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Frontiers in Liver Transplantation| Volume 60, ISSUE 3, P663-670, March 2014

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Timing and benefit of liver transplantation in acute liver failure

  • John O’Grady
    Correspondence
    Corresponding author. Address: Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Fax: +44 207 346 3167.
    Affiliations
    Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, UK
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Open AccessPublished:November 07, 2013DOI:https://doi.org/10.1016/j.jhep.2013.10.024

      Summary

      The case for using emergency liver transplantation in acute liver failure was made two decades ago by a series of single centre experiences. The development of models identifying a poor prognosis assisted the selection of patients for liver transplantation but none of these delivers both high sensitivity and specificity for prediction of death. Enhanced sensitivity favours the individual patient while enhanced specificity targets the pool of organs available at those who will derive greatest benefit. The non-transplant survival rates have improved considerably for certain cohorts of patients and these prognostic models have not been adjusted to reflect these changes. The presumption of transplant benefit can no longer be taken as established in paracetamol-related acute liver failure and a policy review is appropriate. In other scenarios, such as seronegative hepatitis and the phenotype of sub-acute liver failure, spontaneous survival rates remain low and the basis for liver transplantation remains sound. Outcomes after liver transplantation are improving but are not yet comparable to elective transplantation. The understanding of factors associated with failure after liver transplantation is improving but accurate definition of futility has not yet been attained.

