Advertisement

Potentially inappropriate liver transplantation in the era of the “sickest first” policy – A search for the upper limits

Published:November 10, 2017DOI:https://doi.org/10.1016/j.jhep.2017.11.008

      Summary

      Liver transplantation has emerged as a highly efficient treatment for a variety of acute and chronic liver diseases. However, organ shortage is becoming an increasing problem globally, limiting the applicability of liver transplantation. In addition, potential recipients are becoming sicker, thereby increasing the risk of losing the graft during transplantation or in the initial postoperative period after liver transplantation (three months). This trend is challenging the model for end-stage liver disease allocation system, where the sickest candidates are prioritised and no delisting criteria are given. The weighting of the deontological demand for “equity”, trying to save every patient, regardless of the overall utility; and “efficiency”, rooted in utilitarianism, trying to save as many patients as possible and increase the overall quality of life of patients facing the same problem, has to be reconsidered. In this article we are aiming to overcome the widespread concept of futility in liver transplantation, providing a definition of potentially inappropriate liver transplantation and giving guidance on situations where it is best not to proceed with liver transplantation, to decrease the mortality rate in the first three months after transplantation. We propose “absolute” and “relative” conditions, where early post-transplant mortality is highly probable, which are not usually captured in risk scores predicting post-transplant survival. Withholding liver transplantation for listed patients in cases where liver transplant is not deemed clearly futile, but is potentially inappropriate, is a far-reaching decision. Until now, this decision had to be discussed extensively on an individual basis, applying explicit communication and conflict resolution processes, since the model for end-stage liver disease score and most international allocation systems do not include explicit delisting criteria to support a fair delisting process. More work is needed to better identify cases where transplantation is potentially inappropriate and to integrate and discuss these delisting criteria in allocation systems, following a societal debate on what we owe to all liver transplant candidates.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Starzl T.E.
        • Marchioro T.L.
        • Vonkaulla K.N.
        • Hermann G.
        • Brittain R.S.
        • Waddell W.R.
        Homotransplantation of the Liver in Humans.
        Surg Gynecol Obstet. 1963; 117: 659-676
      1. http://www.who.int/transplantation/gkt/statistics/en/ AM, 2016.

        • Kamath P.S.
        • Wiesner R.H.
        • Malinchoc M.
        • Kremers W.
        • Therneau T.M.
        • Kosberg C.L.
        • et al.
        A model to predict survival in patients with end-stage liver disease.
        Hepatology. 2001; 33: 464-470
        • Wiesner R.H.
        • McDiarmid S.V.
        • Kamath P.S.
        • Edwards E.B.
        • Malinchoc M.
        • Kremers W.K.
        • et al.
        MELD and PELD: application of survival models to liver allocation.
        Liver Transpl. 2001; 7: 567-580
        • Freeman R.B.
        • Wiesner R.H.
        • Edwards E.
        • Harper A.
        • Merion R.
        • Wolfe R.
        • et al.
        Results of the first year of the new liver allocation plan.
        Liver Transpl. 2004; 10: 7-15
        • Wiesner R.
        • Edwards E.
        • Freeman R.
        • Harper A.
        • Kim R.
        • Kamath P.
        • et al.
        Model for end-stage liver disease (MELD) and allocation of donor livers.
        Gastroenterology. 2003; 124: 91-96
        • Freeman R.B.
        • Wiesner R.H.
        • Edwards E.
        • Harper A.
        • Merion R.
        • Wolfe R.
        • et al.
        Results of the first year of the new liver allocation plan.
        Liver Transpl. 2004; 10: 7-15
        • Cholongitas E.
        • Burroughs A.K.
        The evolution in the prioritization for liver transplantation.
        Ann Gastroenterol. 2012; 25: 6-13
        • Burns J.P.
        • Truog R.D.
        Futility: a concept in evolution.
        Chest. 2007; 132: 1987-1993
        • Nair-Collins M.
        Laying futility to rest.
        J Med Philos. 2015; 40: 554-583
        • Bosslet G.T.
        • Pope T.M.
        • Rubenfeld G.D.
        • Lo B.
        • Truog R.D.
        • Rushton C.H.
        • et al.
        An official ATS/AACN/ACCP/ESICM/SCCM policy statement: responding to requests for potentially inappropriate treatments in intensive care units.
        Am J Respir Crit Care Med. 2015; 191: 1318-1330
      2. SJ Reiser ADaWC. Hippocrates, “The Art”. In: Historical perspectives and contemporary concerns. MIT Press, Massachusetts; 1977:6.

        • Flannery L.
        • Ramjan L.M.
        • Peters K.
