September 30, 2022 New collaborative research describes the lack of consensus among European transplant centers in the clinical management of patients with ACLF-3 The results from this retrospective study highlight the inequity of access to intensive care unit, waitlisting, and liver transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF-3) in 20 centers from 8 European countries

BARCELONA—Liver transplantation appears to be the most effective treatment for patients with ACLF-3. Yet, in practice, liver transplant is not widely used in Europe for treatment of these patients for being considered to be too sick.

Investigators within the ELITA–EF CLIF Working Group, a joint collaborative research effort between the European Liver and Intestine Transplant Association (ELITA), the European Liver Transplant Registry (ELTR), and the European Foundation for the Study of Chronic Liver Failure (EF CLIF) examined a total of 351 patients with ACLF-3 in 20 European transplant centers with the aim to assess differences in the access to intensive care unit, waitlisting and liver transplantation.

The study first published on 11 May 2022 in Liver Transplantation included patients that were admitted to intensive care unit with ACLF-3 or developed ACLF-3 within three to seven days after admission and/or received a liver transplant with ACLF-3. Data were compared to all liver transplant activities including patients with hepatocellular carcinoma and decompensated cirrhosis from 2018 to 2019. While the number of transplanted patients with hepatocarcinoma and decompensated cirrhosis was proportional to the overall number of transplants in each center, the number of patients with ACLF-3 that received a liver transplant was very heterogenous ranging from 0 to 20 across transplantation centers. Among the high-listing/transplanting centers were four centers in France, and centers in Germany, Italy, Poland, Spain, The Netherlands, and UK were identified as low-listing/transplanting centers.

“There is increasing data to suggest that liver transplantation may be lifesaving for some patients for ACLF. However, many patients are simply not considered for surgery, and there remains a common perception that it is seldom practicable in part because the time ‘window’ for transplantation may be very short. Many of these critically ill patients deteriorate whilst on the standard transplant waitlist and surgery becomes impossible", said William Bernal, joint first author on the paper, Consultant Intensivist at King's College Hospital, UK and Principal Investigator at EF CLIF, Spain.

Reasons for not listing patients once admitted to the intensive care unit included illness severity, comorbidities, and bacterial infection regardless of age and sex. "The lack of equity of access to liver transplantation for patients with severe ACLF, although concerning is not surprising. The transplant teams are concerned about potentially futile transplantation in these very sick patients", said Rajiv Jalan, joint senior author on the paper, Hepatologist at Royal Free Hospital, UK, and Scientific Director of EF CLIF, Spain.

The authors reported that the majority of patients with ACLF-3 that were listed received a liver transplant, and one-year survival was relatively high with no differences between ACLF-3 high-listing/transplanting and low-listing/transplanting centers during the study period. On the contrary, all patients with ACLF-3 that were not transplanted either died before liver transplant while on waitlist or, if delisted, died within one year after listing.

Despite the percentage of patients with ACLF-3 who died on the waiting list or were delisted was lower than previously reported in the United Network for Organ Sharing (UNOS) database, these patients appear to be less likely to be prioritized beyond the model for end-stage liver disease (MELD) score to access liver transplantation. "Successful transplantation depends upon early case recognition and a willingness to waitlist critically ill patients, with prioritization once waitlisted. Our study found wide variation across Europe in waitlisting practice for patients with ACLF – despite excellent survival in those undergoing surgery”, added Bernal.

Altogether, the results from this study reveal important differences on liver transplant referral practices for patients with ACLF-3 across transplantation centers in Europe. While criteria for admission to the intensive care unit may vary across centers, admission of ACLF-3 patients did not translate in more patients in the waitlist or receiving a liver transplant. However, the variability observed across centers relied on the attitude towards waitlisting patients with ACLF-3.

"The data generated by the EF CLIF–ELITA partnership has provided new knowledge which will give more confidence to transplant teams about transplanting these patients with ACLF-3. The ongoing CHANCE study will provide a global perspective and allow the development of robust criteria for better selection of patients with ACLF-3 for transplantation", Jalan explained.

Other authors on the study are Thierry Arzner, Luca S. Belli, Sara Conti, Paolo A. Cortesi, Sophie-Caroline Sacleaux, George-Philippe Pageaux, Sylvie Radenne, Jonel Trebicka, Javier Fernandez, Giovanni Perricone, Salvatore Piano, Silvio Nadalin, Maria C. Morelli, Silcia Martini, Wojciech G. Polak, Krzysztof Zienuewicz, Christian Torso, Marina Berenguer, Claudia Iegri, Federica Invernizzi, Riccardo Volpes, Vincent Karam, René Adam, François Faitot, Liane Rabinowich, Faouzi Saliba, Lucy Meunier, Mickael Lesurtel, Frank E. Uschner, Baptiste Michard, Audrey Coilly, Magdalena Meszaros, Domitille Poinsot, Camille Bresch, Andreas Schnitzbauer, Luciano G. De Carlis, Roberto Fumagalli, Paolo Angeli, Vicente Arroyo, Constantino Fondevila, and Christophe Duvoux.

Publication information

Artzner, T.; Bernal, W.; Belli, L.S.; Conti, S.; Cortesi, P.A.; Sacleux, S.-C.; for the ELITA–EF CLIF Working Group. Location and allocation: Inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe. Liver Transpl. 2022, 28:1429–1440. DOI: 10.1002/lt.26499

About EF CLIF

The European Foundation for the Study of Chronic Liver Failure (EF CLIF) is a private non-profit organization connecting biomedical researchers and healthcare professionals with each other, with patients and patient associations, and with society. The fundamental purpose of EF CLIF, reflected in its founding Statements of 2015, is to advance knowledge and promote research and education in liver disease to improve the prognosis of patients living with chronic liver failure.

The Foundation has made pioneering efforts in conducting a series of large, international prospective studies that have been instrumental in reclassifying the trajectory of patients with chronic liver failure and led to the clinical, prognostic and pathophysiological definition of the syndrome referred to as “acute-on-chronic liver failure” characterized by acute decompensation of cirrhosis, severe systemic inflammation, organ failures, and high short-term mortality. We are inspiring best clinical practices for the management of patients with chronic liver failure and promoting a more sustainable and equitable healthcare system.

Within the Foundation, the European Association for the Study of the Liver (EASL) Chair supports research activities through the EASL-CLIF Consortium, a network of 117 tertiary care and university hospitals in 28 European countries. The Grifols Chair promotes translational studies in centers across Europe and North America within the framework of the European Network for Translational Research (ENTR) with 25 centers in 8 countries. Over the last five years, the Foundation has successfully expanded its geographical scope providing the context to support transcontinental collaborative research projects. The Global Projects chapter provides the framework to promote research in cirrhosis across the world with the aim to help to build consensus and ensure health equity worldwide.