      Keywords

      Historical background

      Acute liver failure (ALF) is the most dramatic clinical situation in which liver transplantation is performed with previously-well patients facing likely death within days or weeks being salvaged by surgical intervention. A National Institutes of Health consensus conference on the indications for liver transplantation in 1983 considered ALF from a largely theoretical perspective [
      • National Institutes of Health
      National institutes of health consensus development statement: liver transplantation, June 20–23 1983.
      ]. By the mid-1990s, the feasibility of liver transplantation had been established by a series of single centre experiences pointing to a significant success rate but with outcomes that were not as good as for elective transplantation and with concerns about failure of recovery of neurological function [
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      Liver transplantation for fulminant hepatocellular failure.
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      A 7-year experience of severe acetaminophen induced hepatotoxicity [1987–1993].
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      • Anselmo D.M.
      • Ghobrial R.M.
      • Yersiz H.
      • McDiarmid S.V.
      • Cao C.
      • et al.
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      ]. The efficacy of liver transplantation for ALF was never established in a randomised controlled trial despite a call in 1990 for a ‘controlled trial between specialist units… to establish the role of emergency hepatic transplantation in patients with fulminant hepatic failure’ [
      • Chapman R.W.
      • Forman D.
      • Peto R.
      • Smallwood R.
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      ]. Instead, liver transplantation became an accepted treatment for patients with ALF and was credited by some as being the only effective treatment for this condition. ALF now accounts for around 8% of liver transplant activity in Europe and the US [
      • 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.
      ,
      • Freeman 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.
      ].
      A number of prognostic models for ALF were described while the early experience with liver transplantation was evolving and these appeared to identify a population of patients with a high likelihood of mortality at a point in the disease that was still compatible with survival after transplantation [
      • O’Grady J.G.
      • Alexander G.J.
      • Hallyar K.M.
      • Williams R.
      Early indicators of prognosis in fulminant hepatic failure.
      ,
      • Bernuau J.
      • Gordeau A.
      • Poynard T.
      • Dubois F.
      • Lesage G.
      • Yvonnet B.
      • et al.
      Multivariate analysis of prognostic factors in fulminant hepatitis B.
      ]. The understanding of prognosis in ALF evolved to recognise the contribution of four key determinants:
      • aetiology
      • rate of progression of the disease
      • age of the patient
      • laboratory markers of disease severity.
      The prognosis was also recognised as being somewhat counter-intuitive. The highest rate of spontaneous survival was seen in patients with the most-dramatic clinical syndrome (hyperacute liver failure), greatest derangement of coagulation and highest incidence of cerebral oedema. The worst survival was seen in patients with slowly evolving disease (sub-acute liver failure) with modest derangement of coagulation parameters and relatively little risk of cerebral oedema [
      • O’Grady J.G.
      • Schalm S.W.
      • Williams R.
      Acute liver failure: redefining the syndromes.
      ].
      The practice of liver transplantation for ALF over the next two decades was largely a process of refinement rather than major advances. Numerous studies addressed prognosis in ALF and from these a number of prognostic models emerged that were used to select patients for emergency liver transplantation (Table 1) [
      • O’Grady J.G.
      • Alexander G.J.
      • Hallyar K.M.
      • Williams R.
      Early indicators of prognosis in fulminant hepatic failure.
      ,
      • Bernuau J.
      • Gordeau A.
      • Poynard T.
      • Dubois F.
      • Lesage G.
      • Yvonnet B.
      • et al.
      Multivariate analysis of prognostic factors in fulminant hepatitis B.
      ,
      • Dhiman R.
      • Jain S.
      • Maheshwari U.
      • Bhalla A.
      • Sharma N.
      • Ahluwalia J.
      • et al.
      Early indicators of prognosis in fulminant hepatic failure: an assessment of the MELD and King’s College hospital criteria.
      ,
      • Yantorno S.E.
      • Kremers W.K.
      • Ruf A.E.
      • Trentadue J.J.
      • Podesta L.G.
      • Villamil F.G.
      MELD is superior to King’s College and Clichy’s criteria to assess prognosis in fulminant hepatic failure.
      ,
      • Schmidt L.E.
      • Larsen F.S.
      MELD score as a predictor of liver failure and death in patients with paracetamol-induced liver injury.
      ,
      • Zaman M.B.
      • Hoti E.
      • Qasim A.
      • Maguire D.
      • McCormick P.A.
      • Hegarty J.E.
      • et al.
      MELD score as a prognostic model for listing acute liver failure patients for liver transplantation.
      ,
      • Bechmann L.P.
      • Jochum C.
      • Kocabayoglu P.
      • Sowa J.-P.
      • Kassalik M.
      • Gieseler R.K.
      • et al.
      Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury.
      ,
      • Rutherford A.
      • King L.Y.
      • Hynan L.S.
      • Vedvyas C.
      • Lin W.
      • Lee W.M.
      • et al.
      Development of an accurate index for predicting outcomes of patients with acute liver failure.
      ,
      • Bernal W.
      • Donaldson N.
      • Wyncoll D.
      • Wendon J.
      Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study.
      ,
      • Schmidt L.E.
      • Larsen F.S.
      Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with paracetamol-induced acute liver failure.
      ,
      • Bates C.M.
      • Kochar N.
      • Davidson J.S.
      • Hayes P.C.
      • Simpson K.
      Blood lactate as a predictor of poor prognosis in acute liver failure in acetaminophen overdose.
      ,
      • Escudie L.
      • Francoz C.
      • Vinel J.-P.
      • Moucari R.
      • Cournot M.
      • Paradis V.
      • et al.
      Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation.
      ,
      • Ganzert M.
      • Felgenhauer N.
      • Ailker T.
      Indication of liver transplantation following amatoxin intoxication.
      ,
