Advertisement

‘Equity’ and ‘Justice’ for patients with acute-on chronic liver failure: A call to action

  • Author Footnotes
    † Joint 1st Authors
    Rajiv Jalan
    Correspondence
    Corresponding author. Address: Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Campus, London, UK.
    Footnotes
    † Joint 1st Authors
    Affiliations
    European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain

    Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Campus, London, UK
    Search for articles by this author
  • Author Footnotes
    † Joint 1st Authors
    Thierry Gustot
    Footnotes
    † Joint 1st Authors
    Affiliations
    European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain

    Liver Transplant Unit, Dep. of Gastroenterology, Hepato-Pancreatology, C.U.B. Hôpital Erasme, Brussels, Belgium

    Digestive Oncology, C.U.B. Hôpital Erasme, Brussels, Belgium

    Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Belgium

    Inserm Unité 1149, Centre de Recherche sur l’inflammation (CRI), Paris, France

    UMR S_1149, Université Paris Diderot, Paris, France
    Search for articles by this author
  • Author Footnotes
    † Joint 1st Authors
    Javier Fernandez
    Footnotes
    † Joint 1st Authors
    Affiliations
    European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain

    Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Spain
    Search for articles by this author
  • Author Footnotes
    † Joint 1st Authors
    William Bernal
    Footnotes
    † Joint 1st Authors
    Affiliations
    European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain

    Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
    Search for articles by this author
  • Author Footnotes
    † Joint 1st Authors

      Summary

      Acute-on-chronic liver failure (ACLF) occurs in hospitalised patients with cirrhosis and is characterised by multiorgan failures and high rates of short-term mortality. Without liver transplantation (LT), the 28-day mortality rate of patients with ACLF ranges from 18–25% in those with ACLF grade 1 to 68–89% in those with ACLF grade 3. It has become clear that patients with ACLF do not have equitable access to LT because of current allocation policies, which are based on prognostic scores that underestimate their risk of death and a lack of appreciation of the clear evidence of transplant benefit in carefully selected patients (who can have excellent post-LT outcomes). In this expert opinion, we provide evidence supporting the argument that patients with ACLF should be given priority for LT based on prognostic models that define the risk of death for these patients. We also pinpoint risk factors for poor post-LT outcomes, identify unanswered questions and describe the design of a global study, the CHANCE study, which will provide answers to the outstanding issues. We also propose the worldwide adoption of new organ allocation policies for patients with ACLF, as have been initiated in the UK and recommended in Spain.

      Keywords

      Linked Article

      Introduction

      Acute-on-chronic liver failure (ACLF) is a well-defined disease entity that occurs in patients with cirrhosis and is characterised by precipitating events, multiorgan failures, systemic inflammation and high rates of short-term mortality. Data from across the globe in over 100,000 patients have validated the diagnostic and prognostic criteria that were developed in the CANONIC study, referred to as the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria (Fig. 1).
      • Arroyo V.
      • Moreau R.
      • Jalan R.
      Acute-on-Chronic liver failure.
      Without liver transplantation (LT), the 28-day mortality of patients with ACLF ranges from 18–25% in those with ACLF Grade 1 to 68–89% in those with ACLF Grade 3.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      The available data indicate that about 30% of patients with cirrhosis who are hospitalised for a liver-related complication will have ACLF or develop it during hospitalisation.
      • Arroyo V.
      • Moreau R.
      • Jalan R.
      Acute-on-Chronic liver failure.
      ,
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Emerging data from retrospective studies and those from large organ transplantation databases provide robust information that LT can save the lives of these patients.
      • Burra P.
      • Samuel D.
      • Sundaram V.
      • Duvoux C.
      • Petrowsky H.
      • Terrault N.
      • et al.
      Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation.
      However, the lack of widespread recognition of the transplant benefit that these patients with severe ACLF obtain, absence of strategies to prioritise ACLF patients for earlier access to donor organs, pre-conceived ideas that patients with ACLF will have poor post-LT outcomes and the fear that higher post-transplant death rates may disadvantage smaller centres, provide the perfect setting for lack of equity of access to LT.
      • Belli L.S.
      • Duvoux C.
      • Artzner T.
      • Bernal W.
      • Conti S.
      • Cortesi P.A.
      • et al.
      Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS).
      Figure thumbnail gr1
      Fig. 1CLIF-organ failure score and ACLF grades.
      (A) CLIF-organ failure score. The dark shaded areas define criteria to diagnose organ failure. (B) Criteria to diagnose different Grades of ACLF using the CLIF-organ failure scoring system. ACLF, acute-on-chronic liver failure; BD, brain dysfunction; CLIF, Chronic Liver Failure; INR, international normalized ratio; KD, kidney dysfunction; MAP, mean arterial pressure; OF, organ failure. Data from Jalan and Saliba et al. J Hepatol 2014 (ref 5).
      Current organ allocation around the world is based on a prognostic model, referred to as the model for end-stage liver disease (MELD) score. Although the model was developed in the US, it is used for organ allocation in most European countries that are in the Eurotransplant organ sharing programme. There are no specific priority points for patients with ACLF. The only option for transplanting patients with ACLF is to stay on the waiting list until an organ is allocated or use organs from deceased donors or use marginal donors. In many Asian countries, living donors provide the organs. As is evident from Table 1, rates of access to LT for patients with ACLF vary widely across Europe.
      • Belli L.S.
      • Duvoux C.
      • Artzner T.
      • Bernal W.
      • Conti S.
      • Cortesi P.A.
      • et al.
      Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS).
      In recognition of this, new policies for organ transplantation for patients with ACLF have been implemented in Spain and the UK.
      Table 1Evidence of lack of equity of access to LT for patients with ACLF across Europe.
      SitesNo. of LTsDCACLF-1 at LTACLF-2 at LTACLF-3 at LT
      France461331619 (6%)27(8.5%)60 (19%)
      Germany2854110 (24%)10 (24%)7 (17%)
      Italy789135314 (3.9%)31 (8.8%)18 (5%)
      Switzerland166261 (3.8%)2 (7.6%)2 (7.6%)
      Poland1184452 (4.4%)3 (6.6%)1 (2.2%)
      Netherlands11145901 (1.7%)3 (5%)
      UK24952754 (1.4%)1 (0.3%)6 (2.1%)
      Spain22291018 (7.9%)4 (4%)1 (1%)
      Total202.677121656 (4.6%)79 (6.5%)98 (8%)
      ACLF, acute-on-chronic liver failure; DC, decompensated cirrhosis; ELTR, European Liver Transplant Registry; LT, liver transplantation.
      2.677/9.000 = 29.7% of all LTs registered in ELTR between January 2018 and June 2019; Poland, the Netherlands, the UK, and Spain: low transplant rates; Italy and Switzerland: Intermediate rates; France and Germany: High rates. Data from Belli et al. J Hepatol 2021 (in press).