        End-of-life decisions in the Intensive Care Unit (ICU) - Exploring the experiences of ICU nurses and doctors - A critical literature review.
        Aust Crit Care. 2016; 29: 97-103
        • Schneiderman L.J.
        • Jecker N.S.
        • Jonsen A.R.
        Medical futility: its meaning and ethical implications.
        Ann Intern Med. 1990; 112: 949-954
        • Krones T.
        • Monteverde S.
        Medical futility from the Swiss perspective.
        in: Bagheri A. Medical futility: A cross-national study. Imperial College Press, London2013: 205-226
        • Savulescu J.
        Is it in Charlie Gard's best interest to die?.
        Lancet. 2017; 389: 1868-1869
        • Gatter Jr., R.A.
        • Moskop J.C.
        From futility to triage.
        J Med Philos. 1995; 20: 191-205
        • Schneiderman L.J.
        • Jecker N.S.
        • Jonsen A.R.
        Medical futility: response to critiques.
        Ann Intern Med. 1996; 125: 669-674
        • Brody B.A.
        • Halevy A.
        Is futility a futile concept?.
        J Med Philos. 1995; 20: 123-144
        • Petrowsky 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: 1186-1194
        • Biggins S.W.
        • Bambha K.
        MELD-based liver allocation: who is underserved?.
        Semin Liver Dis. 2006; 26: 211-220
        • Bernal W.
        • Hyyrylainen A.
        • Gera A.
        • Audimoolam V.K.
        • McPhail M.J.
        • Auzinger G.
        • et al.
        Lessons from look-back in acute liver failure? A single centre experience of 3300 patients.
        J Hepatol. 2013; 59: 74-80
        • Murphy D.J.
        • Finucane T.E.
        New do-not-resuscitate policies. A first step in cost control.
        Arch Intern Med. 1993; 153: 1641-1648
        • Truog R.D.
        • Brett A.S.
        • Frader J.
        The problem with futility.
        N Engl J Med. 1992; 326: 1560-1564
        • Cookson R.
        • McCabe C.
        • Tsuchiya A.
        Public healthcare resource allocation and the Rule of Rescue.
        J Med Ethics. 2008; 34: 540-544
        • Rana 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: 2537-2546
        • Rana A.
        • Jie T.
        • Porubsky M.
        • Habib S.
        • Rilo H.
        • Kaplan B.
        • et al.
        The survival outcomes following liver transplantation (SOFT) score: validation with contemporaneous data and stratification of high-risk cohorts.
        Clin Transplant. 2013; 27: 627-632
        • Lao O.B.
        • Dick A.A.
        • Healey P.J.
        • Perkins J.D.
        • Reyes J.D.
        Identifying the futile pediatric liver re-transplant in the PELD era.
        Pediatr Transplant. 2010; 14: 1019-1029
        • Osborne M.
        • Evans T.W.
        Allocation of resources in intensive care: a transatlantic perspective.
        Lancet. 1994; 343: 778-780
        • Collins E.G.
        • Pfiefer P.B.
        • Mozdzierz G.
        Decisions not to transplant: futility or rationing.
        J Cardiovasc Nurs. 1995; 9: 23-29
        • Feng S.
        • Goodrich N.P.
        • Bragg-Gresham J.L.
        • Dykstra D.M.
        • Punch J.D.
        • DebRoy M.A.
        • et al.
        Characteristics associated with liver graft failure: the concept of a donor risk index.
        Am J Transplant. 2006; 6: 783-790
        • Braat A.E.
        • Blok J.J.
        • Putter H.
        • Adam R.
        • Burroughs A.K.
        • Rahmel A.O.
        • et al.
        The Eurotransplant donor risk index in liver transplantation: ET-DRI.
        Am J Transplant. 2012; 12: 2789-2796
        • Dutkowski P.
        • Schlegel A.
        • Slankamenac K.
        • Oberkofler C.E.
        • Adam R.
        • Burroughs A.K.
        • et al.
        The use of fatty liver grafts in modern allocation systems: risk assessment by the balance of risk (BAR) score.
        Ann Surg. 2012; 256 ([Discussion 868–869]): 861-868
        • Halldorson J.B.
        • Bakthavatsalam R.
        • Fix O.
        • Reyes J.D.
        • Perkins J.D.
        D-MELD, a simple predictor of post liver transplant mortality for optimization of donor/recipient matching.
        Am J Transplant. 2009; 9: 318-326
        • Merion R.M.
        • Wolfe R.A.
        • Dykstra D.M.
        • Leichtman A.B.
        • Gillespie B.
        • Held P.J.