      • Taylor R.M.
      • Davern T.
      • Munoz S.
      • Han S.H.
      • McGuire B.
      • Larson A.
      • et al.
      Fulminant hepatitis A virus infection in the United States: incidence, prognosis and outcomes.
      ,
      • Westbrook R.J.
      • Yeoman A.D.
      • Joshi D.
      • Heaton N.D.
      • Quaglia A.
      • O’Grady J.G.
      • et al.
      Outcomes of severe pregnancy-related liver disease: refining the role of transplantation.
      ,
      • Hadem J.
      • Stiefel P.
      • Bahr M.J.
      • Tillmann H.L.
      • Klempnauer J.
      • Wedemeyer J.
      • et al.
      Prognostic implications of lactate, bilirubin and etiology in patients with acute liver failure.
      ,
      • Bismuth H.
      • Samuel D.
      • Castaing D.
      • Adam R.
      • Saliba F.
      • Johann M.
      • et al.
      Orthotopic liver transplantation in fulminant and sub-fulminant hepatitis.
      ,
      • Schiodt F.V.
      • Ostapowicz G.
      • Murray N.
      • Satyanarana R.
      • Zaman A.
      • Munoz S.
      • et al.
      Alpha-fetoprotein and prognosis in acute liver failure.
      ,
      • Squires R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ,
      • Schiodt F.V.
      • Rossaro L.
      • Stravitz R.T.
      • Shakil A.O.
      • Chung R.T.
      • Lee W.M.
      Gc-globulin and prognosis in acute liver failure.
      ,
      • Periera L.M.M.B.
      • Langley P.G.
      • Hayllar K.M.
      • Tredger J.M.
      • Williams R.
      Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators.
      ]. The application of these prognostic criteria created a tension between sensitivity and selectivity given that none of the models performed extremely well in both respects. Reduced sensitivity could lead to a failure to list a patient for liver transplantation who subsequently died, but reduced specificity carried a risk of ‘unnecessary transplantation’ in a patient who was likely to recover spontaneously. Subsequent modifications to selection criteria have tried to address these imbalances but to date the ideal selection model has not been described (Table 2).
      Table 1Determination of prognosis in acute liver failure.
      KCH, King’s College Hospital; MELD, Mayo End-stage Liver Disease.
      Table 2Modified criteria for listing for emergency liver transplantation in UK.
      Patients are listed under one category. Most categories are based on the King’s College Hospital criteria or data relating to lactate levels. Category 4 is a pragmatic modification intended to improve sensitivity of patient selection with paracetamol-related ALF. An appeals process evaluates patients not covered by these criteria but considered to be in need of liver transplantation.
      Over the past two decades ALF has undergone significant change that has not been consciously incorporated into the selection process for candidates for liver transplantation. In the King’s College Hospital experience of over 3,300 patients treated between 1973 and 2008, the hospital survival rate increased from 16.7% to 62.2% [
      • Bernal W.
      • Hyyryainen A.
      • Gera A.
      • Audimoolam V.K.
      • McPhail M.J.W.
      • Auzinger G.
      • et al.
      Lessons from look-back in acute liver failure? A single centre experience of 3,300 patients.
      ]. There was an improvement in survival after transplantation from 66% to 86% but transplant-free survival also increased to 48%. However, the improved survival without liver transplantation was not seen across the spectrum of the condition but was most apparent in paracetamol-related ALF, intermediate in other drug-induced cases, and absent in cases of indeterminate causation [
      • Bernal W.
      • Hyyryainen A.
      • Gera A.
      • Audimoolam V.K.
      • McPhail M.J.W.
      • Auzinger G.
      • et al.
      Lessons from look-back in acute liver failure? A single centre experience of 3,300 patients.
      ]. This analysis also demonstrated a dramatic fall in the incidence of cerebral oedema, traditionally the most feared complication of ALF, which fell from a peak of 76% to only 20% in the most recent cohort of patients.
      There has been considerable interest in ‘bridging’ mechanisms in ALF that might change the way liver transplantation is utilised. Liver support devices conceptually offered the potential to bridge patients with ALF to transplant-free survival but the key randomised controlled trials failed to demonstrate this capability for the condition in its entirety [
      • Demetriou A.A.
      • Brown R.S.
      • Busuttil R.W.
      • Fair J.
      • McGuire B.
      • Rosenthal P.
      • et al.
      Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.
      ,
      • Saliba F.
      • Camus C.
      • Durand F.
      • Mathurin O.
      • Letierce A.
      • Delafosse B.
      • et al.
      Albumin dialysis with a noncell artificial liver support device in patients with acute liver failure: a randomized, controlled trial.
      ]. However, subset analyses did suggest some benefit in patient populations that are broadly similar to those in which spontaneous survival rates have been increasing, e.g., paracetamol-induced ALF, defined viral aetiologies and hyperacute liver failure. These studies suggest a more achievable expectation for these devices is a role in bridging patients to transplantation. Auxiliary liver transplantation is an elegant concept to ultimately bridge patients to transplant-free survival and its feasibility has been established with near comparable short-term outcomes as compared with standard transplantation [
      • Girlanda R.
      • Vilca-Melendez H.
      • Srinivasan P.
      • Muiesan P.
      • O’Grady J.G.
      • Rela M.
      • et al.
      Immunosuppression withdrawal after auxiliary liver transplantation for acute liver failure.
      ,
      • Jaeck D.
      • Boudjema K.
      • Audet M.
      • Chenard-Neu M.P.
      • Simeoni U.
      • Meyer C.
      • et al.
      Auxiliary partial orthotopic liver transplantation [APOLT] in the treatment of acute liver failure.
      ,
      • Azoulay D.
      • Samuel D.
      • Ichai P.
      • Castaing D.
      • Saliba F.
      • Adam R.
      • et al.
      Auxiliary partial orthotopic vs. standard orthotopic whole liver transplantation for acute liver failure: a reappraisal from a single centre by case-control study.
      ]. However, the uptake of this transplant option has remained limited and it accounted for only 2% of activity in Europe between 1999 and 2009 [
      • 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.
      ].

