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There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US. From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates. The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p = 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant. Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC. The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation. [Display omitted] • Tacrolimus was associated with superior survival compared to cyclosporine after liver transplantation for PSC. • 10-year patient survival estimates were 73% for tacrolimus and 65% for cyclosporine. • 10-year graft survival estimates were 62% for tacrolimus and 54% for cyclosporine. • Findings were consistent across subgroups by age, sex, registry, time period of LT, MELD score, and diabetes status. • Tacrolimus emerges as the preferred calcineurin inhibitor after liver transplantation for PSC. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation is a standard of care and a life-saving procedure for end-stage liver diseases and certain malignancies. The evidence on predictors and risk factors for poor outcomes is lacking. Therefore, we aimed to identify potential risk factors for mortality and to report on overall 90-day mortality after orthotopic liver transplantation (OLT), especially focusing on the role of fungal infections. Methods: We retrospectively reviewed medical charts of all patients undergoing OLT at a tertiary university center in Europe. Results: From 299 patients, 214 adult patients who received a first-time OLT were included. The OLT indication was mainly due to tumors (42%, 89/214) and cirrhosis (32%, 68/214), including acute liver failure in 4.7% (10/214) of patients. In total, 8% (17/214) of patients died within the first three months, with a median time to death of 15 (1–80) days. Despite a targeted antimycotic prophylaxis using echinocandins, invasive fungal infections occurred in 12% (26/214) of the patients. In the multivariate analysis, patients with invasive fungal infections had an almost five times higher chance of death (HR 4.6, 95% CI 1.1–18.8; p = 0.032). Conclusions: Short-term mortality after OLT is mainly determined by infectious and procedural complications. Fungal breakthrough infections are becoming a growing concern. Procedural, host, and fungal factors can contribute to a failure of prophylaxis. Finally, invasive fungal infections may be a potentially modifiable risk factor, but the ideal perioperative antimycotic prophylaxis has yet to be determined. [ABSTRACT FROM AUTHOR]

In Europe alone, each year 5500 people require a life‐saving liver transplantation, but 18% die before receiving one due to the shortage of donor organs. Whole organ engineering, utilizing decellularized liver scaffolds repopulated with autologous cells, is an attractive alternative to increase the pool of available organs for transplantation. The development of this technology is hampered by a lack of a suitable large‐animal model representative of the human physiology and a reliable and continuous cell source. We have generated porcine intrahepatic cholangiocyte organoids from adult stem cells and demonstrate that these cultures remained stable over multiple passages whilst retaining the ability to differentiate into hepatocyte‐ and cholangiocyte‐like cells. Recellularization onto porcine scaffolds was efficient and the organoids homogeneously differentiated, even showing polarization. Our porcine intrahepatic cholangiocyte system, combined with porcine liver scaffold paves the way for developing whole liver engineering in a relevant large‐animal model. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the outcome of marginal liver grafts based on the Eurotransplant extended criteria donor (ECD) criteria., Background: Eurotransplant uses a broad definition of ECD criteria (age >65 years, steatosis >40%, body mass index >30 kg/m 2 , intensive care unit stay >7 days, donation after circulatory death, and certain laboratory parameters) for allocating organs to recipients who have consented to marginal grafts. Historically, marginal liver grafts were associated with increased rates of dysfunction., Methods: Retrospective cohort analysis using the German Transplant Registry and the U.S. Scientific Registry of Transplant Recipients (SRTR) from 2006 to 2016. Results were validated with recent SRTR data (2017-2022). Donors were classified according to the Eurotransplant ECD criteria, donation after circulatory death was excluded. Data were analyzed with cutoff prediction, binomial logistic regression, and multivariate Cox regression., Results: The study analyzed 92,330 deceased brain-dead donors (87% SRTR) and 70,374 transplants (87% SRTR) in adult recipients. Predominant ECD factors were donor age in Germany (30%) and body mass index in the United States (28%). Except for donor age, grafts meeting ECD criteria were not associated with impaired 1 or 3-year survival. Cutoffs had little to no predictive value for 30-day graft survival (area under the receiver operating curve: 0.49-0.52) and were nominally higher for age (72 vs 65 years) in Germany as compared with those defined by current Eurotransplant criteria., Conclusions: The outcome of transplanted grafts from higher risk donors was nearly equal to standard donors with Eurotransplant criteria failing to predict survival of marginal grafts. Modifying ECD criteria could improve graft allocation and potentially expand the donor pool., Competing Interests: S.M. and N.R. are participants in the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin, and the Berlin Institute of Health at Charité (BIH). The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Résumé: L'introduction du traitement par acide ursodésoxycholique a considérablement modifié l'histoire naturelle de la cholangite biliaire primitive. Les patients traités à un stade précoce et ayant une réponse biochimique ont une espérance de vie normale. La cholangite biliaire primitive a acquis au fil des années au sein de la communauté hépato-gastro-entérologique une « réputation » de maladie plutôt indolente alors que 40 % des patients sont non-répondeurs au traitement et que le taux de transplantation hépatique dans cette indication n'infléchit plus depuis 10 ans. Plusieurs scores permettent de mesurer le risque de mortalité chez les patients traités par acide ursodésoxycholique (score Globe, Score UK-PBC). Près de 12 % de la mortalité est prématurée et 80 % des décès surviennent avant d'atteindre l'espérance de vie à la naissance. La transplantation hépatique pour cholangite biliaire primitive apparaît stable dans le temps avec en moyenne entre 30 et 40 patients transplantés par an en France et 200 en Europe. Les indications de greffe sont hétérogènes : ictère en plateau, prurit réfractaire, complications de la cirrhose et carcinome hépatocellulaire. The introduction of ursodeoxycholic acid therapy have improved the natural history of primary biliary cholangitis. Patients treated at an early stage and having a biochemical response have a normal life expectancy. Primary biliary cholangitis has acquired over the years within the hepato-gastroenterological community a "reputation" as a rather indolent disease, whereas 40% of patients are non-responsive to treatment and the rate of liver transplantation in this indication does not change for 10 years. Several scores are used to measure the risk of mortality in patients treated with ursodeoxycholic acid (Globe score, UK-PBC score). Nearly 12% of mortality is premature and 80% of deaths occur before reaching life expectancy at birth. Liver transplantation for primary biliary cholangitis appears to be stable over time with an average of between 30 and 40 patients transplanted per year in France and 200 in Europe. The indications for transplantation are heterogeneous: jaundice, refractory pruritus, complications of cirrhosis and hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Objective. To analyze the diagnosis and treatment of patients with concomitant malignant tumors after organ transplantation by compiling data from organ transplantation patients. Methods. By searching CNKI and PubMed databases, we made a systematic analysis of the studies of postorgan transplantation complicating malignant tumors in the last decade. Results. There were 10 articles on malignant tumors after renal transplantation, 8 articles on liver transplantation, 2 articles on heart transplantation, and 1 article on lung transplantation. The incidence of malignant tumors complicating renal transplantation is 10.4% in Europe, with skin cancer and Kaposi's sarcoma being common; the incidence in the United States is 3.4%, with PTLD having the highest incidence; the incidence of malignant tumors is relatively lowest in Asia, with gastrointestinal malignancies being the main ones. The mean time to complication of malignancy after renal transplantation is 3.83 years. The incidence of concurrent malignancies after liver transplantation is 8.8% in Europe, where skin cancer and Kaposi's sarcoma are common; 5.6% in Asia, where gastrointestinal tract tumors are prevalent; and 4.5% in the United States, where gastrointestinal tract tumors, PTLD, and hematologic diseases are predominant. The mean time to complication of malignancy after liver transplantation is 4.79 years. The incidence of malignancy after heart transplantation is 6.8-10.7%. The incidence of malignancy after lung transplantation is about 10.1%. Minimization of immunosuppression or modification of immunosuppression regimens may be a key component of cancer prevention. mTOR inhibitors and phenolate (MMF) reduce the incidence of de novo malignancies in patients after solid organ transplantation. Surgical treatment improves survival in patients with early malignancies. The use of external beam radiation therapy in the treatment of hepatocellular carcinoma is limited due to the risk of radiation liver disease. Conclusions. The risk of concomitant malignancy needs to be guarded for 5 years of immunosuppressive therapy after organ transplantation surgery. Adjusting the immunosuppressive treatment regimen is an effective way to reduce concurrent malignancies. Systemic chemotherapy or radiotherapy requires vigilance against the toxic effects of drug metabolism kinetics on the transplanted organ. [ABSTRACT FROM AUTHOR]