        Longitudinal assessment of mortality risk among candidates for liver transplantation.
        Liver Transpl. 2003; 9: 12-18
        • Schaubel D.E.
        • Guidinger M.K.
        • Biggins S.W.
        • Kalbfleisch J.D.
        • Pomfret E.A.
        • Sharma P.
        • et al.
        Survival benefit-based deceased-donor liver allocation.
        Am J Transplant. 2009; 9: 970-981
        • Panchal H.J.
        • Durinka J.B.
        • Patterson J.
        • Karipineni F.
        • Ashburn S.
        • Siskind E.
        • et al.
        Survival outcomes in liver transplant recipients with Model for End-stage Liver Disease scores of 40 or higher: a decade-long experience.
        HPB. 2015; 17: 1074-1084
        • Freeman Jr., R.B.
        • Wiesner R.H.
        • Roberts J.P.
        • McDiarmid S.
        • Dykstra D.M.
        • Merion R.M.
        Improving liver allocation: MELD and PELD.
        Am J Transplant. 2004; 4: 114-131
        • Malinchoc M.
        • Kamath P.S.
        • Gordon F.D.
        • Peine C.J.
        • Rank J.
        • ter Borg P.C.
        A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.
        Hepatology. 2000; 31: 864-871
        • Said A.
        • Williams J.
        • Holden J.
        • Remington P.
        • Gangnon R.
        • Musat A.
        • et al.
        Model for end stage liver disease score predicts mortality across a broad spectrum of liver disease.
        J Hepatol. 2004; 40: 897-903
        • Merion R.M.
        • Schaubel D.E.
        • Dykstra D.M.
        • Freeman R.B.
        • Port F.K.
        • Wolfe R.A.
        The survival benefit of liver transplantation.
        Am J Transplant. 2005; 5: 307-313
        • Merion R.M.
        When is a patient too well and when is a patient too sick for a liver transplant?.
        Liver Transpl. 2004; 10: S69-73
        • McDiarmid S.V.
        • Anand R.
        • Lindblad A.S.
        • Principal I.
        Institutions of the Studies of Pediatric Liver Transplantation Research G. Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation.
        Transplantation. 2002; 74: 173-181
      3. www.unos.org/wp-content/uploads/unos/Liver_patient.pdf; accessed October 16.

        • Nekrasov V.
        • Matsuoka L.
        • Rauf M.
        • Kaur N.
        • Cao S.
        • Groshen S.
        • et al.
        National Outcomes of Liver Transplantation for MELD >/= 40: The Impact of Share 35.
        Am J Transplant. 2016; 16: 2912-2924
        • Edwards E.B.
        • Harper A.M.
        • Hirose R.
        • Mulligan D.C.
        The impact of broader regional sharing of livers: 2-year results of “Share 35”.
        Liver Transpl. 2016; 22: 399-409
        • Brennan C.W.
        • Daly B.J.
        Patient acuity: a concept analysis.
        J Adv Nurs. 2009; 65: 1114-1126
        • Lee W.M.
        • Stravitz R.T.
        • Larson A.M.
        Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011.
        Hepatology. 2012; 55: 965-967
        • Lee W.M.
        Etiologies of acute liver failure.
        Semin Liver Dis. 2008; 28: 142-152
        • Oketani M.
        • Ido A.
        • Tsubouchi H.
        Changing etiologies and outcomes of acute liver failure: A perspective from Japan.
        J Gastroenterol Hepatol. 2011; 26: 65-71
        • Mendizabal M.
        • Marciano S.
        • Videla M.G.
        • Anders M.
        • Zerega A.
        • Balderramo D.C.
        • et al.
        Changing etiologies and outcomes of acute liver failure: perspectives from 6 transplant centers in Argentina.
        Liver Transpl. 2014; 20: 483-489
        • Adam R.
        • Karam V.
        • Delvart V.
        • O'Grady J.
        • Mirza D.
        • Klempnauer J.
        • et al.
        Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR).
        J Hepatol. 2012; 57: 675-688
        • Mendizabal M.
        • Silva M.O.
        Liver transplantation in acute liver failure: A challenging scenario.
        World J Gastroenterol. 2016; 22: 1523-1531
        • Freeman Jr., R.B.
        • Steffick D.E.
        • Guidinger M.K.
        • Farmer D.G.
        • Berg C.L.
        • Merion R.M.
        Liver and intestine transplantation in the United States, 1997–2006.
        Am J Transplant. 2008; 8: 958-976
        • Germani G.
        • Theocharidou E.
        • Adam R.
        • Karam V.
        • Wendon J.
        • O'Grady J.
        • et al.
