S. Pollard

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.

Liver transplantation following donation after cardiac death: An analysis using matched pairs

Grafts from donation after cardiac death (DCD) donors are used to increase the number of organs available for liver transplantation. There is concern that warm ischemia may impair graft function. We compared our DCD recipients with a case‐matched group of donation after brain death (DBD) recipients. Between January 2002 and April 2008, 39 DCD grafts were transplanted. These were matched with 39 DBD recipients on the basis of identified variables that had a significant impact on mortality. These were used to individually match DCD and DBD patients with similar predictive mortality. We compared patient/graft survival, primary non‐function (PNF), and rates of complications. Of all liver transplants, 6.1% were DCD grafts. PNF occurred twice in the DCD group. The incidence of nonanastomotic biliary strictures (NABS; 20.5% versus 0%, P = 0.005) and hepatic artery stenosis (HAS; 12.8% versus 0%, P = 0.027) in the DCD group was higher. One‐year (79.5% versus 97.4%, P = 0.029) and 3‐year (63.6% versus 97.4%, P = 0.001) graft survival was lower in the DCD group. Three‐year patient survival was also lower (68.2% versus 100%, P < 0.0001). Our study is the first to use case‐matched patients and compare groups with similar predictive mortality. There was a higher incidence of NABS and HAS in the DCD group. NABS were likely a result of warm ischemia. HAS may have been due to ischemia or arterial injury during retrieval. The DCD group had significantly poorer outcomes, but DCD grafts remain a valuable resource. With careful donor/recipient selection, minimization of ischemia, and good postoperative care, acceptable results can be achieved. Liver Transpl 15:1072–1082, 2009.

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.

12‐month follow‐up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

The LIS2T study was an open‐label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA‐ME) (Neoral) (n = 250) (monitoring of blood concentration at 2 hours postdose) C2 or tacrolimus (n = 245) (monitoring of trough drug blood level [predose]) C0 to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA‐ME patients and 86% of tacrolimus patients survived with a functioning graft (P not significant). Efficacy was similar in deceased‐ and living‐donor recipients. Significantly fewer hepatitis C–positive patients died or lost their graft by 12 months with CsA‐ME (5/88, 6%) than with tacrolimus (14/85, 16%) (P < 0.03). Recurrence of hepatitis C virus in liver grafts was similar in each group. Based on biopsies driven by clinical events, the mean time to histological diagnosis of hepatitis C virus recurrence was significantly longer with CsA‐ME (100 ± 50 days) than with tacrolimus (70 ± 40 days) (P < 0.05). Median serum creatinine at 12 months was 106 μmol/L with CsA‐ME and with tacrolimus. More patients who were nondiabetic at baseline received antihyperglycemic therapy in the tacrolimus group at 12 months (13% vs. 5%, P < 0.01). Of patients who were diabetic at baseline, more tacrolimus‐treated individuals required anti‐diabetic treatment at 12 months (70% vs. 49%, P = 0.02). Treatment for de novo or preexisting hypertension or hyperlipidemia was similar in both groups. In conclusion, the efficacy of CsA‐ME monitored by blood concentration at 2 hours postdose and tacrolimus in liver transplant patients is equivalent to 12 months, and renal function is similar. More patients required antidiabetic therapy with tacrolimus regardless of diabetic status at baseline. Liver Transpl 12:1464–1472, 2006.

Surgical Strategy for Cystic Diseases of the Liver in a Western Hepatobiliary Center