Background: The global organ shortage is the biggest obstacle to expand urgently needed liver transplantation activities. In addition to donation after brain death (DBD), donation after primary circulatory death (DCD) has also been introduced in many European countries to increase the number of donated organs., Objective: This article summarizes the legal and ethical aspects of DCD, the practical donation process of DCD, the clinical results of DCD liver transplantation with a special focus on organ assessment before a planned DCD liver transplantation., Results: In Europe 11 countries have active DCD liver transplantation programs and a total of 1230 DCD liver transplantations were performed in Europe in 2023. The highest proportion of DCD liver transplantations were recorded in Belgium (52.8%), the Netherlands (42.8%) and Switzerland (32.1%). The adequate selection of donors and recipients is crucial in DCD transplantation and the use of DCD livers particularly depends on the preparedness of the healthcare system for routine machine perfusion. The leaders are Belgium, France and Italy which implant around 68-74% of DCD organs. With an adequate organ assessment, the long-term results of DBD and DCD liver transplantations are comparable. To assess mitochondrial damage and thus organ quality, hypothermic oxygenated machine perfusion (HOPE) was introduced and has the secondary benefit of mitochondrial protection through oxygenation. The establishment of aerobic metabolism in mitochondria under hypothermia leads to a reduction of toxic metabolites and the restoration of ATP storage, which subsequently leads to a reperfusion light during implantation., Conclusion: Expanding the donor pool with DCD donors can counteract the global organ shortage. With adequate patient selection and routine organ assessment short-term and also long-term outcomes of DBD and DCD liver transplantation are comparable., (© 2024. The Author(s).)

Summary: Criteria that drive the selection and utilization of living liver donors are limited. Herein, the global availability of living donor liver transplantation (LDLT) and components of donor selection and utilization were assessed via an international survey. There were 124 respondents representing 41 countries, including 47 from Asia/Middle East (A/ME), 20 from Europe, and 57 from the Americas. Responses were obtained from 94.9% of countries with ≥10 LDLT cases/year. Most centers (82.3%) have defined donor age criteria (median 18–60 years), while preset recipient MELD cutoffs (median 18–30) were only reported in 54.8% of programs. Overall, 67.5% of programs have preset donor BMI (body mass index) ranges (median 18–30), and the mean acceptable macrosteatosis was highest for A/ME (20.2 ± 9.2%) and lowest for Americas (16.5 ± 8.4%, P = 0.04). Americas (56.1%) and European (60.0%) programs were more likely to consider anonymous donors versus A/ME programs (27.7%, P = 0.01). There were no differences in consideration of complex anatomical variations. Most programs (75.9%) perform donor surgery via an open approach, and A/ME programs are more likely to use microscopic arterial reconstruction. Despite variations in practice, key aspects of living donor selection were identified. These findings provide a contemporary reference point as LDLT continues to expand into areas with limited access to liver transplantation. [ABSTRACT FROM AUTHOR]

Liver transplant priority in the US and Europe follows the 'sickest-first' principle. However, for patients with hepatocellular carcinoma (HCC), priority is based on binary tumor criteria to expedite transplant for patients with 'acceptable' post-transplant outcomes. Newer risk scores developed to overcome limitations of these binary criteria are insufficient to be used for waitlist priority as they focus solely on HCC-related pre-transplant variables. We sought to develop a risk score to predict post-transplant survival for patients using HCC- and non-HCC-related variables. We performed a retrospective cohort study using national registry data on adult deceased-donor liver transplant (DDLT) recipients with HCC from 2/27/02-12/31/18. We fit Cox regression models focused on 5- and 10-year survival to estimate beta coefficients for a risk score using manual variable selection. We then calculated absolute predicted survival time and compared it to available risk scores. Among 6,502 adult DDLT recipients with HCC, 11 variables were selected in the final model. The AUCs at 5- and 10-years were: 0.62, 95% CI 0.57–0.67 and 0.65, 95% CI 0.58–0.72, which was not statistically significantly different to the Metroticket and HALT-HCC scores. The LiTES-HCC score was able to discriminate patients based on post-transplant survival among those meeting Milan and UCSF criteria. We developed and validated a risk score to predict post-transplant survival for patients with HCC. By including HCC- and non-HCC-related variables (e.g., age, chronic kidney disease), this score could allow transplant professionals to prioritize patients with HCC in terms of predicted survival. In the future, this score could be integrated into survival benefit-based models to lead to meaningful improvements in life-years at the population level. We created a risk score to predict how long patients with liver cancer will live if they get a liver transplant. In the future, this could be used to decide which waitlisted patients should get the next transplant. [Display omitted] • Patients with HCC frequently die of non-HCC-related causes after liver transplant. • Inclusion of non-HCC variables improves the discrimination of a HCC risk score. • Allocation based on predicted survival could improve population-level outcomes. [ABSTRACT FROM AUTHOR]