        Liver transplantation for acute liver failure in Europe: outcomes over 20 years from the ELTR database.
        J Hepatol. 2012; 57: 288-296
        • O'Grady J.G.
        • Alexander G.J.
        • Hayllar K.M.
        • Williams R.
        Early indicators of prognosis in fulminant hepatic failure.
        Gastroenterology. 1989; 97: 439-445
        • Bernuau J.
        • Goudeau A.
        • Poynard T.
        • Dubois F.
        • Lesage G.
        • Yvonnet B.
        • et al.
        Multivariate analysis of prognostic factors in fulminant hepatitis B.
        Hepatology. 1986; 6: 648-651
        • Barshes N.R.
        • Lee T.C.
        • Balkrishnan R.
        • Karpen S.J.
        • Carter B.A.
        • Goss J.A.
        Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.
        Transplantation. 2006; 81: 195-201
        • Bernal W.
        • Cross T.J.
        • Auzinger G.
        • Sizer E.
        • Heneghan M.A.
        • Bowles M.
        • et al.
        Outcome after wait-listing for emergency liver transplantation in acute liver failure: a single centre experience.
        J Hepatol. 2009; 50: 306-313
        • Butterworth R.F.
        The concept of “the inflamed brain” in acute liver failure: mechanisms and new therapeutic opportunities.
        Metab Brain Dis. 2016; 31: 1283-1287
        • Bertino G.
        • Privitera G.
        • Purrello F.
        • Demma S.
        • Crisafulli E.
        • Spadaro L.
        • et al.
        Emerging hepatic syndromes: pathophysiology, diagnosis and treatment.
        Intern Emerg Med. 2016; 11: 905-916
        • Bonnel A.R.
        • Bunchorntavakul C.
        • Reddy K.R.
        Immune dysfunction and infections in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2011; 9: 727-738
        • Busk T.M.
        • Bendtsen F.
        • Moller S.
        Hepatorenal syndrome in cirrhosis: diagnostic, pathophysiological, and therapeutic aspects.
        Expert Rev Gastroenterol Hepatol. 2016; 16: 1-9
        • Newby D.E.
        • Hayes P.C.
        Hyperdynamic circulation in liver cirrhosis: not peripheral vasodilatation but 'splanchnic steal'.
        QJM. 2002; 95: 827-830
        • Wong F.
        • Bernardi M.
        • Balk R.
        • Christman B.
        • Moreau R.
        • Garcia-Tsao G.
        • et al.
        Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
        Gut. 2005; 54: 718-725
        • Krowka M.J.
        • Mandell M.S.
        • Ramsay M.A.
        • Kawut S.M.
        • Fallon M.B.
        • Manzarbeitia C.
        • et al.
        Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database.
        Liver Transpl. 2004; 10: 174-182
        • Marik P.E.
        • Gayowski T.
        • Starzl T.E.
        • Hepatic Cortisol Research and Adrenal Pathophysiology Study Group
        The hepatoadrenal syndrome: a common yet unrecognized clinical condition.
        Crit Care Med. 2005; 33: 1254-1259
        • Anastasiadis S.N.
        • Giouleme O.I.
        • Germanidis G.S.
        • Vasiliadis T.G.
        Relative adrenal insufficiency in cirrhotic patients.
        Clin Med Insights Gastroenterol. 2015; 8: 13-17
        • Moller S.
        • Henriksen J.H.
        • Bendtsen F.
        Extrahepatic complications to cirrhosis and portal hypertension: haemodynamic and homeostatic aspects.
        World J Gastroenterol. 2014; 20: 15499-15517
        • Nadim M.K.
        • Durand F.
        • Kellum J.A.
        • Levitsky J.
        • O'Leary J.G.
        • Karvellas C.J.
        • et al.
        Management of the critically ill patient with cirrhosis: A multidisciplinary perspective.
        J Hepatol. 2016; 64: 717-735
        • Surani S.R.
        • Mendez Y.
        • Anjum H.
        • Varon J.
        Pulmonary complications of hepatic diseases.
        World J Gastroenterol. 2016; 22: 6008-6015
        • Rodriquez-Roisin R.
        • Krowka M.J.
        • Herve P.
        • Fallon M.B.
        Committee ERSTF-PS. Highlights of the ERS Task Force on pulmonary-hepatic vascular disorders (PHD).
        J Hepatol. 2005; 42: 924-927
        • Arguedas M.R.
        • Singh H.
        • Faulk D.K.
        • Fallon M.B.
        Utility of pulse oximetry screening for hepatopulmonary syndrome.
        Clin Gastroenterol Hepatol. 2007; 5: 749-754
        • Swanson K.L.
