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Selected patients with acute-on-chronic liver failure grade 3 are not too sick to be considered for liver transplantation

2017; Elsevier BV; Volume: 67; Issue: 4 Linguagem: Inglês

10.1016/j.jhep.2017.07.017

1600-0641

Thierry Gustot, Banwari Agarwal,

Liver Disease Diagnosis and Treatment

The severe form of acute decompensation of cirrhosis accompanied by organ failure, is now more precisely recognized as acute-on-chronic liver failure (ACLF) syndrome, characterized by organ/system failures, defined by the chronic liver failure (CLIF)-sequential organ failure assessment (SOFA) score, and a 28-day mortality rate of at least 15% in a patient with an acute decompensation of cirrhosis.[1]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 (e1-e9): 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1373) Google Scholar Short- and mid-term prognoses of this syndrome are highly correlated to the number of organ failures (OFs), determining the grade of ACLF (from 1 [one OF] to 3 [three or more OFs]). An absence of improvement or resolution of these organ/system failures despite maximal supportive management, particularly by day 3 to day 7, is associated with a drastic outcomes, leading to futility of care, or consideration of options for salvage liver transplantation (LT).[2]Gustot T. Fernandez J. Garcia E. Morando F. Caraceni P. Alessandria C. et al.Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.Hepatology. 2015; 62: 243-252Crossref PubMed Scopus (305) Google Scholar Transplantation in the sicker recipients, particularly patients with cirrhosis requiring multi-organ support, is unquestionably associated with an improved survival benefit, but could result in less acceptable longer-term survival rates after LT. There seems to be equipoise in the literature regarding outcomes of urgent liver transplantation in patients with ACLF, with acceptable to excellent one-and five-year post-LT survival reported in some studies, but fairly poor outcomes in others. In a European prospective observational study (the CANONIC study), LT of ACLF patients (38% had ACLF grade 3 [ACLF-3]) was associated with an acceptable 1-year survival rate of 75% post-LT.[2]Gustot T. Fernandez J. Garcia E. Morando F. Caraceni P. Alessandria C. et al.Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.Hepatology. 2015; 62: 243-252Crossref PubMed Scopus (305) Google Scholar Similarly, excellent 1- and 5-year survival rates of 87% and 82%, respectively, were reported in a study from Austria of LT in 32 out of 144 ACLF patients.[3]Finkenstedt A. Nachbaur K. Zoller H. Joannidis M. Pratschke J. Graziadei I.W. et al.Acute-on-chronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list.Liver Transplant. 2013; 19: 879-886Crossref PubMed Scopus (107) Google Scholar A 1-year survival rate of 84% was reported in a Canadian analysis of LT in the critically ill patients with cirrhosis.[4]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 Lond Engl. 2013; 17: R28Crossref PubMed Scopus (40) Google Scholar In contrast, a small single center study reported that 13 ACLF-3 patients (all supported by mechanical ventilation and vasopressors, and 77% by renal replacement therapy) were transplanted, and a 1-year post-LT survival rate of 46% was observed.[5]Umgelter A. Lange K. Kornberg A. Büchler P. Friess H. Schmid R.M. Orthotopic liver transplantation in critically ill cirrhotic patients with multi-organ failure: a single-center experience.Transplant Proc. 2011; 43: 3762-3768Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Another recent, small, French retrospective study seemed to confirm these unfavourable results for ACLF-3 (1-year post-LT survival rate of 43%).[6]Levesque E. Winter A. Noorah Z. Daurès J.-P. Landais P. Feray C. et al.Impact of acute-on-chronic liver failure on 90-day mortality following a first liver transplantation.Liver Int. 2017; 37: 684-693Crossref PubMed Scopus (79) Google Scholar Some experiences show that patients transplanted with a model for end-stage liver disease (MELD) >30 or 35 have relatively low post-LT survival rates.7Weismüller T.J. Fikatas P. Schmidt J. Barreiros A.P. Otto G. Beckebaum S. et al.Multicentric evaluation of model for end-stage liver disease-based allocation and survival after liver transplantation in Germany–limitations of the "sickest first"-concept.Transpl Int. 2011; 24: 91-99Crossref PubMed Scopus (116) Google Scholar, 8Jacob M. Copley L.P. Lewsey J.D. Gimson A. Toogood G.J. Rela M. et al.Pretransplant MELD score and post liver transplantation survival in the UK and Ireland.Liver Transplant. 2004; 10: 903-907Crossref PubMed Scopus (108) Google Scholar In the context of scarcity of liver donors, the potential individual benefit of an LT must always be balanced against the need for the rationing of limited resources, taking into consideration the best possible outcome for the individual patient, but also maximization of the organ, in the interest of the wider community of patients on the waiting list.[9]Putignano A. Gustot T. New concepts in acute-on-chronic liver failure: Implications for liver transplantation.Liver Transplant. 2017; 23: 234-243Crossref PubMed Scopus (29) Google Scholar A consensus conference stated that patients should be offered LT if there is more than a 50% expectancy of 5-year survival post-LT and an acceptable quality of life.10Neuberger J. James O. Guidelines for selection of patients for liver transplantation in the era of donor-organ shortage.Lancet Lond Engl. 1999; 354: 1636-1639Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 11Olthoff K.M. Brown R.S. Delmonico F.L. Freeman R.B. McDiarmid S.V. Merion R.M. et al.Summary report of a national conference: Evolving concepts in liver allocation in the MELD and PELD era. December 8, 2003, Washington, DC, USA.Liver Transplant. 