For patients with early-stage hepatocellular carcinoma (HCC), liver transplantation offers the best chance of cure. Over the past two decades, selection criteria to determine eligibility for liver transplantation have been constantly refined but a fair allocation strategy of liver grafts to HCC patients remains challenging. In Europe, over a dozen transplantation networks apply different liver transplantation criteria for HCC patients. In this review, we explore and compare candidate selection and liver graft allocation strategies for patients with HCC with a European perspective and discuss the ethical and technical challenges involved. In addition, we suggest possible paths for future improvement such as transitioning from fixed selection and allocation criteria to a more flexible model of benefit, which includes criteria concerning the graft, response to treatment, the biology of the tumor, and other relevant recipient factors. [ABSTRACT FROM AUTHOR]

Early allograft dysfunction (EAD) following liver transplantation (LT) negatively impacts graft and patient outcomes. Previously we reported that the liver graft assessment following transplantation (L-GrAFT 7) risk score was superior to binary EAD or the model for early allograft function (MEAF) score for estimating 3-month graft failure-free survival in a single-center derivation cohort. Herein, we sought to externally validate L-GrAFT 7 , and compare its prognostic performance to EAD and MEAF. Accuracies of L-GrAFT 7 , EAD, and MEAF were compared in a 3-center US validation cohort (n = 3,201), and a Consortium for Organ Preservation in Europe (COPE) normothermic machine perfusion (NMP) trial cohort (n = 222); characteristics were compared to assess generalizability. Compared to the derivation cohort, patients in the validation and NMP trial cohort had lower recipient median MELD scores; were less likely to require pretransplant hospitalization, renal replacement therapy or mechanical ventilation; and had superior 1-year overall (90% and 95% vs. 84%) and graft failure-free (88% and 93% vs. 81%) survival, with a lower incidence of 3-month graft failure (7.4% and 4.0% vs. 11.1%; p < 0.001 for all comparisons). Despite significant differences in cohort characteristics, L-GrAFT 7 maintained an excellent validation AUROC of 0.78, significantly superior to binary EAD (AUROC 0.68, p = 0.001) and MEAF scores (AUROC 0.72, p < 0.001). In post hoc analysis of the COPE NMP trial, the highest tertile of L-GrAFT 7 was significantly associated with time to liver allograft (hazard ratio [HR] 2.17, p = 0.016), Clavien ≥IIIB (HR 2.60, p = 0.034) and ≥IVa (HR 4.99, p = 0.011) complications; post-LT length of hospitalization (p = 0.002); and renal replacement therapy (odds ratio 3.62, p = 0.016). We have validated the L-GrAFT 7 risk score as a generalizable, highly accurate, individualized risk assessment of 3-month liver allograft failure that is superior to existing scores. L-GrAFT 7 may standardize grading of early hepatic allograft function and serve as a clinical endpoint in translational studies (www.lgraft.com). Early allograft dysfunction negatively affects outcomes following liver transplantation. In independent multicenter US and European cohorts totaling 3,423 patients undergoing liver transplantation, the liver graft assessment following transplantation (L-GrAFT) risk score is validated as a superior measure of early allograft function that accurately discriminates 3-month graft failure-free survival and post-liver transplantation complications. [Display omitted] • Early allograft dysfunction negatively impacts graft and patient outcomes. • L-GrAFT assesses early allograft function based on post-transplant liver function tests. • L-GrAFT was validated as an accurate measure of graft survival, outperforming early allograft dysfunction. • L-GrAFT may be used as an accurate translational end-point in clinical trials. [ABSTRACT FROM AUTHOR]

Background: The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe.Methods: We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons.Results: A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group.Conclusions: In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.). [ABSTRACT FROM AUTHOR]

Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p < 0.001). Spontaneous bacterial peritonitis, pneumonia or infections caused by extensively drug resistant (XDR) bacteria were more frequently associated with ACLF development. More patients with ACLF had a positive quick sequential organ failure assessment score and septic shock, resulting in a lower infection resolution rate (all p < 0.001). Bacterial infections, especially with XDR organisms, are associated with the highest risk of ACLF development, accounting for almost half of cases globally. Geographic differences result in variable epidemiology and clinical outcomes. Bacterial infections can trigger a sudden deterioration in an otherwise stable cirrhotic patient, a condition known as acute-on-chronic liver failure or ACLF. This study has found that the development of ACLF following bacterial infection occurs most commonly in the Indian subcontinent and less so in Southern Europe. The common infections that can trigger ACLF include infection of the abdominal fluid, known as spontaneous bacterial peritonitis, pneumonia and by bacteria that are resistant to multiple antibiotics. Patients who develop ACLF following a bacterial infection have high death rates and are frequently unable to clear the infection. • Among patients with cirrhosis and bacterial infections, 48% have bacterial infection related-ACLF. • ACLF following bacterial infection occurs most commonly in the Indian subcontinent and less so in Southern Europe. • ACLF occurs more frequently following spontaneous bacterial peritonitis, pneumonia, and nosocomial infections. • Patients with ACLF have lower infection resolution rate and higher mortality rate. [ABSTRACT FROM AUTHOR]

Objective: To better understand drivers of disease progression in non-alcoholic steatohepatitis (NASH), we assessed clinical and sociodemographic markers of fibrosis progression in adults with NASH., Patients and Methods: Physician-reported patient demographics and clinical characteristics were utilised from the real-world Global Assessment of the Impact of NASH (GAIN) study. Factors associated with likelihood of fibrosis progression since NASH diagnosis were identified using a logistic regression model., Results: Overall, 2349 patients in Europe from the GAIN study were included; mean age was 54.6 years and 41% were women. Significant covariates included age, years since diagnosis, employment status, fibrosis stage at diagnosis, type 2 diabetes mellitus, hypertension, liver transplant and liver biopsy at diagnosis. Risk of progression was 1.16 (95% confidence interval 1.12-1.20; p<0.001) times higher for each additional year since NASH diagnosis and 5.43 (2.68-11.37; p<0.001) times higher when physicians proposed a liver transplant at diagnosis. Compared with full-time employed patients, risk of progression was 1.77 (1.19-2.60; p=0.004) times higher for unemployed patients and 3.16 (1.30-7.63; p=0.010) times higher for those unable to work due to NASH., Conclusions: Disease duration, NASH severity and presence of other metabolic comorbidities could help to assess risk of progression in patients with NASH., (Copyright © 2023 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Recent series have demonstrated advantages of living donor over deceased donor liver transplantation, with particular benefit for those with low model for end-stage liver disease score. The logic underlying the transplantation of patients before they become too sick is intuitive. It reduces mortality and drop outs from the waiting list and makes transplant surgery less demanding. Those principles have to be balanced with donor safety and transplant benefit for the recipient avoiding early, futile transplantation. The authors report a case of adult to adult right lobe living donor liver transplantation performed for a recipient affected by primary biliary cirrhosis with MELD score of 15, in a transplant center located in an area of Europe characterized by chronic organ shortage. [ABSTRACT FROM AUTHOR]