      Recommendations of the Spanish Society of Liver Transplantation (SETH)

      In a recently published consensus statement, SETH has recommended an expedited organ allocation programme to allow patients with ACLF to be transplanted (Box 1).
      • Rodríguez-Perálvarez M.
      • Miguel Ángel Gómez-Bravo M.A.
      • Sánchez-Antolín G.
      • De la Rosa G.
      • Bilbao I.
      • Colmenero J.
      • et al.
      Expanding indications of liver transplantation in Spain: consensus statement and recommendations by the Spanish society of liver transplantation.
      In brief, they suggest that LT should be considered in patients with ACLF. They recommend the use of the EASL-CLIF criteria to assess prognosis and suggest that MELD score does not recognise the severity of illness in those with ACLF grades 2 or 3. In these patients, they suggest prioritisation given the poor short-term survival.
      Recommendations of Spanish Society of Liver Transplantation.
      ACLF, acute-on-chronic liver failure; LT, liver transplantation; MELD, model for end-stage liver disease. Data from Transplantation 2021;105: 602–607.

      Recommendations of the NHS Blood and Transplant, UK

      A new allocation tier referred to as the ACLF transplantation tier (ACLFLT) has been created in the UK and came into force in May 2021. The ACLFLT priority tier is below that of the superurgent listed patients (e.g. patients with hepatoblastoma, split-able organs and critically ill paediatric patients). The eligibility criteria for expedited transplantation include the presence of cirrhosis, significant liver failure manifested by jaundice and coagulopathy, organ failures necessitating organ support in the intensive care unit (ICU) or equivalent and a risk of 28-day mortality of >50%. This group of patients will usually fulfil the EASL-CLIF criteria for ACLF grade 2 or 3 (www.nhsbt.nhs.uk).
      This expert opinion supports the aforementioned recommendations of the Spanish and UK societies to prioritise patients with ACLF in organ allocation policies. We focus on discussing the evidence that the current allocation policy based on MELD scoring is inadequate and that LT saves the lives of patients with ACLF. The limits, potential futility and contraindications of transplantation are then addressed. Finally, we describe the design of a global study which aims to address remaining questions and refine existing criteria on the role of LT in patients with ACLF.

