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EASL Clinical Practice Guidelines: Liver transplantation

  • European Association for the Study of the Liver
Published:November 17, 2015DOI:https://doi.org/10.1016/j.jhep.2015.10.006

      Introduction

      The first human orthotopic liver transplantation (LT) in Europe was performed by Sir Roy Calne in Cambridge in 1968 [
      • Calne R.Y.
      • Williams R.
      • Dawson J.L.
      • Ansell I.D.
      • Evans D.B.
      • Flute P.T.
      • et al.
      Liver transplantation in man. II. A report of two orthotopic liver transplants in adult recipients.
      ], only one year after the first successful human liver transplantation reported by Thomas Starzl in the United States [
      • Starzl T.E.
      • Marchioro T.L.
      • Porter K.A.
      • Brettschneider L.
      Homotransplantation of the liver.
      ]. Since then LT has evolved rapidly, becoming the standard therapy for acute and chronic liver failure of all aetiologies, with more than 80,000 procedures performed to date. Survival rates have improved significantly in the last 25 years, achieving rates of 96% and 71% at 1 and 10 years after LT respectively [
      • 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).
      ].
      This great success is mostly attributable to several advances such as the introduction of new immunosuppressive agents and preservation solutions, to the improvements in surgical techniques and to the early diagnosis and management of complications after LT [
      • Dutkowski P.
      • De Rougemont O.
      • Mullhaupt B.
      • Clavien P.A.
      Current and future trends in liver transplantation in Europe.
      ]. As a consequence of these achievements, indications for LT have been expanded resulting in a growing demand for transplantable grafts and in a dramatic organ shortage. Therefore, one of the main ongoing challenges the transplant community is facing is to expand the donor pool in order to minimize the rate of patient death on the waiting list [
      • Dutkowski P.
      • Linecker M.
      • DeOliveira M.L.
      • Mullhaupt B.
      • Clavien P.A.
      Challenges to liver transplantation and strategies to improve outcomes.
      ]. On the other hand, liver transplanted patients are surviving longer after the operation and long-term outcomes are becoming the main concern for clinicians, who have to deal with direct and indirect side effects of immunosuppressive therapy.
      This Clinical Practice Guideline (CPG) has been developed to assist physicians and other healthcare providers during the evaluation process of candidates for LT and to help them in the correct management of patients after LT.
      The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ]. The strength of recommendations reflects the quality of underlying evidence. The principles of the GRADE system have been enunciated. The GRADE system offers two grades of recommendation: strong (1) or weak (2) (Table 1). The CPGs thus consider the quality of evidence: the higher the quality of evidence, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted.
      Table 1GRADE system used in EASL Clinical Practice Guidelines
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      .

      The candidate to liver transplantation

      Indications to liver transplantation

      LT should be considered in any patient with end-stage liver disease, in whom the LT would extend life expectancy beyond what the natural history of underlying liver disease would predict or in whom LT is likely to improve the quality of life (QoL). Patients should be selected if expected survival in the absence of transplantation is one year or less, or if the patient had an unacceptable QoL because of liver disease. A detailed medical evaluation is performed to ensure the feasibility of LT.
      LT is indicated in patients with end-stage liver disease, in patients with the development of hepatocellular carcinoma (HCC) and in patients with acute liver failure. The most common indication to LT for end-stage liver disease in adults is cirrhosis. Patients should be referred to transplant centres when major complications of cirrhosis, such as variceal haemorrhage, ascites, hepatorenal syndrome and encephalopathy occur.
      Conversely, acute liver failure represents an urgent indication to LT [
      • Lee W.M.
      • Squires Jr., R.H.
      • Nyberg S.L.
      • Doo E.
      • Hoofnagle J.H.
      Acute liver failure: summary of a workshop.
      ]. Viruses (especially hepatitis viruses A and B), drugs (acetaminophen), and toxic agents are the most common causes of acute liver failure, with the proportions varying between countries. Seronegative hepatitis is also an important cause of LT for acute liver failure, being the most common indication for LT in acute liver failure in the UK [
      • Bernal W.
      Changing patterns of causation and the use of transplantation in the United kingdom.
      ]. Prognosis is essentially determined by neurological status, but is also rapidly affected by damage to other organs. LT has revolutionized the prognosis of acute liver failure, causing survival to increase from 10–20% (all causes combined) to 75–80% at 1 year and 70% at 5 years. Indications for LT in Europe are summarized in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Primary diseases leading to liver transplantation in Europe (01/1988–12/2011) . Others: Budd-Chiari: 792, Bening liver tumours or polycystic diseases: 1228, Parasitic diseases: 80, Other liver diseases: 1304.
      In recent years, an extension of indications has been observed, but in contrast, the transplant community is currently facing organ shortages. Actually, limited organ availability and an increasing demand for organ transplantation has extended transplant waiting times and thus increased morbidity and mortality for potential recipients on these waiting lists. This has led to increased pressure on organ allocation programs. Since a successful outcome requires optimal patient selection and timing, the issue of which patients to list for LT and when to transplant cirrhotic patients has generated great interest as well as considerable controversy.