Summary: Since its foundation in 1985, the European Liver Transplant Registry has evolved to become an important tool to monitor the liver transplantation activity in Europe. The vast amount of data collected on 169 473 liver transplantations performed in 153 238 recipients has also resulted in scientific publications. Without doubt, several of these have influenced the daily practice of liver transplantation. This paper gives an overview of the development, the functioning, and the scientific activity of the European Liver Transplant Registry during more than three decades. Indeed, it can be said that the registry helped to advance the practice of liver transplantation not only in Europe but also worldwide. [ABSTRACT FROM AUTHOR]

Summary: There are scarce data on the impact of COVID‐19 pandemic on liver transplantation (LT) in Europe. The aim of this study was to obtain a preliminary data on incidence, management, and outcome of COVID‐19 in liver transplant recipients and candidates in Europe. An Internet‐based survey was sent to the centers affiliated with European Liver Transplant Registry (ELTR). One hundred nine out of 149 (73%) of ELTR centers located in 28 European countries (93%) responded. Ninety‐four (86%) of the centers tested all donors, and 75 (69%) centers tested all LT recipients for SARS‐CoV‐2. Seventy‐three (67%) centers selected recipients for LT in the COVID‐19 pandemic, whereas 33% did not. Eighty‐eight centers reported COVID‐19 infection in 57 LT candidates and in 272 LT recipients. Overall crude incidence of COVID‐19 among LT candidates and recipients was estimated 1.05% (range 0.5–20%) and 0.34% (range 0.1–4.8%), respectively, and it was significantly higher among candidates (P < 0.001). Crude rate of death was 18% (10/57) among candidates and 15% (36/244) among recipients. This first large‐scale European snapshot study clearly shows that both LT candidates and recipients are at a high risk for COVID‐19. These results plead for an early and pro‐active screening of COVID‐19 symptoms in these populations. [ABSTRACT FROM AUTHOR]

Background & Aims: The impact of gender and donor/recipient gender mismatch on LT outcomes is controversial. The aim of this study was to compare outcomes of LT in Europe, using the ELTR database, between male and female recipients, including donor/recipient gender mismatch. Methods: Recipient, donor and transplant characteristics were compared between male and female patients. Patient survival was compared between groups, and the impact of donor/recipient gender matching as well as donor and recipient anthropometric characteristics were evaluated as potential risk factors for post‐LT death/graft loss. Results: A total of 46,334 LT patients were evaluated (70.5% men and 29.5% women). Ten‐year survival rate was significantly higher in female than in male recipients (66% vs 59%, P <.0001). At multivariate analysis, adjusted for indication to LT and type of graft, donor/recipient gender mismatch (HR 1.12, 95% CI 1.04‐1.2; P =.003), donor age > 60 years (HR 1.09, 95% CI 1.01‐1.18; P =.027) and recipient age (HR 1.02, 95% CI 1.1‐1.02; P <.0001) were significantly associated with post‐LT lower survival rate in men. Conversely in female recipients, donor BMI > 30 (HR 1.32, 95% CI 1.09‐1.6; P =.005), donor age > 60 years (HR 1.15, 95% CI 1.01‐1.32; P =.027) and recipient age (HR 1.02, 95% CI 1.01‐1.02; P <.0001) were significantly associated with lower post‐LT survival rate. Conclusions: Donor/recipient gender mismatch in male recipients and the use of obese donor in female recipients are associated with reduced survival after LT. Therefore, the incorporation of donor and recipient anthropometric quantities in the allocation process should be a matter of further studies, as their matching can significantly influence long‐term outcomes. [ABSTRACT FROM AUTHOR]

Aims: To investigate the relationship between HbA1c and glucose in people with co‐existing liver disease and diabetes awaiting transplant, and in those with diabetes but no liver disease. Methods: HbA1c and random plasma glucose data were collected for 125 people with diabetes without liver disease and for 29 people awaiting liver transplant with diabetes and cirrhosis. Cirrhosis was caused by non‐alcoholic fatty liver disease, hepatitis C, alcoholic liver disease, hereditary haemochromatosis, polycystic liver/kidneys, cryptogenic/non‐cirrhotic portal hypertension and α‐1‐antitrypsin‐related disease. Results: The median (interquartile range) age of the diabetes with cirrhosis group was 55 (49–63) years compared to 60 (50–71) years (P=0.13) in the group without cirrhosis. In the diabetes with cirrhosis group there were 21 men (72%) compared with 86 men (69%) in the group with diabetes and no cirrhosis (P=0.82). Of the group with diabetes and cirrhosis, 27 people (93%) were of white European ethnicity, two (7%) were South Asian and none was of Afro‐Caribbean/other ethnicity compared with 94 (75%), 16 (13%), 10 (8%)/5 (4%), respectively, in the group with diabetes and no cirrhosis (P=0.20). Median (interquartile range) HbA1c was 41 (32–56) mmol/mol [5.9 (5.1–7.3)%] vs 61 (52–70) mmol/mol [7.7 (6.9–8.6)%] (P<0.001), respectively, in the diabetes with cirrhosis group vs the diabetes without cirrhosis group. The glucose concentrations were 8.4 (7.0–11.2) mmol/l vs 7.3 (5.2–11.5) mmol/l (P=0.17). HbA1c was depressed by 20 mmol/mol (1.8%; P<0.001) in 28 participants with cirrhosis but elevated by 28 mmol/mol (2.6%) in the participant with α‐1‐antitrypsin disorder. Those with cirrhosis and depressed HbA1c had fewer larger erythrocytes, and higher red cell distribution width and reticulocyte count. This was reflected in the positive association of glucose with mean cell volume (r=0.39) and haemoglobin level (r=0.49) and the negative association for HbA1c (r=–0.28 and r=–0.26, respectively) in the diabetes group with cirrhosis. Conclusion: HbA1c is not an appropriate test for blood glucose in people with cirrhosis and diabetes awaiting transplant as it reflects altered erythrocyte presentation. What's new?: HbA1c may not be an accurate reflection of blood glucose for the diagnosis/monitoring of diabetes in people with other illnesses or on certain drugs; people with diabetes and liver disease awaiting transplantation are one such group.HbA1c was found to be depressed relative to random plasma glucose by 20 mmol/mol in people with diabetes and cirrhosis (n = 28) compared to people with diabetes but no liver disease (n = 125); however, HbA1c was elevated in one person with cirrhosis attributable to α‐1‐antitrypsin disorder.Compromised HbA1c may be related to haematological differences associated with liver disease involving erythrocyte half‐life, with shorter/longer times giving less/more opportunity for glycation of haemoglobin. [ABSTRACT FROM AUTHOR]