        • Wiesner R.H.
        • Krowka M.J.
        Natural history of hepatopulmonary syndrome: Impact of liver transplantation.
        Hepatology. 2005; 41: 1122-1129
        • Krowka M.J.
        • Wiseman G.A.
        • Burnett O.L.
        • Spivey J.R.
        • Therneau T.
        • Porayko M.K.
        • et al.
        Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99m)Tc MAA lung scanning.
        Chest. 2000; 118: 615-624
        • Schenk P.
        • Schoniger-Hekele M.
        • Fuhrmann V.
        • Madl C.
        • Silberhumer G.
        • Muller C.
        Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis.
        Gastroenterology. 2003; 125: 1042-1052
        • Fallon M.B.
        • Krowka M.J.
        • Brown R.S.
        • Trotter J.F.
        • Zacks S.
        • Roberts K.E.
        • et al.
        Impact of hepatopulmonary syndrome on quality of life and survival in liver transplant candidates.
        Gastroenterology. 2008; 135: 1168-1175
        • Gupta S.
        • Castel H.
        • Rao R.V.
        • Picard M.
        • Lilly L.
        • Faughnan M.E.
        • et al.
        Improved survival after liver transplantation in patients with hepatopulmonary syndrome.
        Am J Transplant. 2010; 10: 354-363
        • Iyer V.N.
        • Swanson K.L.
        • Cartin-Ceba R.
        • Dierkhising R.A.
        • Rosen C.B.
        • Heimbach J.K.
        • et al.
        Hepatopulmonary syndrome: favorable outcomes in the MELD exception era.
        Hepatology. 2013; 57: 2427-2435
        • Schiffer E.
        • Majno P.
        • Mentha G.
        • Giostra E.
        • Burri H.
        • Klopfenstein C.E.
        • et al.
        Hepatopulmonary syndrome increases the postoperative mortality rate following liver transplantation: a prospective study in 90 patients.
        Am J Transplant. 2006; 6: 1430-1437
        • Herve P.
        • Le Pavec J.
        • Sztrymf B.
        • Decante B.
        • Savale L.
        • Sitbon O.
        Pulmonary vascular abnormalities in cirrhosis.
        Best Pract Res Clin Gastroenterol. 2007; 21: 141-159
        • Krowka M.J.
        • Swanson K.L.
        • Frantz R.P.
        • McGoon M.D.
        • Wiesner R.H.
        Portopulmonary hypertension: Results from a 10-year screening algorithm.
        Hepatology. 2006; 44: 1502-1510
        • Rodriguez-Roisin R.
        • Krowka M.J.
        • Herve P.
        • Fallon M.B.
        Committee ERSTFP-HVDS. Pulmonary-Hepatic vascular Disorders (PHD).
        Eur Respir J. 2004; 24: 861-880
        • Humbert M.
        • Sitbon O.
        • Chaouat A.
        • Bertocchi M.
        • Habib G.
        • Gressin V.
        • et al.
        Pulmonary arterial hypertension in France: results from a national registry.
        Am J Respir Crit Care Med. 2006; 173: 1023-1030
        • de Mel S.
        • Chen Y.
        • Gopalakrishnan S.K.
        • Ooi M.
        • Teo C.
        • Tan D.
        • et al.
        The Singapore Myeloma Study Group Consensus Guidelines for the management of patients with multiple myeloma.
        Singapore Med J. 2017; 58: 55-71
        • Krowka M.J.
        • Heimbach J.K.
        Portopulmonary hypertension and liver transplantation: A duo in question.
        Liver Transpl. 2016; 22: 1633-1634
        • Swanson K.L.
        • Wiesner R.H.
        • Nyberg S.L.
        • Rosen C.B.
        • Krowka M.J.
        Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups.
        Am J Transplant. 2008; 8: 2445-2453
        • Krowka M.J.
        • Fallon M.B.
        • Kawut S.M.
        • Fuhrmann V.
        • Heimbach J.K.
        • Ramsay M.A.
        • et al.
        International liver transplant society practice guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension.
        Transplantation. 2016; 100: 1440-1452
        • DeMartino E.S.
        • Cartin-Ceba R.
        • Findlay J.Y.
        • Heimbach J.K.
        • Krowka M.J.
        Frequency and outcomes of patients with increased mean pulmonary artery pressure at the time of liver transplantation.
        Transplantation. 2017; 101: 101-106
        • 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 ([1437 e1421-1429]): 1426-1437
        • Ohnishi H.
        • Sugihara J.
        • Moriwaki H.
        • Muto Y.
        Acute-on-chronic liver failure.
