Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome in patients with cirrhosis, characterized by sudden deterioration and failure of one or more organ systems. Its most severe forms, ACLF-2 and ACLF-3, are associated with very high short-term mortality, while the role and limits of liver transplantation in these patients have remained uncertain for a long time.

Published in the Journal of Hepatology, the CHANCE study provides the first worldwide prospective evidence on outcomes after liver transplantation in patients with severe ACLF. This landmark research demonstrates a substantial survival benefit in patients undergoing liver transplantation, while also identifying a higher risk of mortality after transplantation in patients with five or six organ failures.

Liver transplantation markedly improves survival in severe ACLF

CHANCE prospectively followed 995 patients at 63 liver transplant centers in Asia, Europe, Latin America and North America between 2021 and 2023. Of these, 612 underwent liver transplantation, while 144 patients with ACLF-2 or ACLF-3 were not accepted for transplantation and were followed for one year.

The difference in outcomes was substantial: 73% of patients with ACLF-2 and 88% of patients with ACLF-3 who were not accepted for transplantation died within one year. In comparison, among transplanted patients, the one-year mortality rate without retransplantation was only 10.5% for ACLF-2 —not different from that of transplanted patients without ACLF (9%)— and 20.7% for ACLF-3.

These observations highlight the immediate, real-world impact of liver transplantation on patient outcomes. “Liver transplantation dramatically improves survival in patients with severe ACLF compared with not being accepted for transplantation. These results show that even patients with very severe cirrhosis can have a significant chance of survival after transplantation,” said Thierry Gustot, principal investigator of the CHANCE study, Head of the Department of Transplantation and Organ Procurement and Director of the Liver Transplantation Unit at HUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.

“Vall d’Hebron’s participation in this international study contributes to generating prospective evidence on an especially complex clinical situation. The results show that, in selected patients with severe ACLF, liver transplantation can very significantly change the prognosis and reinforce the importance of an individualized assessment of each patient,” explains Isabel Campos-Varela, specialist in the Hepatology Department of the Digestive Diseases Area at Vall d’Hebron University Hospital and senior researcher in the Liver Diseases Research Group at the Vall d’Hebron Research Institute.

A worldwide study design to overcome the limitations of previous research

Previous research on liver transplantation in severe ACLF has mainly come from retrospective registries or small single-center series of patients from individual regions. CHANCE was designed to address these limitations through the prospective collection of standardized clinical data across a worldwide network of liver transplant centers.

“For many years, ACLF has been considered a contraindication to liver transplantation. The complex management in the intensive care unit and the unfavorable clinical outcomes observed in the early local series contributed to reinforcing this negative perception,” states Javier Fernández, co-principal investigator of the CHANCE study, Head of Clinical Operations at EF CLIF and Head of the Hepatic Intensive Care Unit of the Liver Unit at Hospital Clínic de Barcelona.

The inclusion of 63 centers across four continents allowed the investigators to directly examine patient outcomes in different healthcare settings before liver transplantation and during one year of follow-up.

“Previous single-center and registry-based studies suggested a significant improvement in survival among patients with ACLF undergoing liver transplantation. As the largest prospective investigation conducted to date in this field, the CHANCE study confirms these positive results on a worldwide scale, allowing them to be generalized,” Fernández adds.

The number and type of organ failures define the risk after transplantation

Although the findings support the benefit of liver transplantation in severe ACLF, they also provide important information about where the limits of transplantation may lie.

Among transplanted patients, the one-year mortality rate progressively increased with the number of organ failures present at the time of liver transplantation. The rate was 8.3% in patients without organ failure, 9.6% with one organ failure, 10.5% with two, 14.9% with three and 17.9% with four organ failures. In patients with five or six organ failures, however, the mortality rate increased to 41.7%. The analysis also found that certain types of organ failure were associated with higher mortality after liver transplantation, particularly brain, respiratory and circulatory failure.

“These findings show for the first time, prospectively and across four continents, that survival after liver transplantation in severe ACLF is not simply determined by the severity of ACLF itself, but by the number and type of organs failing at the time of surgery,” states Rajiv Jalan, scientific coordinator of the CHANCE study, Professor of Hepatology at the Institute for Liver and Digestive Health, University College London, and Consultant Hepatologist at the Royal Free Hospital.

The findings point towards a more individualized assessment of patients with the most severe forms of ACLF, based on the number and type of organ failures rather than solely on the severity of ACLF. This distinction is important when considering both the potential benefit of liver transplantation and the appropriate use of scarce donor organs. “Too many patients with severe ACLF have been denied transplantation based on fear rather than evidence, and equitable access to transplantation for these patients is now a moral imperative. As donor organs are a scarce and valuable resource, the data should reassure surgical and medical colleagues that liver transplantation can be safely carried out in patients with up to four organ failures and justify prioritizing them, while recognizing that once five or six organs have failed, the likelihood of benefit falls sharply and every decision requires great care,” Jalan adds.

The findings may contribute to more informed decisions about liver transplantation

The results provide transplant teams with evidence that helps assess patients with ACLF-2 and ACLF-3 and identify those who are most likely to benefit from liver transplantation, offering a practical framework for managing scarce donor organs.

“The CHANCE study has confirmed that, for selected patients with very severe ACLF, we now have a treatment that is both practical and life-saving. Its findings will help us identify which patients are most likely to benefit from liver transplantation, so that we can make the most effective use of the limited number of available liver grafts,” states William Bernal, co-principal investigator of the CHANCE study, Professor of Liver Critical Care Medicine at King’s College London and Consultant in Liver Critical Care at the Liver Intensive Therapy Unit of the Institute of Liver Studies, King’s College Hospital.

The study also found that patients with ACLF-2 or ACLF-3 on the waiting list for liver transplantation had almost twice the risk of dying or being removed from the list due to clinical deterioration as patients without severe ACLF (27% versus 15%), despite shorter waiting times. “This reinforces the importance of timely assessment and supports prioritizing selected patients in organ allocation systems, as has already been successfully tested in the United Kingdom,” Bernal adds.

At the same time, the authors emphasize that the findings should not be interpreted as supporting liver transplantation in all patients with severe ACLF. The markedly worse outcomes observed in the relatively small group of transplanted patients with five or six organ failures highlight the importance of carefully assessing the balance between potential benefit and risk in the most critically ill patients.

CHANCE establishes a resource for future research on ACLF

Beyond the clinical implications of the findings, CHANCE has established an international infrastructure for the prospective collection of data and biological samples. The study brought together 63 liver transplant centers using harmonized procedures and collected clinical information, as well as blood, plasma, urine and DNA samples.

This collective effort represents an important milestone for global clinical research. “CHANCE demonstrates what can be achieved when liver transplant centers around the world work together using harmonized procedures for the prospective collection of data and samples,” says Cristina Sánchez-Garrido, Head of the Data Management Center at EF CLIF. “Coordinating such a large international network has required a major collective effort, but at the same time it has allowed us to build a standardized, high-quality dataset and a biobank that would not have been possible at the level of individual centers.”

The resulting dataset and biobank will provide a basis for subsequent studies. “Beyond its immediate clinical findings, the CHANCE study establishes a unique infrastructure whose value will continue to grow far beyond publication,” says Gustot. “By combining detailed prospectively collected clinical phenotyping with matched biological samples —blood, plasma, urine and DNA— across 63 centers worldwide, the CHANCE cohort provides an unprecedented resource for understanding ACLF and its response to liver transplantation.”