      Score and prognostic factors for end-stage liver disease

      The timing of LT is crucial since patients who should be transplanted for end-stage liver disease need to undergo surgery before life-threatening systemic complications occur. They should not be transplanted too early since the advantage of transplant might be unbalanced by the risk of surgery and immunosuppression for all life.
      Priority on the waiting list was based in the past by the waiting time, and severity of liver disease. The Child-Pugh-Turcotte classification and since 2002 also the model of end-stage liver disease (MELD) score (based on objective measures such as creatinine, bilirubin and international normalized ratio) are used for patient priority [
      • 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.
      ]. The MELD was developed to determine the short-term prognosis for patients undergoing TIPS after gastrointestinal bleeding [
      • 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.
      ], and then proposed for predicting 3-month mortality in patients with end-stage liver disease.
      In patients with MELD ⩽14, 1-year survival was lower with rather than without transplantation [
      • Merion R.M.
      • Schaubel D.E.
      • Dykstra D.M.
      • Freeman R.B.
      • Port F.K.
      • Wolfe R.A.
      The survival benefit of liver transplantation.
      ]. Consequently, a MELD score ⩾15 is recommended to list patients with end-stage liver disease. However, it does not provide a prediction of mortality following LT except for those patients with very high MELD scores over 35 [
      • Habib S.
      • Berk B.
      • Chang C.C.
      • Demetris A.J.
      • Fontes P.
      • Dvorchik I.
      • et al.
      MELD and prediction of post-liver transplantation survival.
      ].
      In very sick patients with MELD >30 the risk of mortality and morbidity after transplantation should be addressed.
      MELD does not reflect the impact of complications such as refractory ascites and recurrent encephalopathy in the risk of mortality without transplantation.
      In fact, there are several exceptions to MELD, including pulmonary complications of cirrhosis, hepatic encephalopathy, amiloidosis, primary hyperoxaluria, etc. (Table 2). In these cases, extra points could be attributed to patients in order to give them priority to transplantation [
      • Freeman Jr., R.B.
      • Gish R.G.
      • Harper A.
      • Davis G.L.
      • Vierling J.
      • Lieblein L.
      • et al.
      Model for end-stage liver disease (MELD) exception guidelines: results and recommendations from the MELD Exception Study Group and Conference (MESSAGE) for the approval of patients who need liver transplantation with diseases not considered by the standard MELD formula.
      ].
      Table 2Exceptions to MELD score.
      Serum sodium (MELD-Na), serum sodium and age (integrated MELD) scores have been proposed to improve the predictive value of MELD [
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.K.
      • Wiesner R.H.
      • Kamath P.S.
      • Benson J.T.
      • et al.
      Hyponatremia and mortality among patients on the liver-transplant waiting list.
      ]. Delta MELD (ΔMELD), meaning the change of MELD over time, might also be a better predictor of mortality [
      • Huo T.I.
      • Wu J.C.
      • Lin H.C.
      • Lee F.Y.
      • Hou M.C.
      • Lee P.C.
      • et al.
      Evaluation of the increase in model for end-stage liver disease (DeltaMELD) score over time as a prognostic predictor in patients with advanced cirrhosis: risk factor analysis and comparison with initial MELD and Child-Turcotte-Pugh score.
      ,
      • 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.
      ].
      Another exception to MELD is HCC. Waiting list time-dependent points can be added to laboratory MELD to give priority to patients with HCC. Additional points can be added depending on the type of tumour (size, number of nodules, alpha fetoprotein [AFP] level, waiting time, response to downstaging procedures).
      MELD score is driving the allocation of grafts in many countries in Europe. However, the final decision for allocation is frequently based on multiple parameters besides MELD including the match with the donor, but also local/regional priorities.