      Listing for liver transplantation

      The principles underpinning the selection of patients with ALF are the accurate identification of those in need, as well as those who will benefit from liver transplantation. One starting point is to use a set of indicators of a poor prognosis that has gained local confidence with respect to utility and accuracy. In the UK, the listing criteria introduced in 2007 were largely a pragmatic modification of King’s College Hospital criteria to improve sensitivity in paracetamol-related ALF [
      • Neuberger J.
      • Gimson A.
      • Davies M.
      • Akyol M.
      • O’Grady J.
      • Burroughs A.
      • et al.
      Selection of patients for liver transplantation and allocation of donated livers in the UK.
      ]. An alternative opening gambit is to consider all patients with ALF as potential candidates for liver transplantation and make the decision as to whether or not to proceed when a donor organ becomes available.
      The perception of the performance of prognostic models is strongly influenced by whether positive or negative predictive accuracy is deemed to be the most important function. A preference for positive predictive accuracy favours the individual patient but the error rate translates to ‘unnecessary’ transplants. Preference for negative predictive accuracy minimises unnecessary transplants, ensuring that an excessive proportion of a limited resource is not diverted to the management of patients with ALF, but the error rate translates to potentially avoidable deaths.
      The King’s College Hospital criteria were described in 1989 and were the first to differentiate between paracetamol-induced and other aetiologies of ALF [
      • O’Grady J.G.
      • Alexander G.J.
      • Hallyar K.M.
      • Williams R.
      Early indicators of prognosis in fulminant hepatic failure.
      ]. These have been extensively used and are acknowledged to have high degree of specificity but have been criticised for lack of sensitivity. The criteria have been subjected to three meta-analyses that reported overall specificity of 82% for non-paracetamol aetiologies and 92–95% for paracetamol-related ALF, respectively [
      • McPhail M.J.W.
      • Wendon J.A.
      • Bernal W.
      Meta-analysis of performance of King’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure.
      ,
      • Craig D.G.N.
      • Ford A.C.
      • Hayes P.C.
      • Simpson K.J.
      Systematic review: prognostic tests of paracetamol-induced acute liver failure.
      ,
      • Bailey B.
      • Amre D.
      • Gaudreault P.
      Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review of the meta-analysis of prognostic criteria determining the need for liver transplantation.
      ]. In the non-paracetamol aetiologies, involving 1105 patients in 18 studies, the specificity increased to 93% in patients with more advanced encephalopathy and to 88% when the criteria were applied dynamically [
      • McPhail M.J.W.
      • Wendon J.A.
      • Bernal W.
      Meta-analysis of performance of King’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure.
      ]. The reduced sensitivity of the King’s College Hospital criteria for paracetamol-related ALF was apparent from the outset as there was a mortality of 17% in patients not meeting the criteria indicative of a poor outcome [
      • O’Grady J.G.
      • Alexander G.J.
      • Hallyar K.M.
      • Williams R.
      Early indicators of prognosis in fulminant hepatic failure.
      ]. In one meta-analysis of 1960 patients in 14 studies the sensitivity was considerably lower at 58% but, again, this was considered to have been reduced by the non-dynamic application of the criteria (often attributable to the use of prophylactic fresh frozen plasma) [
      • Craig D.G.N.
      • Ford A.C.
      • Hayes P.C.
      • Simpson K.J.
      Systematic review: prognostic tests of paracetamol-induced acute liver failure.
      ]. The second meta-analysis of paracetamol-induced ALF involved 8 studied and reported a specificity of 92% but a sensitivity of 69% [
      • Bailey B.
      • Amre D.
      • Gaudreault P.
      Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review of the meta-analysis of prognostic criteria determining the need for liver transplantation.
      ]. The overall sensitivity in the meta-analysis of non-paracetamol ALF was 68%, but this fell sharply from 85% prior to 1995 to 58% after 2005 and was lowest in centres not offering liver transplantation [
      • McPhail M.J.W.
      • Wendon J.A.
      • Bernal W.
      Meta-analysis of performance of King’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure.
      ].
      MELD scores, introduced and validated for use in prognostication in chronic liver disease, have been used in ALF and its utility is not surprising as the 3 components (bilirubin, INR, serum creatinine) figure strongly in other prognostic models. One of four studies found that MELD outperformed the King’s College Hospital criteria in selecting patients for transplantation [
      • Dhiman R.
      • Jain S.
      • Maheshwari U.
      • Bhalla A.
      • Sharma N.
      • Ahluwalia J.
      • et al.
      Early indicators of prognosis in fulminant hepatic failure: an assessment of the MELD and King’s College hospital criteria.
      ,
      • Yantorno S.E.
      • Kremers W.K.
      • Ruf A.E.
      • Trentadue J.J.
      • Podesta L.G.
      • Villamil F.G.
      MELD is superior to King’s College and Clichy’s criteria to assess prognosis in fulminant hepatic failure.
      ,
      • Schmidt L.E.
      • Larsen F.S.
      MELD score as a predictor of liver failure and death in patients with paracetamol-induced liver injury.
      ,
      • Zaman M.B.
      • Hoti E.
      • Qasim A.
      • Maguire D.
      • McCormick P.A.
      • Hegarty J.E.
      • et al.
      MELD score as a prognostic model for listing acute liver failure patients for liver transplantation.
      ]. A hybrid model based on a study in India combined classical early indicators of prognosis (age >50 years, jaundice to encephalopathy time greater than 7 days, prothrombin time >35 seconds and serum creatinine >1.5 mg/dl) with later clinical complications associated with a poor outcome (advanced encephalopathy and cerebral oedema) [
      • Dhiman R.
      • Jain S.
      • Maheshwari U.
      • Bhalla A.
      • Sharma N.
      • Ahluwalia J.
      • et al.
      Early indicators of prognosis in fulminant hepatic failure: an assessment of the MELD and King’s College hospital criteria.
      ]. A recently described prognostic model called the Acute Liver Failure Study Group Index combines three classes of variables – clinical (coma grade), laboratory (INR, serum bilirubin, phosphorus) and a marker of apoptosis (M30) [
      • Rutherford A.
      • King L.Y.
      • Hynan L.S.
      • Vedvyas C.
      • Lin W.
      • Lee W.M.
      • et al.
      Development of an accurate index for predicting outcomes of patients with acute liver failure.
      ]. This was considered to outperform both the King’s College Hospital criteria and MELD with an improved sensitivity of 86% but this was at the cost of a significantly reduced specificity of only 65%. A number of disease specific prognostic models (e.g., mushroom poisoning, pregnancy) have also been described but the parameters utilised are variations of the themes discussed above rather than radically different approaches [
      • Escudie L.
      • Francoz C.
      • Vinel J.-P.
      • Moucari R.
      • Cournot M.
      • Paradis V.
      • et al.
      Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation.
      ,
      • Ganzert M.
      • Felgenhauer N.
      • Ailker T.
      Indication of liver transplantation following amatoxin intoxication.
      ,
      • Taylor R.M.
      • Davern T.
      • Munoz S.
      • Han S.H.
      • McGuire B.
      • Larson A.
      • et al.
      Fulminant hepatitis A virus infection in the United States: incidence, prognosis and outcomes.
      ,
      • Westbrook R.J.
      • Yeoman A.D.
      • Joshi D.
      • Heaton N.D.
      • Quaglia A.
      • O’Grady J.G.
      • et al.
      Outcomes of severe pregnancy-related liver disease: refining the role of transplantation.
      ].

