhosis with hepatocellular carcinoma, alcohol cirrhosis, hepatitis C or primary biliary cirrhosis, donor age 40 years or younger, or less, hepatitis B, and larger size of transplant centre (> or = 70 transplants per year) were associated with improved early outcomes. The 3-month mortality score discriminated well between those who did and did not die in the validation sample (C statistic=0.688). We noted similar findings for 12-month mortality, although deaths were generally underestimated at this timepoint. INTERPRETATION The 3-month and 12-month mortality models can be effectively used to assess outcomes both within and between centres. Furthermore, the models provide a means of assessing the risk of post-transplantation mortality, giving clinicians important data on which to base strategic decisions about transplant policy in particular individuals or groups.

Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study

BACKGROUND No model exists for liver transplantation to estimate the mortality risk in a given patient, and no standard by which to assess performance in different centres. We investigated the intrinsic mortality risk in the absence of known mortality risk factors. METHODS We identified mortality risk factors and risk ratios quantified in data from the European Liver Transplant Registry (22,089 patients at 102 centres in 18 countries) registered from 1988 to 1997. To develop a model of the intrinsic risk and the risk ratios for specific factors, univariate and multivariate analyses were done separately for the overall population, for adults, and for children younger than 15 years, and the number of deaths were estimated. We validated the model by comparing mortality in patients without risk factors with the model-adjusted mortality in patients with risk factors. FINDINGS Overall 5-year and 8-year actuarial survival was 66% (95% CI 65-66) and 61% (60-62). 65% of deaths occurred within 6 months. Retransplantation, transplantation for cancer, acute liver failure, fewer than 20 split-liver grafts per year, and a centre workload of fewer than 25 transplants per year were the main risk factors of 12 identified factors. 1-year and 5-year death rates among adults with no risk factors were similar to model estimates (15 [13-16] vs 14% [13-15], and 22 (20-24) vs 23% [21-24]). Corresponding data for paediatric transplants were 9% (7-12) compared with 11% (9-12) and 13% (10-17) compared with 14% (11-16). The reduction of mortality risk in high-volume centres was even greater in patients without risk factors (48 vs 23%, p<0.001). INTERPRETATION The normalised intrinsic mortality risk can be combined with the relative risk ratios of known risk factors to better estimate the mortality risk of a given procedure in a given patient. Centres can assess performance by removing potential bias of donor and recipient selection.

Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).

Alcohol‐related liver disease (ALD) is one of the most common indications for liver transplantation (LT). Long‐term outcome after LT for ALD versus other etiologies is still under debate. The aim of this study was to compare outcome after LT of patients with ALD, viral (VIR), and cryptogenic cirrhosis. Donor, graft and recipient ELTR variables were analysed in transplants for alcoholic and nonalcoholic cirrhosis (1988–2005) and were correlated with patient survival. Causes of death and/or graft failure were compared between groups. Nine thousand eight hundred eighty ALD, 10 943 VIR, 1478 ALD + VIR and 2410 cryptogenic (CRYP) liver transplants were evaluated. One, 3, 5 and 10 years graft survival rates after LT in ALD patients were 84%, 78%, 73%, 58%, significantly higher than in VIR and CRYP (p = 0.04, p = 0.05). By multivariate analysis, ALD + VIR (RR 1.14) and viral alone (RR 1.06) were significant risk factors for mortality. De novo tumors, cardiovascular and social causes were causes of death/graft failure in higher percentage in ALD groups versus other etiologies. LT for ALD cirrhosis has a favorable outcome, however, hepatitis C virus co‐infection seems to eliminate this advantage. Screening for de novo tumors and prevention of cardiovascular complications are essential to provide better long‐term results.

Quality of life in adult survivors beyond 10 years after liver, kidney, and heart transplantation.

Background. The yearly increasing survival rates testify to the success of transplantation, but questions remain relating to the quality of life (QOL) associated with long-term survival. Methods. A sample of 126 liver recipients (Liver-R), 229 kidney recipients (Kidney-R), and 113 heart recipients (Heart-R) with more than 10 years posttransplant follow-up were included in the study with a response rate of 86%. Respondents were matched with healthy subjects recruited from general population (GP). The three groups of recipients and GP subjects completed a French version of the questionnaire used by the National Institute of Diabetes and Digestive and Kidney Disease, Pittsburgh, PA, and were compared for each score, with adjustments for age and sex. Results. Personal function and measures of disease by the transplant recipients were significantly worse than in the GP (P <0.0001), with the worst score in Kidney-R. No difference, either between organs or between organs and GP, was found regarding the perceived social and role function. However, for psychologic status and general health perception, Kidney-R had the least favorable performance when compared with GP (P <0.01) and also when compared with Liver-R (P <0.05). With the exception of Kidney-R, the well-being index of Liver-R and Heart-R was significantly better than the GP (P <0.001 and P <0.05, respectively). Conclusions. The QOL beyond 10 years after liver, heart, and kidney transplantation is quite similar to the GP, with Kidney-R starting out as the worst, Heart-R as intermediate, and Liver-R the best.