      Management of patients with liver cirrhosis (without HCC)

      The management of a patient in the waiting list aims at eliminating not only contraindications of surgery, but also contraindications to taking long-term immunosuppressive treatment. This assessment is not uniform and should be discussed in each transplant centre. Contraindications to LT are dynamic, changing over time and may vary among liver transplant centres, depending on their local expertise.
      Evaluating and selecting a good recipient for LT thus requires the collaboration of several specialists, who account for all comorbidities. The final decision should be made, within each expert centre, among a multidisciplinary group of staff including transplant hepatologist, transplant surgeon, anaesthetist, intensivist, cardiologist, etc., that considers the benefit and risk for each recipient.

      Hepatitis B virus (HBV)-related liver disease

      The indication of decompensated HBV cirrhosis is declining probably due to the outcome of HBV vaccination and advent of oral antiviral agents. The indication for transplantation is similar to other causes of cirrhosis. In addition, it is essential to know the precise HBV status of the patient and in particular the existence of HBV replication. Whatever the level of HBV DNA, if detectable, antiviral treatment with entecavir or tenofovir should be started as soon as possible [
      • EASL Clinical Practice Guidelines
      Management of chronic hepatitis B.
      ]. The need for an antiviral treatment with nucleot(s)ide analogues (NUCs) has two objectives: 1) the improvement of liver function; and 2) to decrease the risk of HBV recurrence after transplantation since viral replication level at the time of LT is correlated with the risk of HBV recurrence. Positive HBV DNA at the time of LT seems to influence the rate of death due to HBV recurrence in HBV/HCC patients [
      • Burra P.
      • Germani G.
      • Adam R.
      • Karam V.
      • Marzano A.
      • Lampertico P.
      • et al.
      Liver transplantation for HBV-related cirrhosis in Europe: an ELTR study on evolution and outcomes.
      ].
      Since interferon (IFN) is contraindicated in patients with decompensated cirrhosis, the only choice for these patients is treatment with NUCs. Lamivudine first and adefovir [
      • Schiff E.
      • Lai C.L.
      • Hadziyannis S.
      • Neuhaus P.
      • Terrault N.
      • Colombo M.
      • et al.
      Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results.
      ] have been widely used to treat hepatitis B in patients awaiting LT. However, tenofovir and entecavir are currently the first-line drugs in patients with chronic hepatitis B, which have a greater potency and higher barriers to resistance [
      • EASL Clinical Practice Guidelines
      Management of chronic hepatitis B.
      ]. In case of previous resistance to lamivudine, tenofovir is the drug of choice; in case of resistance to adefovir the switch to entecavir is preferred (or tenofovir). The efficacy and safety of these drugs in patients with advanced liver disease have been assessed in different series, showing good efficacy in reducing levels of HBV DNA and a good safety profile [
      • Liaw Y.F.
      • Raptopoulou-Gigi M.
      • Cheinquer H.
      • Sarin S.K.
      • Tanwandee T.
      • Leung N.
      • et al.
      Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study.
      ,
      • Liaw Y.F.
      • Sheen I.S.
      • Lee C.M.
      • Akarca U.S.
      • Papatheodoridis G.V.
      • Suet-Hing Wong F.
      • et al.
      Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease.
      ,
      • Shim J.H.
      • Lee H.C.
      • Kim K.M.
      • Lim Y.S.
      • Chung Y.H.
      • Lee Y.S.
      • et al.
      Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis.
      ]. Lactic acidosis has been reported in some patients with MELD score >20, particularly when treated with entecavir [
      • Lange C.M.
      • Bojunga J.
      • Hofmann W.P.
      • Wunder K.
      • Mihm U.
      • Zeuzem S.
      • et al.
      Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function.
      ]. Clinical and laboratory follow-up of patients with these characteristics is warranted. It is important to note that the dose of all NUCs needs to be adjusted in patients with low creatinine clearance (<50 ml/min). Importantly, about one third of patients who initiate therapy have improvements in liver function, which in some cases might result in patient delisting [
      • Schiff E.
      • Lai C.L.
      • Hadziyannis S.
      • Neuhaus P.
      • Terrault N.
      • Colombo M.
      • et al.
      Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results.
      ,
      • Kapoor D.
      • Guptan R.C.
      • Wakil S.M.
      • Kazim S.N.
      • Kaul R.
      • Agarwal S.R.
      • et al.
      Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis.
      ].
      Cases of severe HBV reactivation should be considered specifically: the treatment with NUCs is an emergency. In 25% of cases, despite effective antiviral treatment, there is a deterioration of liver function and death may occur during the first 6 months of treatment. There is no specific prognosis factor identified to predict those patients who will recover without LT or who will die without LT.
      Patients with fulminant or severe hepatitis may benefit from NUCs treatment. Available data are based on study using mainly lamivudine [
      • Tillmann H.L.
      • Hadem J.
      • Leifeld L.
      • Zachou K.
      • Canbay A.
      • Eisenbach C.
      • et al.
      Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience.
      ], but as for chronic hepatitis, entecavir or tenofovir should be used.
      In patients with HBV/hepatitis D virus (HDV) coinfection, HBV replication can be suppressed, but HDV replication cannot be treated at the decompensated stage. In case of deterioration of liver disease despite effective anti-HBV therapy, HDV might be the cause of the deterioration and HDV RNA in serum should be evaluated. The presence of HDV replication is not a contraindication to transplantation, since HBV prophylaxis after transplantation will prevent symptomatic HDV reinfection of the graft [
      • Roche B.
      • Samuel D.
      Liver transplantation in delta virus infection.
      ].