• An increasing proportion of patients are being transplanted for non-alcoholic steatohepatitis (NASH) in Europe. • Hepatocellular carcinoma was more common in patients transplanted with NASH. • Survival in recipients with NASH is comparable to that of other disease indications. • Age, BMI, and advanced liver disease predicted poorer outcomes in NASH recipients. Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors. We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival. Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH – an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p < 0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61–65 years: HR 2.07, p < 0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m2: HR 4.29, p = 0.048) or high (>40 kg/m2: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors. The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications. The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

• Ursodeoxycholic acid is associated with prolonged survival in primary biliary cholangitis. • This positive association is significant irrespective of age, sex, or disease stage. • The association remains significant in cases where the established criteria for therapeutic response are not met. The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1–12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1–81.2) among UDCA-treated patients and 60.7% (95% CI 58.2–63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40–0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45–0.69; p <0.001). The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC. In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy. [ABSTRACT FROM AUTHOR]

Aim: Corticosteroids are the most widely used agents for the treatment of severe alcoholic hepatitis (SAH). The therapeutic effectiveness of corticosteroids is assessed by the Lille model, which has been validated well in patient cohorts in North America and Europe; however, its usefulness has not yet been confirmed independently in Japanese patients. The present study aimed to determine whether the Lille model could predict the prognosis of SAH in Japanese patients. Methods: This was a retrospective cohort study including 32 SAH patients who were admitted to our institute from April 2011 to February 2018. According to the previously validated Lille model cut‐off value, patients who received corticosteroids were classified as corticosteroid responders or non‐responders (with responders obtaining a Lille score ≥ 0.45), followed by assessment for the 6‐month prognosis. Results: Out of 32 patients, 26 were treated with corticosteroids. The 28‐day and 6‐month mortality rates in the corticosteroid‐treated group were 23.1% and 46.2%, respectively. The median Lille score was significantly higher in patients who died or underwent liver transplantation (0.647) than in those who survived without undergoing transplantation (0.226; P < 0.0182). The 6‐month transplant‐free survival rate of non‐responders (Lille score ≥ 0.45) was significantly lower (27.3%; 95% confidence interval, 9.0–58.6%) than that of responders (Lille score < 0.45, 73.3%; 95% confidence interval, 46.7–90.0%; P = 0.0149, log–rank test). Conclusions: The Lille score could be useful for predicting the 6‐month prognosis of Japanese SAH patients after corticosteroid therapy. [ABSTRACT FROM AUTHOR]

Surgical factors and direct cytotoxicity of bile salts on cholangiocytes may play a role in the development of ischemic cholangiopathy (IC) after liver transplantation (LTx). There is no validated consensus on how to protect the bile ducts during procurement, static preservation, and LTx. Meanwhile, IC remains the most troublesome complication after LTx. To characterize bile duct management techniques during the LTx process among European transplant centers in cases of donation after brain death (DBD) and circulatory death (DCD). An European Liver and Intestine Transplant Association–European Liver Transplant Registry web survey designed to conceal respondents' personal information was sent to surgeons procuring and/or transplanting livers in Europe. Sixty-five percent of responses came from large transplant centers (>50 procurements/y). In 8% of DBDs and 14% of DCDs the bile duct is not rinsed. In 46% of DBDs and 52% of DCDs surgeons prefer to remove the gallbladder after graft reperfusion. Protocols concerning preservation solutions (nature, pressure, volume) are extremely heterogeneous. In 54% of DBDs and 61% of DCDs an arterial back table pressure perfusion is performed. Steroids (20%-10%), heparin (72%-60%), prostacyclin (3%-7%), and fibrinolytics (4%-11%) are used as donor-protective interventions in DBD and DCD cases, respectively. In 2% of DBD and 6% of DCD cases a hepatic artery reperfusion is performed first. In 4% of DBD and 6% of DCD cases, fibrinolytics are administered through the hepatic artery during the bench and/or implantation. This European web survey shows for the first time the heterogeneity in the management of bile ducts during procurement, preservation, and transplantation in Europe. In the context of sharing more marginal liver grafts, an expert meeting must be organized to formulate guidelines to be applied to protect liver grafts against IC. • Ischemic cholangiopathy is still a major complication after liver transplantation. • Surgical factors and bile cytotoxicity may play a role in ischemic cholangiopathy. • There is no validated consensus or guidelines to protect bile ducts. • Bile duct management during the LTx process is heterogeneous across Europe. [ABSTRACT FROM AUTHOR]

Background: Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. However, technical aspects of OLT are still subject of ongoing debate and are widely based on personal experience and local institutional protocols.Methods: An international online survey was sent out to all liver transplant centers (n = 52) within the Eurotransplant, Swisstransplant, Scandiatransplant, and British Transplant Society networks. The survey sought information on center-specific OLT caseload, vascular and biliary reconstruction, graft reperfusion, intraoperative control of hemodynamics, and drain policies.Results: Forty-two centers gave a valid response (81%). Out of these, 50% reported piggy-back and 40.5% total caval replacement as their standard technique. While 48% of all centers generally do not apply veno-venous bypass (vvBP) or temporary portocaval shunt (PCS) during OLT, vvBP/PCS are routinely used in six centers (14%). Portal vein first reperfusion is used in 64%, followed by simultaneous (17%), and retrograde reperfusion (12%). End-to-end duct-to-duct anastomosis without biliary drain (67%) is the most frequently performed method of biliary reconstruction. No significant associations were found between the center caseload and the surgical approach used. The predominant part of the centers (88%) stated that techniques of OLT are not evidence-based and 98% would participate in multicenter clinical trials on these topics.Conclusion: Technical aspects of OLT vary widely among European centers. The extent to which center-specific variation of techniques affect transplant outcomes in Europe should be elucidated further in prospective multicenter trials. [ABSTRACT FROM AUTHOR]