The aim of this study was to define the indications and evaluate the results of various management options in patients with cystic liver disease. Between 1992 and 1999 we managed 60 consecutive patients with cystic liver disease. Diagnoses included a simple cyst (solitary 12, multiple 10), adult polycystic liver disease (APLD 17), Caroli’s disease (8), hydatid cysts (4), and neoplastic cysts (9). Half of the patients with simple cysts had mild or no symptoms and required no treatment. Percutaneous drainage in eight patients (simple cyst 4, APLD 4) was followed by symptomatic recurrence in three. Laparoscopic deroofing in three patients (multiple simple cysts 2, APLD 1) was followed by symptomatic enlargement of the remaining cysts that required further intervention (laparoscopic deroofing 2, transplantation 1). Laparoscopic hepatectomy was successful in three patients with solitary simple cysts. Of 18 patients who underwent open hepatic resection (neoplastic 8, Caroli’s 4, simple cysts 3, hydatid cysts 2, APLD 1), 2 patients with Caroli’s disease required liver transplantation for disease progression. Nine patients (Caroli’s 5, APLD 4) underwent liver transplantation, and three had a concomitant renal transplant. Seven patients developed complications, and three died (5%). Cholangiocarcinoma developed in three patients with bilateral Caroli’s disease, and all died. Radiologic treatment has a limited role in the management of patients with simple cysts or APLD. Laparoscopic deroofing of simple cysts may have to be repeated, whereas resection minimizes cyst recurrence. Unilobar Caroli’s disease may be resected, whereas bilateral disease requires early liver transplantation owing to the high risk of malignancy. Transplantation is a reserved option in patients with extensive APLD.

A Pharmacokinetic and Clinical Review of the Potential Clinical Impact of Using Different Formulations of Cyclosporin A

Abstract A meeting of 14 transplant and pharmacokinetic specialists from Europe and North America was convened in November 2001 to evaluate scientific and clinical data regarding the use of different formulations of cyclosporin A (CsA). The following consensus was achieved. (1) CsA is a critical-dose drug with a narrow therapeutic window. Clinical outcomes after transplantation are affected by the pharmacokinetic properties of CsA, particularly by its bioavailability, and by intrapatient variability in CsA exposure. (2) Standard bioequivalence criteria do not address differences in CsA pharmacokinetics between transplant recipients and healthy volunteers, or between subpopulations of transplant recipients. (3) In some circumstances, currently available formulations of CsA that meet standard bioequivalence criteria are likely to be nonequivalent with respect to pharmacokinetic characteristics. (4) The choice of CsA formulation can affect the short- and long-term clinical outcome. Currently, there is a lack of clinical comparisons between generic CsA formulations and the Neoral® formulation (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). Initial retrospective data from the Collaborative Transplant Study suggest that use of generic CsA formulations may result in reduced graft survival at 1 year. (5) Management of transplant recipients by monitoring Neoral concentrations 2 hours after dosing (C 2 ) reduces the incidence and severity of acute rejection compared with monitoring of trough concentrations with no increase in toxicity. C 2 monitoring has been developed based on the pharmacokinetics of Neoral only and has not been evaluated or validated for generic formulations of CsA. (6) The major costs of care after transplantation relate to the management of poor clinical outcomes and toxicity. CsA formulations with different pharmacokinetic properties may be associated with varying clinical outcomes, which would be expected to affect total health care costs. (7) The transplant physician is responsible for selecting immunosuppressive agents and formulations for his or her patients. Any switch between CsA formulations in a particular patient should take place only in a controlled setting with adequate pharmacokinetic monitoring.

Donor risk index and MELD interactions in predicting long-term graft survival: a single-centre experience.

Introduction. Feng et al. described the donor risk index (DRI) in North American liver transplant recipients. We evaluated the effect of the DRI and model for end-stage liver disease (MELD) score on liver transplant recipients from a single center in the United Kingdom. Method. Prospectively, collected data of all patients transplanted at our center between January 1995 and December 2005 were included in the analysis (n=1090). Outcomes evaluated included patient-censored and death-censored graft survival. Outcomes of liver transplantation from “high” and “low” DRI groups (≥1.8 and <1.8, respectively) on patients categorized into low (<15), intermediate (15-30), and high (>30) MELD categories were analyzed. Results. MELD at transplant was the only significant predictor of patient survival. MELD at transplant and DRI more than 1.7 were associated with a poorer graft survival (P=0.03). There was a trend toward poorer graft survival in high DRI grafts transplanted in low and “intermediate” MELD categories (P=0.47 and 0.006, respectively). However, in the high MELD category, there was a similar graft survival for both high and low DRI grafts. Conclusion. Patients with low and intermediate MELDs at transplantation may be better served by a low DRI graft, whereas patients with high MELD may not be compromised by receiving a high DRI graft.