      MELD-based allocation systems disadvantage patients with ACLF

      Data from the CANONIC study published about 7-years ago confirmed that the risk of short-term mortality was better identified by the EASL-CLIF based organ failure (OF) grading system than the MELD score, which also validated the scoring system for sequential use.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      The EASL-CLIF predictive model reached an AUROC of 0.8 by Day 3-7 from the time the patient with cirrhosis was hospitalised.
      • Jalan R.
      • Saliba F.
      • Pavesi M.
      • Amoros A.
      • Moreau R.
      • Ginès P.
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      The superior performance of the ACLF classification over MELD has been validated by many investigators. The study from Hernaez et al., which included over 70,000 patients from 127 VA hospitals showed that at each MELD decile, the EASL-CLIF model was able to identify patients at risk of death. The data suggest that the MELD scoring system underestimates the risk of death in patients with ACLF (Fig. 2A).
      • Hernaez R.
      • Liu Y.
      • Kramer J.R.
      • Rana A.
      • El-Serag H.B.
      • Kanwal F.
      Model for end-stage liver disease-sodium underestimates 90-day mortality risk in patients with acute-on-chronic liver failure.
      Figure thumbnail gr2
      Fig. 2Data showing mortality rates according to MELD decile and ACLF grade.
      (A) The data here show that at each MELD decile, the EASL-CLIF model was able to identify patients at risk of death. (B) The data show that patients with relatively low MELD scores (<25) had high mortality rates, ranging between 30-40% if they had ACLF grades 2 or 3. ACLF, acute-on-chronic liver failure; EASL-CLIF, European Association for the Study of the Liver-Chronic Liver Failure; MELD, model for end-stage liver disease. Data from Hernaez et al. J Hepatol. 2020;73:1425-1433 and Sundaram and Jalan et al. Gastroenterology 2019;156:1381-1391 (refs 7 and 8 respectively).
      In an important study using data from the United Network for Organ Sharing (UNOS) database, mortality on the waiting list was assessed in about 79,000 patients. The data confirmed that patients with relatively low MELD scores (<25) had high mortality rates, ranging between 30-40%, if they had ACLF grades 2 or 3 (Fig. 2B).
      • Sundaram V.
      • Jalan R.
      • Wu T.
      • Volk M.L.
      • Asrani S.K.
      • Klein A.S.
      • et al.
      Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
      In order to enable more equitable distribution of organs, a share-35 rule was introduced in the US in 2014. In a study of the UNOS database between 2010-2017, including only patients with MELD ≥35, the mortality rate of patients on the waiting list was 16% if they had ACLF grade 2 and 30% if they had ACLF grade 3. In studying the impact of share-35, the data suggested that transplantation rates for patients with ACLF increased, but no impact was observed in those with ACLF grade 3, particularly patients with 4-6 OFs.
      • Sundaram V.
      • Shah P.
      • Mahmud N.
      • Lindenmeyer C.C.
      • Klein A.S.
      • Wong R.J.
      • et al.
      Patients with severe acute-on-chronic liver failure are disadvantaged by model for end-stage liver disease-based organ allocation policy.
      In another study, the interaction between MELD and EASL-CLIF classification was explored and a new scoring system including age, MELDs, aetiology, ACLF grade, ethnicity, obesity, sex and Karnofsky score has been proposed.
      • Abdallah M.A.
      • Kuo Y.F.
      • Asrani S.
      • Wong R.J.
      • Ahmed A.
      • Kwo P.
      • et al.
      Validating a novel score based on interaction between ACLF grade and MELD score to predict waitlist mortality.
      This requires further validation.
      Taken together, the overwhelming evidence points to replacing the MELD-based allocation system with the EASL-CLIF classification for patients with ACLF. This is not surprising as the MELD score fails to recognise the importance of brain, circulation and respiratory failures in defining short-term mortality in patients with ACLF. The UK and the Spanish pilot programmes will provide information on areas that need further refinement.