Objective: EMA decided that with ulipristal acetate (UPA) treatment for uterine fibroids, should be discontinued due to the associated risk of hepatic failure, We analyzed whether the risk of recurrent symptoms due to fibroids may lead to an increased risk of Covid -19 infection and death, that would exceed the former risk of hepatic failure and transplantation.Study Design, Size, Duration: We used a Markov model to generate probabilities.Participants/materials, Setting, Methods: There are currently about 36,250 treated patients in Europe. We estimated bleeding probabilities, while using or discontinuing UPA, which may induce a need of medical or surgical management in symptomatic patients, and increase the risk of acquiring a Covid-19 infection, and die from it. We also estimated the risk of suffering a hepatic failure and hepatic transplantation.Main Results and the Role Of Chance: Based on our assumptions, ceasing UPA during a Covid 19 pandemic may be associated with a fatality ratio between 4 and 18, due to the Pandemic, whereas pursuing UPA would be associated with a fatality rate due to the pandemic between 1-2, and an added fatality rate due to hepatic impairment of 1. The added risk of stopping UPA may range between 2 and 15 additional deaths. Our calculations suggest that the decision to stop UPA in the middle of the Covid- 19 pandemic may be untimely, since it may result in an increased risk of Covid-19 infection, due to the recurrence of symptoms and the need for medical and surgical treatment.Wider Implications Of the Findings: A decision, like the one EMA took need to be taken in a wider health context of a population, than simply analyzing its role as regulating agent for medications. [ABSTRACT FROM AUTHOR]

On 5 April 2022, the United Kingdom reported an increase of cases of severe acute hepatitis of unknown aetiology in children, several needing hospitalisation and some required liver transplant or died. Thereafter, 35 countries reported probable cases, almost half of them in Europe. Facing the alert, on 28 April, Portugal created a multidisciplinary Task Force (TF) for rapid detection of probable cases and response. The experts of the TF came from various disciplines: clinicians, laboratory experts, epidemiologists, public health experts and national and international communication. Moreover, Portugal adopted the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) case definition and recommendations. By 31 December 2022, 28 probable cases of severe acute hepatitis of unknown aetiology were reported: 16 male and 17 aged under 2 years. Of these cases, 23 were hospitalised but none required liver transplant or died. Adenovirus was detected from nine of 26 tested cases. No association was observed between adenovirus infection and hospital admission after adjusting for age, sex and region in a binomial regression model. The TF in Portugal may have contributed to increase awareness among clinicians, enabling early detection and prompt management of the outbreak.

Autoimmune hepatitis (AIH) is an immune-mediated, inflammatory liver disease. Clinical presentation of AIH in children is highly variable. It can present acutely, chronically, or silently. There are two main types of AIH-type 1 and type 2, which are differentiated and defined by the presence of specific autoantibodies. AIH eventually progresses to cirrhosis when left untreated, and occasionally even with treatment. AIH must be suspected and excluded in all children presenting with signs of acute, prolonged, or severe liver disease. The diagnosis of AIH is made by a combination of clinical manifestations, laboratory evaluation, histopathology, and the exclusion of other more common liver diseases. The best outcome for AIH is dependent on early diagnosis as well as early initiation of immunosuppressant therapy. [Pediatr Ann. 2018;47(2):e81-e86.]. [ABSTRACT FROM AUTHOR]

Background: There is limited evidence for the effectiveness of daclatasvir in patients whose hepatitis C threatens their life expectancy. The Named Patient Program in Europe included patients with advanced chronic hepatitis C, a life expectancy of less than 12 months and no other treatment options.Methods: A retrospective multi-country cohort of patients with chronic hepatitis C who received daclatasvir as part of the Named Patient Program in Austria, Denmark, Spain, Sweden, Switzerland and the United Kingdom. Treatment response was defined as a sustained virologic response (unquantifiable hepatitis C RNA) at 12 weeks post treatment. We summarised the characteristics of the patients in this cohort and estimated the rate of sustained virologic response for patients receiving daclatasvir and sofosbuvir with or without ribavirin using hierarchical Bayesian modelling.Results: The 249 patients included had a median age of 56 years; most were male (78%), hepatitis C genotype 1 (75%), treatment experienced (65%) and with decompensated cirrhosis (59%). Many had had a liver transplant before receiving daclatasvir (40%). Of the 249 patients, 242 patients received daclatasvir and sofosbuvir and either reached 12 weeks post treatment or died during (n = 9) or after treatment (n = 4) or were lost to follow up during treatment (n = 1). The estimated rate of sustained virologic response at 12 weeks post treatment was 87% (95% credible interval 75 to 94%) for previously treated genotype 1 patients with decompensated cirrhosis.Conclusions: Daclatasvir with sofosbuvir is an effective treatment in clinical practice for hepatitis C genotype 1 patients with decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

The article highlights raised concerning the growing burden of non-alcoholic steatohepatitis (NASH) in liver transplantation. Topics discussed include increase in obesity and type-2 diabetes mellitus which are two major risk factors for non-alcoholic liver disease (NAFLD) and NASH; European Liver Transplant Registry (ELTR) aiming for analyzing in liver transplantation for NASH throughout 174 transplant centres; and highlights the Hepatologists and the liver transplant community to face NASH.

End-stage liver disease secondary to hepatitis C virus (HCV) infection is the major indication for orthotopic liver transplantation (OLT) worldwide. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East, including Saudi Arabia, G4 infection is the most common genotype among transplant recipients. Due to the low prevalence of HC V-G4 in Europe and the United States, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes and remains the least studied variant. The aim of this review is to summarize the natural history and treatment outcome of HCV-G4 following liver transplantation, with particular attention to new HCV therapies. This review incorporates all published studies and abstracts including HCV-G4 patients. [ABSTRACT FROM AUTHOR]

Liver transplantation is now a standard procedure for the treatment of end stage liver diseases. Since 1968 until 2012, a number of 113,627 liver transplantations were performed in Europe, in 28 countries and 153 institutions. Despite these impressive figures the waiting list is growing every year. Transplant surgeons were preoccupied to find new ways to increase the donor pool. Among them: reduced size liver transplantation, split liver technique and more recently living donor liver transplantation. At first in the early `90, living donor liver transplantation was used for pediatric patients because the left lateral hepatic segments were harvested. This graft is too small for the metabolic demands of an adult patient. So the next step was the harvesting of the right liver lobe from the donor and transplantation to adult patients. Living donor liver transplantation has gained fast a wide acceptance but there are a few issues to discuss. The main concern is about the donor safety which is a healthy person undergoing major surgery with potential risks. Also the surgical technique evolved due to a better understanding of the anatomy and physiology of the liver and the right liver graft. We discuss here the anatomical and surgical basis for living donor liver transplantation with the right liver lobe. [ABSTRACT FROM AUTHOR]

Purpose: The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case-population study, named SALT (Study of Acute Liver Transplant), is documented here. Methods: This was a multicentre, multinational retrospective case-population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005-31 December 2007). Cases were patients ≥18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals. Results: The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy. Conclusion: The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF. [ABSTRACT FROM AUTHOR]