      Listing for transplantation in the absence of encephalopathy

      The presence of encephalopathy is an integral component of definition of ALF. However, it can be argued that in the some circumstances the severity of the liver injury is apparent from the extent of the coagulopathy and postponing a decision on listing for liver transplantation is wasting valuable time. However, a prospective study of 68 consecutive patients of mixed aetiologies with severe acute liver injury defined by a derangement of coagulation factors (INR >1.7) found that 88% did not progress to encephalopathy and survived without transplantation [
      • Elinav E.
      • Ben-Dov I.
      • Hai-Am E.
      • Ackerman Z.
      • Ofran Y.
      The predictive value of admission and follow-up factor V and VII levels in patients with acute hepatitis and coagulopathy.
      ]. The mean INRs were significantly elevated at 4.1 and 6.5 in survivors and non-survivors, respectively. In this study, serum bilirubin and Factor VII levels were better predictors of outcome than the INR [
      • Elinav E.
      • Ben-Dov I.
      • Hai-Am E.
      • Ackerman Z.
      • Ofran Y.
      The predictive value of admission and follow-up factor V and VII levels in patients with acute hepatitis and coagulopathy.
      ]. The dissociation between an isolated coagulopathy and a poor outcome is most dramatically seen in paracetamol-related ALF. In this condition a poor prognosis may be evident before the onset of encephalopathy, not on the basis of the coagulopathy but rather the severe acidosis that does not correct rapidly after fluid resuscitation [
      • O’Grady J.G.
      • Alexander G.J.
      • Hallyar K.M.
      • Williams R.
      Early indicators of prognosis in fulminant hepatic failure.
      ]. This is the only clinical situation where listing for emergency liver transplantation is permitted for adults in the UK in the absence of encephalopathy. Children under the age of two years are also not required to demonstrate encephalopathy prior to listing for liver transplantation.
      Adults with sub-acute liver failure represent a subgroup that arguably is disadvantaged by the need to demonstrable encephalopathy prior to being listed for liver transplantation. This more indolent variant of ALF typically manifests a less severe derangement of coagulation, often with INR <2, as the serum bilirubin rises and the disease progresses. Infection is a well recognised trigger for worsening encephalopathy in ALF [
      • Vaquero J.
      • Polson J.
      • Chung C.
      • Helenowski I.
      • Schiodt F.V.
      • Reisch J.
      • et al.
      Infection and the progression of hepatic encephalopathy in acute liver failure.
      ]. This observation is particularly pertinent in sub-acute liver failure because when the onset of encephalopathy is precipitated by infection this may delay eligibility for liver transplantation or contribute to poorer outcomes after transplantation. Earlier prediction of the poor outcome in sub-acute liver failure to facilitate more timely intervention is currently an un-met need. At present, the best pre-emptive information may be liver volume, as a poor prognosis is suggested by a progressive reduction as assessed by CT scanning. One study found a 97% death or transplantation rate when the liver volume was less than 1,000 ml and although this was not specific to sub-acute liver failure this is the clinical situation when this is most frequently encountered [
      • Shakil A.O.
      • Jones B.C.
      • Lee R.G.
      • Federle M.P.
      • Fung J.J.
      • Rakela J.
      Prognostic value of abdominal CT scanning and hepatic histopathology in patients with acute liver failure.
      ].