      Evidence of transplant benefit in patients with ACLF

      Although there is ongoing debate on the details of the definitions used to categorise the stages of ACLF, there is unequivocal evidence of a close relationship between the number and severity of organ system failures and survival. The EASL-CLIF diagnostic and prognostic criteria have been shown to be superior to the Asian Pacific Association for the Study of the Liver (APASL) or North American Consortium for the Study of End Stage Liver Disease (NACSELD) criteria in various studies.
      • Mahmud N.
      • Kaplan D.E.
      • Taddei T.H.
      • Goldberg D.S.
      Incidence and mortality of acute-on-chronic liver failure using two definitions in patients with compensated cirrhosis.
      ,
      • Li F.
      • Thuluvath P.J.
      EASL-CLIF criteria perform better than NACSELD to diagnose and prognosticate ACLF.
      In patients with cirrhosis and ≥3 organ system failures, the 90-day mortality rate consistently exceeds 60% despite the best available medical therapies.
      • Arroyo V.
      • Moreau R.
      • Jalan R.
      Acute-on-Chronic liver failure.
      Experimental extracorporeal liver assist devices are yet to demonstrate consistent and convincing improvements in survival. In contrast, there are consistent and strong indications of a survival benefit from LT in carefully selected patients.
      Post-LT patient survival for recipients transplanted from the ICU has shown progressive improvement over time and in many series now approaches that of elective surgery.
      • Bernal W.
      Improving outcomes for transplantation of critically ill patients with cirrhosis?.
      ,
      • Moon D.B.
      • Lee S.G.
      • Kang W.H.
      • Song G.W.
      • Jung D.H.
      • Park G.C.
      • et al.
      Adult living donor liver transplantation for acute-on-chronic liver failure in high-model for end-stage liver disease score patients.
      Comparison with transplantation for non-ACLF indications does however indicate that ACLF transplants are associated with longer post-operative ICU and hospital stay.
      • Karvellas C.J.
      • Lescot T.
      • Goldberg P.
      • Sharpe M.D.
      • Ronco J.J.
      • Renner E.L.
      • et al.
      Liver transplantation in the critically ill: a multicenter Canadian retrospective cohort study.
      Though the use of LT for ACLF has not been – and probably never will be – tested in randomised controlled trials, patient survival in recent series reporting the outcome of LT of recipients with ACLF consistently exceeds that expected with medical therapies alone (Table 2). In a recently published collaborative study between EFCLIF and ELITA (ECLIS study), the outcomes of LT for ACLF were evaluated in 20 centres from 8 European countries. Patients on the waiting list over 18 months between 2018 and 2019 were included. Only 234 (19%) patients with decompensated cirrhosis had ACLF at listing. Mortality on the waiting list even in this very carefully selected group was 31.6%, but the 1-year post-LT survival was 81% providing clear evidence of transplant benefit.
      • Belli L.S.
      • Duvoux C.
      • Artzner T.
      • Bernal W.
      • Conti S.
      • Cortesi P.A.
      • et al.
      Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS).
      Data from other single and multicentre studies, as well as from large registries, support this more granular observation in the ECLIS study.
      • Burra P.
      • Samuel D.
      • Sundaram V.
      • Duvoux C.
      • Petrowsky H.
      • Terrault N.
      • et al.
      Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation.
      Table 2Reports of patient survival after liver transplantation for ACLF.
      SiteCohortNEraPatient survivalIllness severityReference
      KoreaSingle site1901998-20151-year 72%ACLF 1-3Moon et al. 2017
      • Moon D.B.
      • Lee S.G.
      • Kang W.H.
      • Song G.W.
      • Jung D.H.
      • Park G.C.
      • et al.