Background & Aims: HBV-related chronic liver disease is one of the most common indications for liver transplantation (LT) in Europe. The ELTR database was used to evaluate outcomes and evolution over 20years (01/1988 and 12/2010). Methods: HBV transplanted patients were analysed according to indication for LT: decompensated cirrhosis (HBVdec) or hepatocellular carcinoma (HBV/HCC). These groups were compared with co-infected patients HBV/HDV (HBDV), HBV/HCV (HBCV), HBV/HDV/HCV (HBDCV); n=16,664 and with HCV patients (n=2452) according to LT indication. Results: 5912 patients were transplanted for HBV (78% HBVdec, 22% HBV/HCC), with HBV/HCC patients who increased from 15.8% in 1988–1995 to 29.6% in 2006–2010 (p <0.001). In HBVdec patients, 1, 3, 5, and 10year patient and graft survival was 83%, 78%, 75%, 68%, and 80%, 74%, 71%, 64%, respectively, significantly better than HBV/HCC (84%, 73%, 68%, 61%, and 81%, 70%, 65%, 58% respectively; p= 0.001 and p= 0.026). In 2006–2010 patient and graft survival significantly improved compared to 1988–1995, both for HBVdec and HBV/HCC (each p<0.001). A better patient and graft survival was seen in HBV/HCC patients with HBV-DNA(−) compared to HBV-DNA(+) at the time of LT (p<0.001). Disease recurrence, as cause of death/graft loss, was significantly reduced in recent years compared to the past: currently <1% for HBVdec and 3% for HBV/HCC. Conclusions: Outcomes of LT for HBV have improved in recent years, with disease recurrence being no longer a significant cause of death/graft loss. HBV-DNA at the time of LT seems to influence survival only in HBV/HCC patients. [ABSTRACT FROM AUTHOR]

In Europe, living organ donation ( LOD) is increasingly accepted as a valuable solution to overcome the organ shortage. However, considerable differences exist between European countries regarding frequency, practices and acceptance of donor-recipient relations. As a response, the Coordination Action project ' Living Organ Donation in Europe' (www.eulod.eu), funded by the Seventh Framework Programme of the European Commission, was initiated. Transplant professionals from 331 European kidney and liver transplant centres were invited to complete an online survey on living kidney donation ( LKD) and living liver donation ( LLD). In total, 113 kidney transplant centres from 40 countries and 39 liver transplant centres from 24 countries responded. 96.5% and 71.8% performed LKD and LLD respectively. The content of the medical screening of donors was similar, but criteria for donor acceptance varied. Few absolute contraindications for donation existed. The reimbursement policies diverged and the majority of the donors did not get reimbursed for their income loss during recovery. Large discrepancies were found between geographical European regions (the Eastern, the Mediterranean and the North- Western). As a result of this survey we suggest several recommendations to improve quality and safety of LOD in Europe. [ABSTRACT FROM AUTHOR]

At the beginning of April 2022, 10 cases of severe acute hepatitis of unknown origin in children <10 years of age were reported across central Scotland. Since then, case numbers have increased rapidly, with 191 probable cases identified across Europe, the United States of America, Israel and Japan. Until now, 17 children required liver transplantation and 1 died. Accordingly, the Centers for Disease Control and Prevention and the European Centre for Diseases Prevention and Control have both issued a warning on a hepatitis of unknown origin in children. This review focuses on the available information concerning this recent outbreak and introduces some of the potential explanations for its development., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Liver transplantation for acute liver failure (ALF) still has a high early mortality. We evaluated changes during 20years, 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 50years. 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 >60years 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 >50years (1.26), incompatible ABO matching (1.93), donors >60years (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 >50years were associated only at 12months. Both models had reasonable discriminative ability with good calibration at 3months. Recipients >50years, combined with donors >60years resulted in 57% mortality/graft loss within the first year. Conclusions: Survival after liver transplantation has improved despite increases in donor/recipient age. Recipients >50years paired with donors >60years had a very high mortality/graft loss within the first year. [Copyright &y& Elsevier]

Cross TJS, Jothimani D, Heneghan MA, Harrison PM. Non-invasive assessment of fibrosis in liver grafts due to hepatitis C virus recurrence. Clin Transplant 2011: 25: 345-351. © 2011 John Wiley & Sons A/S. Hepatitis C virus (HCV) infection has become the most common indication for liver transplantation in the United States and Europe. Recurrence of HCV is universal in all liver graft recipients, but the natural history of the disease is variable with some patients displaying slowly progressive liver injury, while approximately 30% become cirrhotic within five yr of surgery. Currently, liver biopsy is the reference standard to assess liver injury in the post-transplant setting. But biopsy is associated with complications such as bleeding and pain, as well as the risk of sampling error and discordance in reporting between histopathologists. Thus, as in the pre-transplant setting, there is increasing attention being drawn to the use of non-invasive tests of liver fibrosis. This review examines the role of non-invasive assessment of hepatic fibrosis in the post-transplant setting including simple tests such as aspartate aminotransferase-to-platelet ratio index, the Benlloch formula, London Transplant Centre score, and finally transient elastography. The authors assess the respective advantages and disadvantages of the tests and consider how non-invasive tests of liver fibrosis can be utilized in the future management of post-transplant HCV infection. [ABSTRACT FROM AUTHOR]

Background: Accurate knowledge of biliary anatomy and its variants is essential to ensure successful hepatic surgery; however, data from European countries are lacking.Methods: Two hundred cholangiograms obtained from patients submitted to whole liver transplantation were reviewed; donors' characteristics were related to the prevalence of typical biliary anatomy and its variants. A comprehensive literature search was performed with MEDLINE and EMBASE from 1980 to 2010 to investigate whether geographical origin could be related to biliary abnormalities.Results: Typical biliary anatomy was observed in 64.5% of cases, but female donors more frequently presented an anatomic variation; typical anatomy was present in 55.0% of females and in 74.0% of males (P = 0.005). Twenty-two reports were identified by the literature search with a total of 7,559 cases, including the present series; heterogeneity was low (Q = 14.60; I2 < 5.0%) after exclusion of three outlier reports. Prevalence of typical biliary anatomy was similar in Europeans and Americans (∼60%); a slightly higher prevalence was observed in Asiatics (∼65%).Conclusions: Anatomic variants seem to be more frequent in females, probably as a consequence of different embryologic development. Available data suggest that typical biliary anatomy can be more frequent in Asiatics, but an accurate means of classification is essential to making comparison realistic. [ABSTRACT FROM AUTHOR]