      Grafts and graft allocation

      Series from specialised centres in the US, continental Europe and the UK are consistent in showing that around 45–50% of patients admitted with ALF underwent liver transplantation. The UK figures exclude cases due to paracetamol as only 7–9% of these underwent transplantation. Organ allocation systems prioritise patients with ALF and as a consequence the majority of patients are transplanted within 4 days of being placed on the waiting list. Waiting times influence policy on the use of ABO mismatched grafts, steatotic livers, liver from non-heart-beating deceased donors and other sub-optimal potential grafts. European registry data show that the use of ABO incompatible liver grafts for emergency transplantation was associated with a more than doubling of the rate of graft loss at 3 months [
      • 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.
      ]. Living-related donation is well established in Asia where deceased-donor donation is limited, but it accounted for only 1.8% of transplant activity for ALF in Europe between 2004 and 2009 [
      • 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.
      ].
      Full-size organs are used in over 90% of transplants in adults. Auxiliary orthotopic transplantation peaked at 4% in Europe between 1994 and 1998 but fell to only 2% in 2004–2009 [
      • 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.
      ]. Auxiliary transplantation as a bridge to survival without the need for life-long immunosuppression is an exciting concept [
      • Girlanda R.
      • Vilca-Melendez H.
      • Srinivasan P.
      • Muiesan P.
      • O’Grady J.G.
      • Rela M.
      • et al.
      Immunosuppression withdrawal after auxiliary liver transplantation for acute liver failure.
      ,
      • Jaeck D.
      • Boudjema K.
      • Audet M.
      • Chenard-Neu M.P.
      • Simeoni U.
      • Meyer C.
      • et al.
      Auxiliary partial orthotopic liver transplantation [APOLT] in the treatment of acute liver failure.
      ,
      • Azoulay D.
      • Samuel D.
      • Ichai P.
      • Castaing D.
      • Saliba F.
      • Adam R.
      • et al.
      Auxiliary partial orthotopic vs. standard orthotopic whole liver transplantation for acute liver failure: a reappraisal from a single centre by case-control study.
      ]. The right lobe is typically replaced and the native left lobe is left in situ and regenerates in about 70% of cases within 1–3 years. The optimal indications are a combination of the ability of the native liver to regenerate to normal morphology and the absence of a clinical syndrome that would benefit from the total removal of the diseased liver (typically severe neurological complications or cardiovascular instability and high inotrope requirements).