Primary liver transplantation for autoimmune hepatitis: A comparative analysis of the European Liver Transplant Registry

The principal aim of this study was to compare the probability of and potential risk factors for death and graft loss after primary adult and pediatric liver transplantation in patients undergoing transplantation for autoimmune hepatitis (AIH) to those in patients undergoing transplantation for primary biliary cirrhosis (PBC; used as the reference group) or alcoholic cirrhosis (used as an example of a nonautoimmune liver disease). The 5‐year survival of patients undergoing transplantation for AIH (n = 827) was 0.73 [95% confidence interval (CI) = 0.67‐0.77]. This was similar to that of patients undergoing transplantation for alcoholic cirrhosis (0.74, 95% CI = 0.72‐0.76, n = 6424) but significantly worse than that of patients undergoing transplantation for PBC (0.83, 95% CI = 0.80‐0.85, n = 1588). Fatal infectious complications occurred at an increased rate in patients with AIH (hazard ratio = 1.8, P = 0.002 with PBC as the reference). The outcome of pediatric AIH patients was similar to that of adult patients undergoing transplantation up to the age of 50 years. However, the survival of AIH patients undergoing transplantation beyond the age of 50 years (0.61 at 5 years, 95% CI = 0.51‐0.70) was significantly reduced in comparison with the survival of young adult AIH patients (0.78 at 18‐34 years, 95% CI = 0.70‐0.86) and in comparison with the survival of patients of the same age group with PBC or alcoholic cirrhosis. In conclusion, age significantly affects patient survival after liver transplantation for AIH. The increased risk of dying of infectious complications in the early postoperative period, especially above the age of 50 years, should be acknowledged in the management of AIH patients with advanced‐stage liver disease who are listed for liver transplantation. It should be noted that not all risk factors relevant to patient and graft survival could be analyzed with the European Liver Transplant Registry database. Liver Transpl , 2010.

Emergency Subtotal Hepatectomy: A New Concept for Acetaminophen-Induced Acute Liver Failure : Temporary Hepatic Support by Auxiliary Orthotopic Liver Transplantation Enables Long-term Success

Introduction:Acetaminophen (paracetamol) overdose (AOD) has recently emerged as the leading cause of acute liver failure (ALF) in the United States, with an incidence approaching that seen in the United Kingdom. We describe a new way to treat AOD ALF patients fulfilling Kings College criteria for “super-urgent” liver transplantation. Methods:Beginning in June 1998, we have been piloting a clinical program of subtotal hepatectomy and auxiliary orthotopic liver transplantation (ALT) for AOD ALF. Our technique is based on the following principles: (1) subtotal hepatectomy; (2) auxiliary transplantation of a whole liver graft; (3) gradual withdrawal of immunosuppression after recovery. Results were compared with patients who had undergone an orthotopic liver transplantation (OLT) for AOD ALF in the same period. Quality of life comparisons were made using the SF36 questionnaire. Results:Thirteen patients underwent this procedure between June 1998 and March 2005. Median survival is 68 months (range, 0–102 m). Actual survival data show that 9 of 13 patients are alive (69%) compared with 7 of 13 OLT patients (54%). One ALT patient required a retransplantation with an OLT due to hepatic vein thrombosis, and immunosuppression is therefore maintained. The other 8 surviving ALT patients are off immunosuppression. These 8 ALT patients have normal liver function and have a better quality of life compared with the 7 surviving OLT patients. Conclusion:Our results with this new technique are encouraging: 69% actual survival, no long-term immunosuppression requirement, and improved quality of life in the 62% successful cases.