        Ryoikibetsu shokogun shirizu. 1995; 7: 217-219
        • Sarin S.K.
        • Kumar A.
        • Almeida J.A.
        • Chawla Y.K.
        • Fan S.T.
        • Garg H.
        • et al.
        Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL).
        Hepatol Int. 2009; 3: 269-282
        • Olson J.C.
        • Kamath P.S.
        Acute-on-chronic liver failure: concept, natural history, and prognosis.
        Curr Opin Crit Care. 2011; 17: 165-169
        • Jalan R.
        • Gines P.
        • Olson J.C.
        • Mookerjee R.P.
        • Moreau R.
        • Garcia-Tsao G.
        • et al.
        Acute-on chronic liver failure.
        J Hepatol. 2012; 57: 1336-1348
        • Wehler M.
        • Kokoska J.
        • Reulbach U.
        • Hahn E.G.
        • Strauss R.
        Short-term prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems.
        Hepatology. 2001; 34: 255-261
        • Das V.
        • Boelle P.Y.
        • Galbois A.
        • Guidet B.
        • Maury E.
        • Carbonell N.
        • et al.
        Cirrhotic patients in the medical intensive care unit: early prognosis and long-term survival.
        Crit Care Med. 2010; 38: 2108-2116
        • Levesque E.
        • Hoti E.
        • Azoulay D.
        • Ichai P.
        • Habouchi H.
        • Castaing D.
        • et al.
        Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit.
        J Hepatol. 2012; 56: 95-102
        • Vincent J.L.
        • Moreno R.
        • Takala J.
        • Willatts S.
        • De Mendonca A.
        • Bruining H.
        • et al.
        The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the European society of intensive care medicine.
        Intensive Care Med. 1996; 22: 707-710
        • Jalan R.
        • Saliba F.
        • Pavesi M.
        • Amoros A.
        • Moreau R.
        • Gines 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
        • Shi Y.
        • Yang Y.
        • Hu Y.
        • Wu W.
        • Yang Q.
        • Zheng M.
        • et al.
        Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
        Hepatology. 2015; 62: 232-242
        • 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: 243-252
        • 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 Transpl. 2013; 19: 879-886
        • 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: 708-715
        • Levesque E.
        • Winter A.
        • Noorah Z.
        • Daures 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: 684-693
        • Ling Q.
        • Xu X.
        • Wei Q.
        • Liu X.
        • Guo H.
        • Zhuang L.
        • et al.
        Downgrading MELD improves the outcomes after liver transplantation in patients with acute-on-chronic hepatitis B liver failure.
        PLoS One. 2012; 7: e30322
        • Chan A.C.
        • Fan S.T.
        • Lo C.M.
        • Liu C.L.
        • Chan S.C.
        • Ng K.K.
        • et al.
        Liver transplantation for acute-on-chronic liver failure.
        Hepatol Int. 2009; 3: 571-581
        • Sutherland A.I.
        • IJzermans J.N.
        • Forsythe J.L.
        • Dor F.J.
        Kidney and liver transplantation in the elderly.
        Br J Surg. 2016; 103: e62-72
        • Kim W.R.
        • Lake J.R.
        • Smith J.M.
        • Skeans M.A.
        • Schladt D.P.
        • Edwards E.B.
        • et al.
        OPTN/SRTR 2013 Annual Data Report: liver.
        Am J Transplant. 2015; 15: 1-28
        • Collins B.H.
        • Pirsch J.D.
        • Becker Y.T.
        • Hanaway M.J.
        • Van der Werf W.J.
        • D'Alessandro A.M.
        • et al.
        Long-term results of liver transplantation in older patients 60 years of age and older.
        Transplantation. 2000; 70: 780-783
        • Aloia T.A.
        • Knight R.
        • Gaber A.O.
        • Ghobrial R.M.
        • Goss J.A.
        Analysis of liver transplant outcomes for United Network for Organ Sharing recipients 60 years old or older identifies multiple model for end-stage liver disease-independent prognostic factors.
        Liver Transpl. 2010; 16: 950-959
        • Schwartz J.J.
        • Pappas L.
        • Thiesset H.F.
        • Vargas G.
        • Sorensen J.B.
        • Kim R.D.
        • et al.
        Liver transplantation in septuagenarians receiving model for end-stage liver disease exception points for hepatocellular carcinoma: the national experience.
        Liver Transpl. 2012; 18: 423-433
        • Malinis M.F.
        • Chen S.
        • Allore H.G.
        • Quagliarello V.J.
        Outcomes among older adult liver transplantation recipients in the model of end stage liver disease (MELD) era.