Split-liver Transplantation for Two Adult Recipients: Feasibility and Long-term Outcomes

ObjectiveTo identify the outcomes and risks of split-liver transplantation (SLT) for two adult recipients to determine the feasibility of more widespread use of this procedure to increase the graft pool for adults. Summary Background DataThe shortage of cadaver liver grafts for adults is increasing. Using livers from donors defined as optimal, the authors have been developing techniques for SLT for two adult recipients at their center. MethodsFrom July 1993 to December 1999, 34 adults have undergone SLT with grafts from optimal donors prepared by ex situ split (n = 30) or in situ split (n = 4), and 88 adults received optimal whole-liver grafts that were not split. Four split-grafts were transplanted at other centers. The outcomes of transplantation with right and left split-liver grafts were compared with those of whole-liver transplants. The main end points were patient and graft survival at 1 and 2 years and the incidence and types of complications. ResultsFor whole-liver, right and left split-liver grafts, respectively, patient survival rates were 88%, 74%, and 88% at 1 year and 85%, 74%, and 64% at 2 years. Graft survival rates were 88%, 74%, and 75% at 1 year and 85%, 74%, and 43% at 2 years. Patient survival was adversely affected by graft steatosis and recipients inpatient status before transplantation. Graft survival was adversely affected by steatosis and a graft-to-recipient body weight ratio of less than 1%. Primary nonfunction occurred in three left split-liver grafts. The rates of arterial (6%) and biliary (22%) complications were similar to published data from conventional transplantation for an adult and a child. SLT for two adults increased the number of recipients by 62% compared with whole-liver transplantation and was logistically possible in 16 of the 104 (15%) optimal cadaver donors. ConclusionsSplit-liver transplantation for two adults is technically feasible. Outcomes and complication rates can be improved by rigid selection criteria for donors and recipients, particularly for the smaller left graft, and possibly also by in situ splitting in cadaver donors. Wider use will require changes in the procedures for graft allocation and coordination between centers experienced in the techniques.

Liver Transplantation for Hereditary Hemorrhagic Telangiectasia: Report of the European Liver Transplant Registry

Background:Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is a rare disease characterized by the presence of arteriovenous malformations. Hepatic involvement can lead to life-threatening conditions. Material and Methods:Forty patients, reported to the European Liver Transplant Registry, were analyzed to define the role of liver transplantation in the treatment of the hepatic disease form. Indications for transplantation were classified according to Garcia-Tsao: cardiac failure (14 patients), biliary necrosis causing hepatic failure (12 patients), severe portal hypertension (5 patients), cardiac failure and biliary necrosis (6 patients), cardiac failure and portal hypertension (2 patients), and cardiac failure associated with biliary necrosis and portal hypertension (1 patient). Eighteen (81%) of 22 patients had pulmonary artery hypertension. Twelve (30%) patients had pretransplant hepatic interventions. Follow-up was complete for all patients with a mean of 69 months (range, 0–230 months). Results:One-, 5- and 10-year actuarial patient and graft survival rates are 82.5%. Six of the 7 pretransplant procedures performed on the hepatic artery were severely complicated. Cardiovascular function documented in 24 patients improved in 18 patients and remained stable in 5 patients; 1 patient died perioperatively of acute heart failure. Twenty-four (60%) patients had post-transplant complications, all but one occurring within the first 4 posttransplant months. Seven (17.5%) patients died perioperatively, 6 of them due to bleeding and 1 due to cardiac failure; 1 (2.5%) patient died late due to chronic rejection. There were 2 possible recurrences. Quality of life markedly improved in all 32 surviving patients. Conclusion:The results of the largest reported transplant series in the treatment of hepatic-based HHT are excellent. Elimination of hepatobiliary sepsis and reversal of cardiopulmonary changes dramatically improve quality of life of the recipients. LT should be proposed earlier in the course of symptomatic hepatic HHT presenting with life-threatening conditions. Palliative interventions, especially on the hepatic artery, should be avoided in view of their high (infectious) complication rate.

The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry.