      Adult living donor liver transplantation for acute-on-chronic liver failure in high-model for end-stage liver disease score patients.
      CanadaMulti-site1982000-091-year 74%Median SOFA 14Karvellas et al. 2013
      • Karvellas C.J.
      • Lescot T.
      • Goldberg P.
      • Sharpe M.D.
      • Ronco J.J.
      • Renner E.L.
      • et al.
      Liver transplantation in the critically ill: a multicenter Canadian retrospective cohort study.
      USARegistry35562002-161-year 81-84%3+ Organ failuresThuluvath et al. 2018
      • Thuluvath P.J.
      • Thuluvath A.J.
      • Hanish S.
      • Savva Y.
      Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
      AustriaSingle site332002-101- year 87%ACLF: APASL classificationFinkensetdt et al. 2013
      USARegistry63812005-161-year 81.8%ACLF-3 onlySundaram et al. 2019
      • Sundaram V.
      • Jalan R.
      • Wu T.
      • Volk M.L.
      • Asrani S.K.
      • Klein A.S.
      • et al.
      Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
      USASingle Site1012006-131-year 82%ACLF 1-3Agbim et al. 2020
      FranceSingle Site552007-141-year 60%Median SOFA 13Michard et al. 2017
      FranceSingle Site1402008-131-year 70%ACLF 1-3Levesque et al. 2017
      FranceMulti-site732008-141-year 84%ACLF-3 onlyArtru et al. 2017
      • Karvellas C.J.
      • Lescot T.
      • Goldberg P.
      • Sharpe M.D.
      • Ronco J.J.
      • Renner E.L.
      • et al.
      Liver transplantation in the critically ill: a multicenter Canadian retrospective cohort study.
      GermanySingle Site982009-141-year 62%ACLF 1-3Huebner et al. 2018
      UKRegistry652011-161-year 90%3+ Organ failuresBernal W. 2017
      N. AmericaMulti-site572015-176-month 93%ACLF NACSELD classificationO’Leary et al.
      PakistanSingle Site602012-161-year 92%ACLF 1-3Bhatti et al. 2018
      France / UKMulti-site1522007-171-year 67%ACLF-3 onlyArtzner et al. 2020
      KoreaSingle site442011-141-year 84%ACLF 1-3Hong et al. 2016
      ACLF, acute-on-chronic liver failure; APASL, Asian Pacific Association for the Study of the Liver; NACSELD, North American Consortium for the Study of End Stage Liver Disease; SOFA, Sequential Organ failure Assessment. Refs: Finkenstedt et al. Liver Transplantation 2013;19:879-886; Agbim et al. Transplant Direct 2020;6:e544; Michard et al. Clinical Transplantation 2017;31; Levesque et al. Liver International 2017;37:684-693; Huebner et al. Alimentary Pharmacology & Therapeutics 2018;02:02; Bernal W. Clinical Liver Disease 2017;10:25-28; O’Leary et al. Liver Transplantation 2019;25:571-579; Bhatti et al. Journal of Clinical & Experimental Hepatology 2018;8:136-143; Artzner et al. American Journal of Transplantation 2020;20:2437-2448; Hong et al. World Journal of Gastroenterology 2016;22:3785-3792.
      There are few studies of patients with ACLF that have directly compared survival with and without transplantation. To date, retrospective comparison with matched, non-transplanted controls has been made in 3 studies which, when combined in a meta-analysis, showed ‘huge benefit of LT for select ACLF patients’(Fig. 3).
      • Abdallah M.A.
      • Waleed M.
      • Bell M.G.
      • Nelson M.
      • Wong R.
      • Sundaram V.
      • et al.
      Systematic review with meta-analysis: liver transplant provides survival benefit in patients with acute on chronic liver failure.
      Importantly, this meta-analysis also confirmed key features required in future research to determine standardised criteria for LT selection and facilitate analysis of outcome in this patient group – with need for robust prospective multicentre data collection using standardised definitions of ACLF.
      Figure thumbnail gr3
      Fig. 3Forest plots of 30-day and 1-year patient survival of ACLF patients who did or did not receive liver transplantation.
      ACLF, acute-on-chronic liver failure; LT, liver transplantation. Data from Abdallah et al. Alimentary Pharmacology & Therapeutics. 2020;52:222-232 (ref 16).