      Recommendations:

      Figure thumbnail fx9

      Hepatitis C virus (HCV)-related liver disease

      HCV decompensated cirrhosis is frequently associated with a persistent HCV replication and an increased level of alanine aminotransferase. Until recently there was almost no possibility to treat patients with decompensated liver disease with antiviral therapy. To date this strategy has been proven to be suboptimal when using IFN-based therapies, especially regarding safety and tolerability [
      • Berenguer M.
      Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin.
      ,
      • Crespo G.
      • Marino Z.
      • Navasa M.
      • Forns X.
      Viral hepatitis in liver transplantation.
      ]. The advent of IFN-free antiviral therapy has modified this approach [
      • Pawlotsky J.M.
      New hepatitis C therapies: the toolbox, strategies, and challenges.
      ]. Importantly, recent data has shown that the clearance of HCV RNA from serum and sustained virological response (SVR) is associated with an improvement in liver function in some patients with decompensated liver cirrhosis [
      • Charlton M.
      • Everson G.T.
      • Flamm S.L.
      • Kumar P.
      • Landis C.
      • Brown Jr., R.S.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced disease.
      ] (and some individuals can be delisted). We do not know which variables are associated with liver function improvement after viral clearance and if there is a limit (“too advanced liver disease”) after which improvement is not possible. This will be an important issue to address in the coming years also in patients with hepatocellular carcinoma in whom the priority to LT is not only liver disease but the risk of tumour progression and in these cases antiviral therapy would improve liver function, but would not change the priority based on tumour staging.
      The presence of HCV replication at time of transplantation is not a contraindication for the procedure, but antiviral treatment will be necessary after transplantation.
      The primary goal of antiviral treatment while on the waiting list is to prevent HCV infection of the new liver, which is universal in patients with detectable HCV RNA at the time of transplantation. A potential second aim would be to improve liver function in those patients clearing HCV (which might, in some cases, avoid the need for LT).