The worldwide shortage of adequate donor organs implies that living donor liver transplantation represents a valuable alternative to cadaveric transplantation. In addition to the complex surgical procedure the correct identification of eligible donors and recipients plays a decisive role in living donor liver transplantation. Donor safety must be of ultimate priority and overrules all other aspects involved. In contrast to the slightly receding numbers in Europe and North America, in recent years Asian programs have enjoyed constantly increasing living donor activity. The experience of the past 15 years has clearly demonstrated that technical challenges of both bile duct anastomosis and venous outflow of the graft significantly influence postoperative outcome. While short-term in-hospital morbidity remains increased compared to cadaveric transplantation, long-term survival of both graft and patient are comparable or even better than in deceased donor transplantation. Especially for patients expecting long waiting times under the MELD allocation system, living donor liver transplantation offers an excellent therapeutic alternative. Expanding the so-called „Milan criteria“ for HCC patients with the option for living donor liver transplantation is currently being controversially debated. [ABSTRACT FROM AUTHOR]

We describe the first case of West Nile virus infection in Europe with transmission from donor to recipient following liver transplantation. The infection was detected in the recipient 3 days after transplantation, during the asymptomatic phase. We also report an innovative prophylactic strategy based on infusion of West Nile virus hyperimmune plasma and gamma globulins that could be effective in preventing the appearance of a neuroinvasive disease. [ABSTRACT FROM AUTHOR]

Perioperative infections remain an important problem for patients undergoing liver transplantation (LT). For prevention of these infections, perioperative prophylaxis has become the standard procedure. Yet, either guidelines or data on current practice are lacking. The aim of the study was to gain insight into prophylactic antimicrobial strategies used in Europe. A survey questionnaire was sent out to all LT centers that are member of the European Liver and Intestine Transplant Association. In the survey questionnaire, we asked for details on the prophylactic antimicrobial regimen used in LT recipients. The response rate was 48%. Antibiotic prophylaxis for elective LT was provided by a first-line betalactam antibiotic or co-trimoxazole in 25%. Seventy-three per cent of those centers surveyed gave an extended spectrum, and one center used a 6-month rotation strategy. Antifungal prophylaxis was administered in 35% of centers in all LT recipients, in 53% of centers in patients at risk, and in 12% of centers not at all. Cytomegalovirus prophylaxis was never administered in 10%. In 12% of the centers surveyed, all the patients received cytomegalovirus prophylaxis, and another 78% of the centers gave it only to risk groups. In Europe, there is a considerable variation in the different antibiotic, antifungal and cytomegalovirus prophylactic strategies used for LT. These findings underscore the need for randomized controlled trials to determine the optimal prophylactic antimicrobial regimen. [ABSTRACT FROM AUTHOR]

The reported prevalence of autoantibodies (AAB) (ANA, SMA, LKM, SLA) after pediatric liver transplantation (pLTX) varies considerably from 26–75%, but their clinical impact on outcome is uncertain. We aimed to study the prevalence of AAB after pLTX, their association with donor-, transplant-, and recipient-characteristics, and their relation to outcome. In our multicenter retrospective study, we aimed to clarify conflicting results from earlier studies. Six ERN TransplantChild centers reported data on 242 patients, of whom 61% were AAB positive. Prevalence varied across these centers. Independent of the interval between pLTX and AAB analysis, a one-hour increase in CIT resulted in an odds ratio (OR) of 1.37 (95% CI 1.11–1.69) for SMA positivity and an OR of 1.42 (95%CI 1.18–1.72) for ANA positivity. Steroid-free immunosuppression (IS) versus steroid-including IS (OR 5.28; 95% CI 1.45–19.28) was a risk factor for SMA positivity. Liver enzymes were not associated with ANA or SMA positivity. We did not observe an association of rejection activity index with ANA or SMA. However, the liver fibrosis score in follow-up biopsies was associated with ANA titer and donor age. In conclusion, this first multicenter study on AAB after pLTX showed high AAB prevalence and varied widely between centers. Longer CIT and prednisolone-free-IS were associated with AAB positivity, whereas AAB were not indicative of rejection, but instead were associated with graft fibrosis. The detection of AAB may be a marker of liver fibrosis and may be taken into consideration when indications for liver biopsy and immunosuppressive regimes, or reduction of immunosuppression in long-term follow-up, are being discussed. Prospective immunological profiling of pLTX patients, including AAB, is important to further improve our understanding of transplant immunology and silent graft fibrosis. [ABSTRACT FROM AUTHOR]

Background: Liver retransplantation (ReLT) is the only therapeutic option that offers a chance at long-term survival when a liver graft fails. Careful analysis of the results and potential benefits is needed to justify its role in the current era of donor shortage and economical concerns. We reviewed all retransplants performed in our hospital and tried to determine if there is a high risk group of patients in whom its use would be contraindicated. Methods: Between June 1988 and January 2006, 1,226 liver transplants were performed in 1,118 patients at our institution. Among them, 108 retransplants (8.8%) were performed in 98 patients. Preoperative, intraoperative, and postoperative data were gathered from our prospectively collected liver transplant database. The entire series of patients was divided between two periods of equal duration and patients were also classified according to the interval between retransplantation and the previous transplant. Results: Concerning indications, only chronic rejection was a more frequent etiology in the first period versus the second period. When comparing first and second periods, 1-, 5-, and 10-year graft survival was 66%, 45%, and 40% and 76%, 69%, and 69%, respectively (P = .014). No significant differences in post-ReLT survival were found when the indication was HCV recurrence versus other non-urgent causes (1-, 5-, and 10-year graft survival: 70%, 57%, and 57% vs 72%, 50%, and 45%). According to the UNOS Rosen risk score, patients in the low-risk group showed significantly greater survival with respect to patients in the high-risk group though 5-year survival in the high-risk group was still greater than 50%. Conclusions: ReLT indications have changed over time, with better results being achieved in more recent years. Candidate selection in elective ReLT is critical to improve the results, though current criteria do not allow for the identification of a single patient subset in which ReLT would be contraindicated. [Copyright &y& Elsevier]

During the last decade, biliary atresia (BA) has attained more interest and the frequency of BA-related publications has increased continuously. Pediatric hepatologists and pediatric surgeons are very active in improving diagnosis and treatment modalities of BA patients, in order to prolong the survival rate of their native liver. Together with transplant surgeons, the bridging of BA patients to liver transplantation (LTx) becomes optimized and as a consequence of this interdisciplinary approach, the overall survival of babies with BA has already reached 90%. Furthermore, basic research into the still unknown origin of BA has advanced, and numerous scientific programs have already linked together. The overriding interest is to discover at least BA's etiology and to turn the treatment of BA patients from a symptomatic to a causative approach. Interdisciplinary and international programs are mandatory and already existing initiatives in Europe, the United States and Japan are going to coordinate their registries, clinical trials and basic research studies for the benefit of the patients and solve the riddle of BA. [ABSTRACT FROM AUTHOR]