      Limits, futility and contraindications

      Despite clear evidence of transplant benefit in carefully selected patients with ACLF, the limits and contraindications for proceeding or denying LT in these patients have not been well defined.
      • Burra P.
      • Samuel D.
      • Sundaram V.
      • Duvoux C.
      • Petrowsky H.
      • Terrault N.
      • et al.
      Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation.
      ,
      • Belli L.S.
      • Duvoux C.
      • Artzner T.
      • Bernal W.
      • Conti S.
      • Cortesi P.A.
      • et al.
      Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS).
      ,
      • Sundaram V.
      • Jalan R.
      • Wu T.
      • Volk M.L.
      • Asrani S.K.
      • Klein A.S.
      • et al.
      Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
      ,
      • Artru F.
      • Louvet A.
      • Ruiz I.
      • Levesque E.
      • Labreuche J.
      • Ursic-Bedoya J.
      • et al.
      Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3.
      LT should be cautiously considered in the following situations.
      • 1.
        Higher grades of ACLF in patients with cirrhosis have been suggested as a possible pre-transplant condition that defines potentially futile LT. Patients with 4 to 6 OFs, especially if they require renal, vascular and ventilatory support, have traditionally been considered too sick for LT due to their expected poor prognosis after surgery.
        • Linecker M.
        • Krones T.
        • Berg T.
        • Niemann C.U.
        • Steadman R.H.
        • Dutkowski P.
        • et al.
        Potentially inappropriate liver transplantation in the era of the "sickest first" policy. A search for the upper limits.
        However, recent studies show that although mortality increases with the number of OFs, the price to pay is minor with just a 9% reduction in 1-year survival after LT in patients with 5-6 OFs compared to those without ACLF.
        • Thuluvath P.J.
        • Thuluvath A.J.
        • Hanish S.
        • Savva Y.
        Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
        The type of OF also has a minor impact on post-LT survival with only mechanical ventilation being identified as an independent predictor of mortality (hazard ratio 1.5–1.7).
        • Burra P.
        • Samuel D.
        • Sundaram V.
        • Duvoux C.
        • Petrowsky H.
        • Terrault N.
        • et al.
        Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation.
        ,
        • Sundaram V.
        • Jalan R.
        • Wu T.
        • Volk M.L.
        • Asrani S.K.
        • Klein A.S.
        • et al.
        Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
        ,
        • Thuluvath P.J.
        • Thuluvath A.J.
        • Hanish S.
        • Savva Y.
        Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
        Patients requiring full organ support at LT (dialysis, mechanical ventilation and vasopressors) also show excellent survival at 1-year (77%).
        • Thuluvath P.J.
        • Thuluvath A.J.
        • Hanish S.
        • Savva Y.
        Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
        The severity of specific OFs and overall clinical course of the syndrome are therefore clinically more relevant than the number or type of OFs.
        • Weiss E.
        • Saner F.
        • Asrani S.K.
        • Biancofiore G.
        • Blasi A.
        • Lerut J.
        • et al.
        When is a critically ill cirrhotic patient too sick to transplant? Development of consensus criteria by a multidisciplinary panel of 35 international experts.
        Three OFs are of major importance in the decision to delay or deny LT: respiratory, circulatory and metabolic failures. Moderate or severe respiratory failure (PaO2/FiO2 <150), refractory shock (noradrenaline >0.6–1.0 μg/kg/min or need for 2 vasopressors) and high arterial lactate levels (>9 mmol/L) should be considered major contraindications to proceed to LT as they are indicative of poor post-LT outcome.
        • Abdallah M.A.
        • Waleed M.
        • Bell M.G.
        • Nelson M.
        • Wong R.
        • Sundaram V.
        • et al.
        Systematic review with meta-analysis: liver transplant provides survival benefit in patients with acute on chronic liver failure.
        ,
        • Artru F.
        • Louvet A.
        • Ruiz I.
        • Levesque E.
        • Labreuche J.
        • Ursic-Bedoya J.
        • et al.
        Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3.
        ,
        • Weiss E.
        • Saner F.
        • Asrani S.K.
        • Biancofiore G.
        • Blasi A.
        • Lerut J.
        • et al.
        When is a critically ill cirrhotic patient too sick to transplant? Development of consensus criteria by a multidisciplinary panel of 35 international experts.
      • 2.
        LT should also be delayed or denied in the following circumstances
        • Abdallah M.A.
        • Waleed M.
        • Bell M.G.
        • Nelson M.
        • Wong R.
        • Sundaram V.
        • et al.
        Systematic review with meta-analysis: liver transplant provides survival benefit in patients with acute on chronic liver failure.
        ,
        • Artru F.
        • Louvet A.
        • Ruiz I.
        • Levesque E.
        • Labreuche J.
        • Ursic-Bedoya J.
        • et al.
        Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3.
        ,
        • Weiss E.
        • Saner F.
        • Asrani S.K.
        • Biancofiore G.
        • Blasi A.
        • Lerut J.
        • et al.
        When is a critically ill cirrhotic patient too sick to transplant? Development of consensus criteria by a multidisciplinary panel of 35 international experts.
        :
        • a.
          active gastrointestinal bleeding
        • b.
          severe pancreatitis and
        • c.
          suspicion of ongoing infection identified by presence of one of the following; (i) persistent fever >39ºC, (ii) leukopenia <0.5 g/L, (iii) appropriate antibiotic therapy of severe infections for <72 h, (iv) infection by pandrug-resistant bacteria and invasive fungal infections.
      • 3.
        Poor functional status and severe frailty (clinical frailty score >6) are also considered major contraindications for LT in ACLF. Additionally, severe sarcopenia and advanced age (>60 years old in the UK recommendations but needs to be considered on a case-by-case basis) are factors with major prognostic impact in critical care and should be considered as potential contraindications for LT in this setting.
        • Weiss E.
        • Saner F.
        • Asrani S.K.
        • Biancofiore G.
        • Blasi A.
        • Lerut J.
        • et al.
        When is a critically ill cirrhotic patient too sick to transplant? Development of consensus criteria by a multidisciplinary panel of 35 international experts.
      Finally, there is firm evidence that early LT is crucial to ensure the success of LT in patients with ACLF-3. The median time between listing and LT in studies reporting good outcomes in these patients ranged from 4 to 8 days, indicating that the window for LT in this setting is extremely narrow and that the decision to transplant must be taken rapidly.
      • Burra P.
      • Samuel D.
      • Sundaram V.
      • Duvoux C.
      • Petrowsky H.
      • Terrault N.
      • et al.
      Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation.
      ,
      • Sundaram V.
      • Jalan R.
      • Wu T.
      • Volk M.L.
      • Asrani S.K.
      • Klein A.S.
      • et al.
      Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
      ,
      • Abdallah M.A.
      • Waleed M.
      • Bell M.G.
      • Nelson M.
      • Wong R.
      • Sundaram V.
      • et al.
      Systematic review with meta-analysis: liver transplant provides survival benefit in patients with acute on chronic liver failure.
      ,
      • Thuluvath P.J.
      • Thuluvath A.J.
      • Hanish S.
      • Savva Y.
      Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
      After initial stabilisation and adequate control of infections, patients should have a quick assessment for LT. Standard evaluations will delay LT in frail patients at very high risk of new infections, myopathy and further OFs.
      Further prospective studies will objectively define the limits and contraindications for LT in ACLF-3 and, therefore, when transplantation should be considered futile or inappropriate in the era of the “sickest first “policy.