      Determinants of outcome

      The one-year survival rates based on registry data were 74% in Europe between 1988 and 2000 and 82% in the US between 1999 and 2008 [
      • 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.
      ,
      • Freeman 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.
      ]. Survival rates improved considerably over time to 79% in the European database [
      • 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.
      ]. Better outcomes are reported by individual centres, e.g., the King’s College experience reported 86% post-transplant survival in the latest cohort (2004–2008) [
      • Bernal W.
      • Hyyryainen A.
      • Gera A.
      • Audimoolam V.K.
      • McPhail M.J.W.
      • Auzinger G.
      • et al.
      Lessons from look-back in acute liver failure? A single centre experience of 3,300 patients.
      ]. The overall results are not as good as for transplantation for other indications but compare very favourably to those seen in patients with chronic liver disease who were in intensive care or ventilated at the time of organ allocation (78.6% vs. 64.45 vs. 54.3%, respectively) [
      • Freeman 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.
      ]. It should be noted that patients receiving liver transplants for ALF are younger than their counterparts not receiving transplant and markedly younger than those undergoing elective transplantation. Survival rates decrease with age as illustrated by European data indicating that the one and five-year survival rates are 51% and 42%, respectively, for patients aged 60 years or older.
      Three large studies have attempted to define the characteristics associated with a poor outcome after liver transplantation for ALF (Table 3) [
      • 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.
      ,
      • Barshes N.R.
      • Lee T.C.
      • Balkrishnan R.
      • Karpen S.J.
      • Carter B.A.
      • Goss J.A.
      • et al.
      Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.
      ,
      • Bernal W.
      • Cross T.J.S.
      • 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.
      ]. Age was the only factor identified in all three studies with a discriminatory threshold of 45 years in one of these and 50 years in the other two. The higher mortality in those over 50 years has been attributed to a reduction in physiological reserve [
      • 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.
      ]. BMI >29 was identified in one of these studies, when it had a similar weighting as age over 50 years [
      • Barshes N.R.
      • Lee T.C.
      • Balkrishnan R.
      • Karpen S.J.
      • Carter B.A.
      • Goss J.A.
      • et al.
      Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.
      ]. None of the studies identified any specific characteristics of the severity of ALF pre-transplant (e.g., severity of coagulopathy) as predictive of outcome but three broad indicators were identified – renal dysfunction (creatinine >2 mg/dl), mechanical ventilation and inotrope dependence. In terms of defining futility, one study demonstrated a progressive reduction in survival with accumulation of risk factors from 81% in the low-risk patients (no risk factors) as compared with 42% in the highest-risk group (all four risk factors) [
      • Barshes N.R.
      • Lee T.C.
      • Balkrishnan R.
      • Karpen S.J.
      • Carter B.A.
      • Goss J.A.
      • et al.
      Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.
      ]. However, only 2% of patients fell into the highest risk group and therefore this has very limited capability to define futility.
      Table 3Determinants of outcome at 90 days after liver transplantation for acute liver failure.
      Data from two studies point to the contribution of graft characteristics to outcome, both in terms of ABO matching and quality of the graft. ABO identical matches accounted for 72% of transplants in the European experience while 22.4% were compatible and 5.6% incompatible, and the latter had significantly worse outcomes [
      • 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.
      ]. The European experience also showed reduced survival in recipients of split or reduced-sized organs. The impact of the quality of the matched graft was also demonstrated in a centre-based study and an equivalent level of increased risk was identified for donor age >60 years, non-ABO compatibility, steatosis and non-whole organs, which in total accounted for 22% of the grafts utilised but as high as 29% of the 2000–2004 cohort [
      • Neuberger J.
      • Gimson A.
      • Davies M.
      • Akyol M.
      • O’Grady J.
      • Burroughs A.
      • et al.
      Selection of patients for liver transplantation and allocation of donated livers in the UK.
      ]. The principle of compounding risk was demonstrated in both of these studies. In the King’s College Hospital series risk was more than doubled in ABO incompatible grafts that were either split or steatotic and quadrupled if a non-whole steatotic graft was used [
      • Neuberger J.
      • Gimson A.
      • Davies M.
      • Akyol M.
      • O’Grady J.
      • Burroughs A.
      • et al.
      Selection of patients for liver transplantation and allocation of donated livers in the UK.
      ]. The study based on the European registry data took a subpopulation already at increased risk (patients over the age of 50 years) and showed an additional escalating and compounding risk when the recipient was male, the donor was over the age of 60 years and the ABO-match was incompatible. High donor BMI, defined as greater than 35 and presumed to be a marker of steatosis, was the single most important determinant of early mortality in a series of 110 patients with seronegative ALF [
      • McPhail M.J.W.
      • Wendon J.A.
      • Bernal W.
      Meta-analysis of performance of King’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure.
      ]. Potentially these data could be used to influence the type of organ that should not be matched with individual patients.
      The cause of death or graft failure could potentially give insight into the gap in survival rates in ALF as compared with elective liver transplantation. There is evidence that the legacy of the neurological and infectious complications of ALF extend into the post-transplant period. The contribution from neurological causes to mortality rates was 13% in both the study based on UNOS data and the single centre study from the UK, which extended up to 2004 [
      • Barshes N.R.
      • Lee T.C.
      • Balkrishnan R.
      • Karpen S.J.
      • Carter B.A.
      • Goss J.A.
      • et al.
      Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.
      ,
      • Bernal W.
      • Cross T.J.S.
      • 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.
      ]. Since that time there has been a remarkable reduction in the incidence of cerebral oedema in the ALF population, which was coincident with an incremental increase in survival after transplantation to 86% [
      • Bernal W.
      • Hyyryainen A.
      • Gera A.
      • Audimoolam V.K.
      • McPhail M.J.W.
      • Auzinger G.
      • et al.
      Lessons from look-back in acute liver failure? A single centre experience of 3,300 patients.
      ]. The ETLR and UNOS data attribute death to infection in 18–24% of cases with an additional 5.6% linked to fungal infection in the UNOS study [
      • 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.
      ,
      • Barshes N.R.
      • Lee T.C.
      • Balkrishnan R.
      • Karpen S.J.
      • Carter B.A.
      • Goss J.A.
      • et al.
      Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.
      ]. These data emphasise the importance of robust policies for prevention, early diagnosis and treatment of infection in ALF patients who are potential candidates for liver transplantation. Early referral to specialist centres has also been nominated as one of the most important contributors to improved outcomes in ALF and this should be particularly true for patients managed with liver transplantation [
      • Bernal W.
      • Hyyryainen A.
      • Gera A.
      • Audimoolam V.K.
      • McPhail M.J.W.
      • Auzinger G.
      • et al.
      Lessons from look-back in acute liver failure? A single centre experience of 3,300 patients.
      ].