2003; 2004: A6-A22Google Scholar Currently, controversies remain about ACLF, particularly ACLF-3, as an indication for LT. In this month's issue of the Journal of Hepatology, Artru et al. reported the retrospective experiences regarding LT in patients with ACLF-3, from three French liver centers.[12]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: 708-715Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar In this study, 73 patients with ACLF-3 received LT with an outstanding 1-year-post-LT survival of 84%, suggesting that ACLF-3 per se should not be viewed as a contraindication for LT. Moreover, the classical scores to predict post-LT outcomes, such as pre-allocation survival outcomes following liver transplantation (P-SOFT), balance of risk (BAR) and UCLA futility risk score were inaccurate for prediction of post-LT mortality in transplanted patients with ACLF-3.13Rana A. Hardy M.A. Halazun K.J. Woodland D.C. Ratner L.E. Samstein B. et al.Survival outcomes following liver transplantation (SOFT) score: a novel method to predict patient survival following liver transplantation.Am J Transplant. 2008; 8: 2537-2546Crossref PubMed Scopus (271) Google Scholar, 14Dutkowski P. Oberkofler C.E. Slankamenac K. Puhan M.A. Schadde E. Müllhaupt B. Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the model for end-stage liver disease era.Ann Surg. 2011; 254 ([Discussion 753]): 745-753Crossref PubMed Scopus (145) Google Scholar, 15Petrowsky H. Rana A. Kaldas F.M. Sharma A. Hong J.C. Agopian V.G. et al.Liver transplantation in highest acuity recipients: identifying factors to avoid futility.Ann Surg. 2014; 259: 1186-1194Crossref PubMed Scopus (116) Google Scholar In their experience, active gastrointestinal bleeding, control of sepsis for less than 24 h, hemodynamic instability requiring a dose of norepinephrine >3 mg/h and severe lung impairment, defined by a ratio PaO2/FiO2 <150, were considered as absolute contraindications for LT. These limits could explain the better results observed in this study compared to previous studies.5Umgelter A. Lange K. Kornberg A. Büchler P. Friess H. Schmid R.M. Orthotopic liver transplantation in critically ill cirrhotic patients with multi-organ failure: a single-center experience.Transplant Proc. 2011; 43: 3762-3768Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 6Levesque E. Winter A. Noorah Z. Daurès J.-P. Landais P. Feray C. et al.Impact of acute-on-chronic liver failure on 90-day mortality following a first liver transplantation.Liver Int. 2017; 37: 684-693Crossref PubMed Scopus (79) Google Scholar Indeed, besides the presence/absence, the intensity of organ support (dosage of catecholamines, positive end-expiratory pressure, PaO2/FiO2), and/or its duration could drastically influence the success of LT. Some OFs, such as liver, coagulation and neurological failures might be associated with better post-LT outcomes than others (circulation, lung and renal failures). Finally, the optimization of the clinical situation in the pre-LT period (OF resolution and/or improvement) and the ideal timing of LT might be the crucial determinants of good post-LT outcomes. In this study, the complications after LT of ACLF-3 patients (observed in 100% of cases) were associated with longer intensive care unit (2–3 weeks) and hospital (2 months) stays after LT compared to patients without ACLF. Infectious, renal, pulmonary and neurological complications were the main events after LT. These complications induce longer hospitalization, mobilization of resources and extra-costs which we must be considered. Several unanswered questions remain in this challenging topic; which criteria for objective listing/de-listing of patients with ACLF-3 should be used? What is the ideal timing of LT? Is MELD-driven allocation of organs adequate for these patients to reduce the high waiting list mortality rate? The limits of this strategy need to be urgently addressed in a prospective way, to maintain a system of fair allocation of organs among different recipients, whilst not denying LT in those who are at high risk of death without transplantation. Progress in medicine is always riddled with some degree of uncertainty, but that should not deter us from objectively treating the emerging evidence and striving to search for more evidence to minimise this level of uncertainty. Currently, ACLF is not routinely considered an indication for priority organ allocation, but with evidence gradually mounting of a reasonable short and even long-term outcome post-LT, the option of salvage LT in severe grade ACLF must be given consideration in selected patients. The authors received no financial support in relation to the production of the manuscript. TG and BA have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details. TG and BA designed and wrote the manuscript, and approved the final version. Download .pdf (.09 MB) Help with pdf files Supplementary data Liver transplantation in the most severely ill cirrhotic patients: A multicenter study in acute-on-chronic liver failure grade 3Journal of HepatologyVol. 67Issue 4PreviewMost countries have adopted the policy of allocating livers to the most severely ill patients when selecting candidates for liver transplantation (LT) with decompensated cirrhosis. This involves providing grafts to patients with the most advanced liver disease. Indeed, these patients are at the greatest risk of dying on the waiting list and therefore benefit most from LT, confirmed by a hazard ratio for mortality that decreases along with the severity of liver failure.1 End-stage cirrhosis is associated with the failure of other organs (renal insufficiency, encephalopathy, coagulopathy etc.). Full-Text PDF