      Unanswered questions and the CHANCE study

      All published data on LT in ACLF comes from relatively small mono/multicentric cohort studies
      • Burra P.
      • Samuel D.
      • Sundaram V.
      • Duvoux C.
      • Petrowsky H.
      • Terrault N.
      • et al.
      Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation.
      ,
      • Belli L.S.
      • Duvoux C.
      • Artzner T.
      • Bernal W.
      • Conti S.
      • Cortesi P.A.
      • et al.
      Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS).
      ,
      • Karvellas C.J.
      • Lescot T.
      • Goldberg P.
      • Sharpe M.D.
      • Ronco J.J.
      • Renner E.L.
      • et al.
      Liver transplantation in the critically ill: a multicenter Canadian retrospective cohort study.
      ,
      • Abdallah M.A.
      • Waleed M.
      • Bell M.G.
      • Nelson M.
      • Wong R.
      • Sundaram V.
      • et al.
      Systematic review with meta-analysis: liver transplant provides survival benefit in patients with acute on chronic liver failure.
      or large national databases (UNOS)
      • Sundaram V.
      • Jalan R.
      • Wu T.
      • Volk M.L.
      • Asrani S.K.
      • Klein A.S.
      • et al.
      Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
      ,
      • Thuluvath P.J.
      • Thuluvath A.J.
      • Hanish S.
      • Savva Y.
      Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
      with several limitations: potential misclassification of organ failures and ACLF definition, selection bias, absence of detailed data about clinical trajectory, infectious complications, management, donor organ selection, short and long-term post-LT outcomes. Numerous unanswered questions remain in specific populations of patients with severe ACLF (ACLF-2 or 3) such as:
      • lack of intention-to-treat results of LT from the time of wait listing
      • detailed information about waiting list outcomes
      • best organ allocation system for this specific population
      • objective limits to define futile LT
      • ideal timing
      • characteristics of donor organ to ensure acceptable post-LT outcomes
      • long-term post-LT survival rates and impact on the quality of life
      • resource utilisation of performing LT and
      • the overall results across the different continents
      The answers to these questions are an urgent medical need to ensure ‘justice’ among LT candidates. Indeed, due to the scarcity of liver donors, we need a strategy of rationing where the success of LT will be maximised among different indications with the best equilibrium to limit mortality on the waiting list.
      In this context, the EASL-CLIF Consortium in collaboration with the International Liver Transplantation Society (ILTS) and the European Liver and Intestine Transplant Association (ELITA) have designed a prospective non-interventional observational global study (CHANCE, liver transplantation in patients with CirrHosis and severe ACLF: iNdications and outcome, ClinicalTrials.gov: NCT04613921). The primary objective of the study is to compare 1-year graft and patient survival rates after LT in patients with ACLF-2 or 3 at the time of LT with patients with decompensated cirrhosis without ACLF 2-3 and transplant-free survival of patients with ACLF-2 or 3 not listed for LT. The project plans to recruit 3,000 patients of whom 2,000 will have ACLF-2 or 3 (based on the EASL-CLIF definition) and will be registered on the LT waiting list around the world (Fig. 3). With detailed follow-up on the waiting list and during the first year after LT and precise graft and surgical data collection, we expect to accumulate sufficient data to answer the challenging questions described above. Up-to-date validated scores/questionnaires will be used to assess the impact of frailty and sarcopenia on post-LT outcomes and the effect of LT on quality of life (Fig. 4).
      Figure thumbnail gr4
      Fig. 4Design of the CHANCE study.
      The patients with ACLF-2 or 3 referred to the LT team will be screened and included in either the group of transplant candidates at the time of listing (n = 2,000) or in the group of non-listed patients (n = 500). Patients with decompensated cirrhosis without ACLF-2 or 3 but MELD ≥20 listed for transplantation (n = 500) will also be included as a control group. The follow-up will end 12 months (M12) either after LT or M12 after decision of non-listing. ClinicalTrials.gov: NCT04613921. ACLF, acute-on-chronic liver failure; MELD, model for end-stage liver disease; LT, liver transplantation.
      The international nature of the CHANCE study will allow for deep assessments of the potential impact of different precipitating factors of ACLF (e.g. alcohol vs. HBV flare), different types of LT (deceased donor LT vs. living donor LT) and different regional/national allocation systems on transplant outcomes. Beside these clinical objectives, the CHANCE study aims to build a repository of biological samples to explore new biomarkers to predict prognosis on the waiting list and after LT, and mechanisms of liver and extrahepatic organ recovery after LT. The recruitment of patients is expected to start in the second half of 2021.

      Conclusions

      We believe that the current organ allocation system disadvantages patients with ACLF and clear evidence of transplant benefit for these patients is overwhelming. We therefore suggest that the widespread inequity of access to transplantation should be addressed urgently, with ACLF patients prioritised in organ allocation systems. The recent recommendations from the SETH to consider prioritisation and UK LT regulators implementing strategies to prioritise organs for patients with ACLF in a special category allows other countries to follow their lead.

      Abbreviations

      ACLF, acute-on-chronic liver failure; EASL-CLIF, European Association for the Study of the Liver-Chronic Liver Failure; ICU, intensive care unit; LT, liver transplantation; MELD, model for end-stage liver disease; OF, organ failure; SETH, Spanish Society of Liver Transplantation; UNOS, United Network for Organ Sharing.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      All 4 of the authors (RJ, TG, JF and WB) contributed equally to the manuscript including Concept and Design; Drafting of the manuscript; Revising and Reviewing the final version.

      Conflict of interest

      Rajiv Jalan has research collaborations with Yaqrit and Takeda. Rajiv Jalan is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Ltd, a spin out company from University College London. Thierry Gustot is on the advisory board for Promethera Biosciences, GoLiver Therapeutics and Abbvie and has a Grant from Gilead. Javier Fernandez has received grant and research support from Grifols, speaker honorarium from MSD and educational grant from Pfizer. William Bernal is on the advisory board, Versantis AG and has Research funding from Synapse Research Institute.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