      Transplant benefit

      The original premise supporting the empirical adoption of emergency liver transplantation in ALF holds strongest for subgroups of patients with an aetiological category of indeterminate aetiology/seronegative hepatitis and a phenotypic category of sub-acute liver failure [
      • Wigg A.J.
      • Gunson B.K.
      • Mutimer D.J.
      Outcomes following liver transplantation for seronegative acute liver failure: experience during a 12-year period with more than 100 patients.
      ]. The spontaneous survival in these patients does not exceed 20% and is showing little sign of improvement. The improvement in survival for seronegative hepatitis in the King’s College Hospital from 4.2% pre-1979 to 67.6% in 2004–2008 was almost entirely due to liver transplantation as 88% of the survivors received grafts [
      • Bernal W.
      • Hyyryainen A.
      • Gera A.
      • Audimoolam V.K.
      • McPhail M.J.W.
      • Auzinger G.
      • et al.
      Lessons from look-back in acute liver failure? A single centre experience of 3,300 patients.
      ]. However, at the other end of the spectrum there is now some doubt about transplant benefit in patients with paracetamol-related ALF. This is because of a combination of reduced specificity in selection, higher mortality on the waiting list, lower survival rates after transplantation, and improved transplant-free survival rates.
      In the King’s College Hospital experience, the overall hospital survival rate between 1999 and 2008 for patients with paracetamol-related ALF and grade 3 or 4 encephalopathy was 66%. However, three-quarters of these patients did not receive liver transplants but still had a survival rate of 52% [
      • Bernal W.
      • Hyyryainen A.
      • Gera A.
      • Audimoolam V.K.
      • McPhail M.J.W.
      • Auzinger G.
      • et al.
      Lessons from look-back in acute liver failure? A single centre experience of 3,300 patients.
      ]. A prospective study of 275 paracetamol-related ALF carried out by the US Acute Liver Failure Group included 72 patients who were placed on the waiting list for transplantation [
      • Larson A.M.
      • Polson J.
      • Fontana R.J.
      • Davern T.J.
      • Lalani E.
      • Hynan L.S.
      • et al.
      Acetaminophen-induced acute liver failure: results of a United States multicenter prospective study.
      ]. The overall survival rate was 73%, increasing to only 78% after liver transplantation and, most notably, 59% in patients placed on the waiting-list for transplantation but did not undergo a transplant [
      • Craig D.G.N.
      • Ford A.C.
      • Hayes P.C.
      • Simpson K.J.
      Systematic review: prognostic tests of paracetamol-induced acute liver failure.
      ]. There was no statistically significant difference in survival after listing for transplantation based on whether or not a transplant took place but the sample size should be considered as reasonably small. Patients listed for liver transplantation with paracetamol-related ALF had a 2.5-fold higher risk of death on the waiting list as compared with other aetiologies [
      • Bernal W.
      • Cross T.J.S.
      • 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.
      ]. Finally, there was a 24% increase in risk of death after liver transplantation and most of this was due to suicide, trauma or non-adherence to immunosuppression regimens and 57% of these deaths occurred within 12 months of transplantation [
      • 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.
      ].
      These data do not readily endorse the practice of routinely offering liver transplantation in the setting of paracetamol-related ALF. If the call for randomised controlled trials made in the early 1990s was repeated today, the argument in support would carry considerable weight. Pragmatically, the design and conduct of randomised controlled trials in ALF would be extremely challenging, but in their absence, it is timely to undertake a policy review for this indication for emergency liver transplantation.
      Understanding benefit for an individual patient is clearly important. The clinical condition for a patient with ALF can change significantly even when the interval between listing for transplantation and the allocation of an organ is less than 72 hours. However, defining the point when the anticipated outcome no longer justifies the utilisation of the organ is both difficult from an evidence base and emotive. An outline of some indicators of when to proceed to transplantation, pause to consider, or abandon a plan to transplant is presented in Fig. 1. Although the risk stratification studies described above give some insight, these have not generated the practical clinical end-points to assist decision making. Objective evidence of brainstem injury with established fixed and fully dilated pupils should preclude liver transplantation. Active sepsis is an accepted contraindication to liver transplantation, but in the context of ALF this can be a difficult diagnosis to establish or refute. Confirmed systemic fungal infection is another specific contraindication to liver transplantation. Inotrope requirements are an effective surrogate marker of disease severity and both absolute levels and the rate of change in dosing requirements may indicate a poor outcome with transplantation. In general, a pragmatic case by case evaluation of the risk/benefit profile is employed and this should include consideration of the significant contribution the quality of the organ to outcomes.
      Figure thumbnail gr1
      Fig. 1Decision making triggers in patients with acute liver failure.

      Conclusions

      Liver transplantation has made an enormous contribution to the improved survival in ALF with over 60% of afflicted patients now expected to survive the illness. However, the application of liver transplantation has not changed significantly over the past 15–20 years despite changes in overall management. The ideal prognostic model remains illusive with currently used systems being relatively strong on confirming need in individual patients but weaker in identifying all those who would benefit from liver transplantation. Some patient subgroups, exemplified by seronegative hepatitis and Wilson’s disease, remain dependent on liver transplantation for enhanced prospects of survival. In others, particularly paracetamol-related ALF, the gap between transplant-free and post-transplant survival has narrowed dramatically and to the point that a fundamental review of the role of liver transplantation is indicated. Sub-acute liver failure is an example of a cohort that is sub-optimally served by liver transplant services, principally because of lack of progress in recognising the poor prognosis at an early stage. This subgroup is worthy of focus to define prognostic and management milestones that accurately reflect the natural history of this condition.

      Conflict of interest

      The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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