Background:Hepatic epitheloid hemangioendothelioma (HEHE) is a rare low-grade vascular tumor. Its treatment algorithm is still unclear mainly due to a lack of larger clinical experiences with detailed long-term follow-up. Material and Methods:Fifty-nine patients, reported to the European Liver Transplant Registry, were analyzed to define the role of liver transplantation (LT) in the treatment of this disease. Eleven (19%) patients were asymptomatic. Eighteen (30.5%) patients had pre-LT surgical [hepatic (7 patients) and extrahepatic (3 patients)] and/or systemic or locoregional (10 patients) medical therapy. Ten (16.9%) patients had extrahepatic disease localization before or at the time of LT. Follow-up was complete for all patients with a median of 92.5 (range, 7–369) from moment of diagnosis and a median of 78.5 (range, 1–245) from the moment of LT. Results:HEHE was bilobar in 96% of patients; 86% of patients had more than 15 nodules in the liver specimen. Early (<3 months) and late (>3 months) post-LT mortality was 1.7% (1 patient) and 22% (14 patients). Fourteen (23.7%) patients developed disease recurrence after a median time of 49 months (range, 6–98). Nine (15.3%) patients died of recurrent disease and 5 are surviving with recurrent disease. One-, 5-, and 10- year patient survival rates from moment of transplantation for the whole series are 93%, 83%, 72%. Pre-LT tumor treatment (n = 18) (89%, 89%, and 68% 1-, 5-, and 10-year survival rates from moment of LT vs. 95%, 80%, and 73% in case of absence of pre-LT treatment), lymph node (LN) invasion (n = 18) (96%, 81%, and 71% 1-, 5-, and 10-year survival rates vs. 83%, 78%, and 67% in node negative patients) and extrahepatic disease localization (n = 10) (90%, 80%, and 80% 1-, 5-, and 10-year survival rates vs. 94%, 83%, and 70% in case of absence of extrahepatic disease) did not significantly influence patient survival whereas microvascular (n = 24) (96%, 75%, 52% 1-, 5-, and 10-year survival vs. 96%, 92%, 85% in case of absence of microvascular invasion) and combined micro- and macrovascular invasion (n = 28) (90%, 72%, and 54% 1-,5-, and 10-year survival vs. 96%, 92%, and 85% in case of absence of vascular invasion, P = 0.03) did. Disease-free survival rates at 1, 5, and 10 years post-LT are 90%, 82%, and 64%. Disease-free survival is not significantly influenced by pre-LT treatment, LN status, extrahepatic disease localization, and vascular invasion. Conclusions:The results of the largest reported transplant series in the treatment of HEHE are excellent. Preexisting extrahepatic disease localization as well as LN involvement are not contraindications to LT. Microvascular or combined macro-microvascular invasion significantly influence survival after LT. LT therefore should be offered as a valid therapy earlier in the disease course of these, frequently young, patients. Recurrent (allograft) disease should be treated aggressively as good long-term survivals can be obtained. Long-term prospective follow-up multicenter studies as well as the evaluation of antiangiogenic drugs are necessary to further optimize the treatment of this rare vascular hepatic disorder.

Liver transplantation for acute liver failure in Europe: Outcomes over 20 years from the ELTR database

BACKGROUND & AIMS Liver transplantation for acute liver failure (ALF) still has a high early mortality. We evaluated changes during 20 years, and identified risk factors for poor outcome. METHODS Donor, graft, and recipient variables from the European Liver Transplant Registry database (January 1988-June 2009), were analysed. Aetiologies and time periods were compared. Three and 12-month survival models were generated from separate training data sets, which were validated. A sub-analysis was performed for recipient older than 50 years. RESULTS Four thousand nine hundred and three patients were evaluated. One, 5- and 10-year patient, and graft survival rates were 74%, 68%, 63%, and 63%, 57%, 50%, respectively. Survival was better in 2004-2009 compared to previous quinquennia (p<0.001), despite donors >60 years increased from 1.8% to 21%. A higher incidence of suicide or non-adherence occurred in paracetamol-related ALF (p<0.001). Death or graft loss were independently associated with male recipients (adjusted OR 1.25), recipient >50 years (1.26), incompatible ABO matching (1.93), donors >60 years (1.21), and reduced size graft (1.54). For both 3- and 12-month models, incompatible ABO matching, non-viral aetiology, reduced size graft, and non-UW preservation fluid were associated with increased mortality/graft loss, whereas male recipients and age >50 years were associated only at 12 months. Both models had reasonable discriminative ability with good calibration at 3 months. Recipients >50 years, combined with donors >60 years resulted in 57% mortality/graft loss within the first year. CONCLUSIONS Survival after liver transplantation has improved despite increases in donor/recipient age. Recipients >50 years paired with donors >60 years had a very high mortality/graft loss within the first year.

Herpes simplex virus-associated acute liver failure : A difficult diagnosis with a poor prognosis

We report 5 cases of acute liver failure related to herpes simplex (HSV) infection in 1 immunocompetent and 4 immunosuppressed patients. One patient was too ill for liver transplantation indication. Three patients, among the 4 listed, underwent liver transplantation. Three patients died 11 days to 1 year after transplantation and 2 patients died 2 to 3 days after admission. All presented with fever and none with skin lesions. The diagnosis of HSV‐related hepatitis was made antemortem in only 2 patients on the basis of positive blood cultures and/or immunohistochemic findings. In the remaining patients, HSV diagnosis was made retrospectively on further histologic and virologic investigations. Primary HSV infection was certain or likely in all cases, including an HSV2 superinfection of an anti‐HSV1‐positive patient and two HSV superinfections of hepatitis B virus (HBV)‐related chronic liver disease. In these latter patients, HSV diagnosis was totally unsuspected, despite fever. HSV superinfection has significantly contributed to liver dysfunction aggravation and death. In conclusion, the diagnosis of HSV hepatitis is difficult to establish in the absence of specific clinical signs. This may suggest the need for early administration of acyclovir in patients with suspected HSV hepatitis, without waiting for virologic confirmation. Diagnosis methods providing fast results (real‐time polymerase chain reaction [PCR]) should be implemented. (Liver Transpl 2005;11:1550–1555.)