      References

        • Arroyo V.
        • Moreau R.
        • Jalan R.
        Acute-on-Chronic liver failure.
        N Engl J Med. 2020; 382: 2137-2145
        • Moreau R.
        • Jalan R.
        • Gines P.
        • Pavesi M.
        • Angeli P.
        • Cordoba J.
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144: 1426-1437
        • Burra P.
        • Samuel D.
        • Sundaram V.
        • Duvoux C.
        • Petrowsky H.
        • Terrault N.
        • et al.
        Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation.
        J Hepatol. 2021; 75: S178-S190
        • Belli L.S.
        • Duvoux C.
        • Artzner T.
        • Bernal W.
        • Conti S.
        • Cortesi P.A.
        • et al.
        Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS).
        J Hepatol. 2021; 75: 610-622
        • Rodríguez-Perálvarez M.
        • Miguel Ángel Gómez-Bravo M.A.
        • Sánchez-Antolín G.
        • De la Rosa G.
        • Bilbao I.
        • Colmenero J.
        • et al.
        Expanding indications of liver transplantation in Spain: consensus statement and recommendations by the Spanish society of liver transplantation.
        Transplantation. 2021; 105: 602-607
        • Jalan R.
        • Saliba F.
        • Pavesi M.
        • Amoros A.
        • Moreau R.
        • Ginès P.
        • et al.
        Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
        J Hepatol. 2014; 61: 1038-1047
        • Hernaez R.
        • Liu Y.
        • Kramer J.R.
        • Rana A.
        • El-Serag H.B.
        • Kanwal F.
        Model for end-stage liver disease-sodium underestimates 90-day mortality risk in patients with acute-on-chronic liver failure.
        J Hepatol. 2020; 73: 1425-1433
        • Sundaram V.
        • Jalan R.
        • Wu T.
        • Volk M.L.
        • Asrani S.K.
        • Klein A.S.
        • et al.
        Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
        Gastroenterology. 2019; 156: 1381-1391
        • Sundaram V.
        • Shah P.
        • Mahmud N.
        • Lindenmeyer C.C.
        • Klein A.S.
        • Wong R.J.
        • et al.
        Patients with severe acute-on-chronic liver failure are disadvantaged by model for end-stage liver disease-based organ allocation policy.
        Aliment Pharmacol Ther. 2020; 52: 1204-1213
        • Abdallah M.A.
        • Kuo Y.F.
        • Asrani S.
        • Wong R.J.
        • Ahmed A.
        • Kwo P.
        • et al.
        Validating a novel score based on interaction between ACLF grade and MELD score to predict waitlist mortality.
        J Hepatol. 2021; 74: 1355-1361
        • Mahmud N.
        • Kaplan D.E.
        • Taddei T.H.
        • Goldberg D.S.
        Incidence and mortality of acute-on-chronic liver failure using two definitions in patients with compensated cirrhosis.
        Hepatology. 2019; 69: 2150-2163
        • Li F.
        • Thuluvath P.J.
        EASL-CLIF criteria perform better than NACSELD to diagnose and prognosticate ACLF.
        J Hepatol. 2021; (in press)
        • Bernal W.
        Improving outcomes for transplantation of critically ill patients with cirrhosis?.
        Clin Liver Dis. 2017; 10: 25-28
        • Moon D.B.
        • Lee S.G.
        • Kang W.H.
        • Song G.W.
        • Jung D.H.
        • Park G.C.
        • et al.
        Adult living donor liver transplantation for acute-on-chronic liver failure in high-model for end-stage liver disease score patients.
        Am J Transplant. 2017; 17: 1833-1842
        • Karvellas C.J.
        • Lescot T.
        • Goldberg P.
        • Sharpe M.D.
        • Ronco J.J.
        • Renner E.L.
        • et al.
        Liver transplantation in the critically ill: a multicenter Canadian retrospective cohort study.
        Crit Care. 2013; 17: R28
        • Abdallah M.A.
        • Waleed M.
        • Bell M.G.
        • Nelson M.
        • Wong R.
        • Sundaram V.
        • et al.
        Systematic review with meta-analysis: liver transplant provides survival benefit in patients with acute on chronic liver failure.
        Aliment Pharmacol Ther. 2020; 52: 222-232
        • Artru F.
        • Louvet A.
        • Ruiz I.
        • Levesque E.
        • Labreuche J.
        • Ursic-Bedoya J.
        • et al.
        Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3.
        J Hepatol. 2017; 67: 708-771
        • Linecker M.
        • Krones T.
        • Berg T.
        • Niemann C.U.
        • Steadman R.H.
        • Dutkowski P.
        • et al.
        Potentially inappropriate liver transplantation in the era of the "sickest first" policy. A search for the upper limits.
        J Hepatol. 2018; 68: 798-813
        • Thuluvath P.J.
        • Thuluvath A.J.
        • Hanish S.
        • Savva Y.
        Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
        J Hepatol. 2018; 69: 047-56
        • Weiss E.
        • Saner F.
        • Asrani S.K.
        • Biancofiore G.
        • Blasi A.
        • Lerut J.
        • et al.
        When is a critically ill cirrhotic patient too sick to transplant? Development of consensus criteria by a multidisciplinary panel of 35 international experts.
        Transplantation. 2021; 105: 561-568