        Ann Transplant. 2014; 19: 478-487
        • VanWagner L.B.
        • Lapin B.
        • Levitsky J.
        • Wilkins J.T.
        • Abecassis M.M.
        • Skaro A.I.
        • et al.
        High early cardiovascular mortality after liver transplantation.
        Liver Transpl. 2014; 20: 1306-1316
        • Tovikkai C.
        • Charman S.C.
        • Praseedom R.K.
        • Gimson A.E.
        • van der Meulen J.
        Time-varying impact of comorbidities on mortality after liver transplantation: a national cohort study using linked clinical and administrative data.
        BMJ Open. 2015; 5: e006971
        • Johnston S.D.
        • Morris J.K.
        • Cramb R.
        • Gunson B.K.
        • Neuberger J.
        Cardiovascular morbidity and mortality after orthotopic liver transplantation.
        Transplantation. 2002; 73: 901-906
        • Malik M.U.
        • Russell S.D.
        • Pustavoitau A.
        • Chacko M.
        • Cosar A.M.
        • Thompson C.B.
        • et al.
        The predictors of post-transplant coronary events among liver transplant recipients.
        Hepatol Int. 2016; 10: 974-982
        • Yong C.M.
        • Sharma M.
        • Ochoa V.
        • Abnousi F.
        • Roberts J.
        • Bass N.M.
        • et al.
        Multivessel coronary artery disease predicts mortality, length of stay, and pressor requirements after liver transplantation.
        Liver Transpl. 2010; 16: 1242-1248
        • VanWagner L.B.
        • Ning H.
        • Whitsett M.
        • Levitsky J.
        • Uttal S.
        • Wilkins J.T.
        • et al.
        A point-based prediction model for cardiovascular risk in orthotopic liver transplantation: The CAR-OLT score.
        Hepatology. 2017; 66: 1968-1979
        • Watt K.D.
        • Coss E.
        • Pedersen R.A.
        • Dierkhising R.
        • Heimbach J.K.
        • Charlton M.R.
        Pretransplant serum troponin levels are highly predictive of patient and graft survival following liver transplantation.
        Liver Transplant. 2010; 16: 990-998
        • Alvarez J.
        • Mei X.
        • Daily M.
        • Shah M.
        • Grigorian A.
        • Berger J.
        Tipping the scales: liver transplant outcomes of the super obese.
        J Gastrointest Surg. 2016; 20: 1628-1635
        • Dick A.A.
        • Spitzer A.L.
        • Seifert C.F.
        • Deckert A.
        • Carithers Jr., R.L.
        • Reyes J.D.
        • et al.
        Liver transplantation at the extremes of the body mass index.
        Liver Transpl. 2009; 15: 968-977
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • MacKenzie C.R.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chron Dis. 1987; 40: 373-383
        • Volk M.L.
        • Hernandez J.C.
        • Lok A.S.
        • Marrero J.A.
        Modified Charlson comorbidity index for predicting survival after liver transplantation.
        Liver Transpl. 2007; 13: 1515-1520
        • Lai J.C.
        Defining the threshold for too sick for transplant.
        Curr Opin Organ Transplant. 2016; 21: 127-132
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • Newman A.B.
        • Hirsch C.
        • Gottdiener J.
        • et al.
        Frailty in older adults: evidence for a phenotype.
        J Gerontol A Biol Sci Med Sci. 2001; 56: M146-156
        • Lai J.C.
        • Feng S.
        • Terrault N.A.
        • Lizaola B.
        • Hayssen H.
        • Covinsky K.
        Frailty predicts waitlist mortality in liver transplant candidates.
        Am J Transplant. 2014; 14: 1870-1879
        • Carey E.J.
        • Steidley D.E.
        • Aqel B.A.
        • Byrne T.J.
        • Mekeel K.L.
        • Rakela J.
        • et al.
        Six-minute walk distance predicts mortality in liver transplant candidates.
        Liver Transpl. 2010; 16: 1373-1378
        • Tapper E.B.
        • Finkelstein D.
        • Mittleman M.A.
        • Piatkowski G.
        • Lai M.
        Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis.
        Hepatology. 2015; 62: 584-590
        • Lai J.C.
        • Covinsky K.E.
        • Dodge J.L.
        • Boscardin W.J.
        • Segev D.L.
        • Roberts J.P.
        • et al.
        Development of a novel frailty index to predict mortality in patients with end-stage liver disease.
        Hepatology. 2017; 66: 564-574
        • Ghaferi A.A.
        • Birkmeyer J.D.
        • Dimick J.B.
        Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
        Ann Surg. 2009; 250: 1029-1034
        • Underwood P.W.
        • Cron D.C.
        • Terjimanian M.N.
        • Wang S.C.
        • Englesbe M.J.
        • Waits S.A.
        Sarcopenia and failure to rescue following liver transplantation.
        Clin Transplant. 2015; 29: 1076-1080
        • Dutkowski P.
        • Linecker M.
        • DeOliveira M.L.
        • Mullhaupt B.
        • Clavien P.A.
        Challenges to liver transplantation and strategies to improve outcomes.
        Gastroenterology. 2015; 148: 307-323
        • Nocito A.
        • El-Badry A.M.
        • Clavien P.A.
        When is steatosis too much for transplantation?.
        J Hepatol. 2006; 45: 494-499
        • Spitzer A.L.
        • Lao O.B.
        • Dick A.A.
        • Bakthavatsalam R.
        • Halldorson J.B.
        • Yeh M.M.
        • et al.
        The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment.
        Liver Transpl. 2010; 16: 874-884
        • Busuttil R.W.
        • Tanaka K.
        The utility of marginal donors in liver transplantation.
        Liver Transpl. 2003; 9: 651-663
        • Taner C.B.
        • Bulatao I.G.
        • Perry D.K.
        • Sibulesky L.
        • Willingham D.L.
        • Kramer D.J.
        • et al.
        Asystole to cross-clamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors.
        Transpl Int. 2012; 25: 838-846
        • Mathur A.K.
        • Heimbach J.
        • Steffick D.E.
        • Sonnenday C.J.
        • Goodrich N.P.
        • Merion R.M.
        Donation after cardiac death liver transplantation: predictors of outcome.
        Am J Transplant. 2010; 10: 2512-2519
        • Peralta C.
        • Jimenez-Castro M.B.
        • Gracia-Sancho J.
        Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu.
        J Hepatol. 2013; 59: 1094-1106
        • Dutkowski P.
        • Oberkofler C.E.
        • Slankamenac K.
        • Puhan M.A.
        • Schadde E.
        • Mullhaupt B.
        • et al.
        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]): 745-753
        • Charpentier K.P.
        • Mavanur A.
        Removing patients from the liver transplant wait list: A survey of US liver transplant programs.
        Liver Transpl. 2008; 14: 303-307
        • Reddy K.R.
        • O'Leary J.G.
        • Kamath P.S.
        • Fallon M.B.
        • Biggins S.W.
        • Wong F.
        • et al.
        High risk of delisting or death in liver transplant candidates following infections: Results from the North American Consortium for the Study of End-Stage Liver Disease.
        Liver Transpl. 2015; 21: 881-888
        • Bremmer D.N.
        • Garavaglia J.M.
        • Shields R.K.
        Spontaneous fungal peritonitis: a devastating complication of cirrhosis.
        Mycoses. 2015; 58: 387-393
        • Lahmer T.
        • Brandl A.
        • Rasch S.
        • Schmid R.M.
        • Huber W.
        Fungal peritonitis: underestimated disease in critically Ill patients with liver cirrhosis and spontaneous peritonitis.
        PLoS One. 2016; 11: e0158389
        • Mounzer R.
        • Malik S.M.
        • Nasr J.
        • Madani B.
        • Devera M.E.
        • Ahmad J.
        Spontaneous bacterial peritonitis before liver transplantation does not affect patient survival.
        Clin Gastroenterol Hepatol. 2010; 8 ([e621]): 623-628
        • Fagiuoli S.
        • Colli A.
        • Bruno R.
        • Craxi A.
        • Gaeta G.B.
        • Grossi P.
        • et al.
        Management of infections pre- and post-liver transplantation: report of an AISF consensus conference.
        J Hepatol. 2014; 60: 1075-1089
        • Kalafateli M.
        • Mantzoukis K.
        • Choi Yau Y.
        • Mohammad A.O.
        • Arora S.
        • Rodrigues S.
        • et al.
        Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score.
        J Cachexia Sarcopenia Muscle. 2017; 8: 113-121
        • Pham P.T.
        • Lunsford K.E.
        • Bunnapradist S.
        • Danovitch G.M.
        Simultaneous liver-kidney transplantation or liver transplantation alone for patients in need of liver transplantation with renal dysfunction.
        Curr Opin Organ Transplant. 2016; 21: 194-200
        • Lunsford K.E.
        • Bodzin A.S.
        • Markovic D.
        • Zarrinpar A.
        • Kaldas F.M.
        • Gritsch H.A.
        • et al.
        Avoiding futility in simultaneous liver-kidney transplantation: analysis of 331 consecutive patients listed for dual organ replacement.
        Ann Surg. 2016;