      IFN-based regimens

      Current IFN-based treatments are far from optimal in patients with advanced cirrhosis and should be only considered in those settings where IFN-free regimens are not available and in patients with compensated cirrhosis (and HCC). Peginterferon (PegIFN) plus ribavirin (RBV) administered on the waiting list can prevent graft infection in patients who achieve viral clearance (undetectable HCV RNA) at the time of LT. Rates of SVR are low in genotype 1-infected patients (∼20%) and acceptable (∼50%) in those infected with genotypes 2 and 3 [
      • Carrion J.A.
      • Martinez-Bauer E.
      • Crespo G.
      • Ramirez S.
      • Perez-del-Pulgar S.
      • Garcia-Valdecasas J.C.
      • et al.
      Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: a retrospective study.
      ,
      • Everson G.T.
      • Terrault N.A.
      • Lok A.S.
      • Rodrigo del R.
      • Brown Jr., R.S.
      • Saab S.
      • et al.
      A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation.
      ]. Apart from genotype, variables associated with higher response rates are IL28B CC genotype and treatment duration (>16 weeks). IFN-based therapies are contraindicated in patients with advanced liver disease (Child-Pugh B and C, MELD >18) since they are associated with a high incidence of serious adverse events (particularly bacterial infections) [
      • Carrion J.A.
      • Martinez-Bauer E.
      • Crespo G.
      • Ramirez S.
      • Perez-del-Pulgar S.
      • Garcia-Valdecasas J.C.
      • et al.
      Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: a retrospective study.
      ,
      • Everson G.T.
      • Terrault N.A.
      • Lok A.S.
      • Rodrigo del R.
      • Brown Jr., R.S.
      • Saab S.
      • et al.
      A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation.
      ].
      The combination of PegIFN, RBV and first generation protease inhibitors boceprevir and telaprevir improved the efficacy of IFN-based therapies in genotype 1 patients. Unfortunately, response rates are low in cirrhotic patients, particularly in those who are previous null responders (a common situation in patients awaiting LT) [
      • Zeuzem S.
      • Andreone P.
      • Pol S.
      • Lawitz E.
      • Diago M.
      • Roberts S.
      • et al.
      Telaprevir for retreatment of HCV infection.
      ]. Importantly, this regimen was associated with a relatively high incidence of severe adverse events (SAEs) in “real-life” cirrhotic patients (45.2% and 32.7% for telaprevir and boceprevir, respectively) [
      • Hezode C.
      • Fontaine H.
      • Dorival C.
      • Larrey D.
      • Zoulim F.
      • Canva V.
      • et al.
      Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890.
      ]. Variables independently associated with the occurrence of SAEs (infections, clinical decompensation) were a low platelet count (<100,000/ml, as a marker of portal hypertension) and low albumin levels (<35 g/L, as a marker of impaired liver function). Thus, these drugs should not be used any more in patients awaiting LT.
      Alternative drugs that can be used in combination with PegIFN and RBV are the protease inhibitor simeprevir (genotypes 1 and 4), the NS5B polymerase inhibitor sofosbuvir or the NS5A inhibitor daclatasvir. Data regarding the use of these drugs are available in compensated cirrhotic patients (mostly naïve patients); the higher SVR rates were obtained with the combination of PegIFN, RBV and sofosbuvir [
      • Gambato M.
      • Lens S.
      • Navasa M.
      • Forns X.
      Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation.
      ].

      IFN-free regimens

      In November 2013, the first data on the safety and efficacy of an all-oral IFN-free regimen (sofosbuvir plus RBV) in patients with compensated cirrhosis and HCC awaiting LT were reported. In this phase II open-label study, 61 patients infected with genotypes 1 or 4 received up to 48 weeks of treatment while on the waiting list (median duration 17 weeks) [
      • Curry M.P.
      • Forns X.
      • Chung R.T.
      • Terrault N.
      • Brown R.S.
      • Fenkel J.M.
      • et al.
      Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study.
      ]; 46 of them were transplanted. The per-protocol efficacy was assessed in 43 patients with a HCV RNA level <25 IU/ml at the time of transplantation. Among them, 30 (70%) had post-transplantation SVR12, meaning no recurrence of infection. The duration of undetectable HCV RNA pre-transplant was the best predictor of response (undetectable HCV RNA for more than 30 continuous days). This proof of concept study demonstrated that an IFN-free regimen administered for a few weeks before transplantation prevented HCV graft infection in a majority of treated patients. Safety and tolerance of this regimen was good: the most frequently reported adverse events were mild and only one patient discontinued treatment due to anaemia attributed to RBV.
      Data using other IFN-free combinations are available from clinical trials and real-life cohorts in patients with compensated and decompensated cirrhosis (not specifically awaiting LT). The combination of sofosbuvir and ledipasvir with RBV for 12 or 24 weeks was assessed in genotype 1 and 4 patients with compensated (Child-Pugh A) or decompensated (Child-Pugh B and C, up to 12 points) cirrhosis [
      • Charlton M.
      • Everson G.T.
      • Flamm S.L.
      • Kumar P.
      • Landis C.
      • Brown Jr., R.S.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced disease.
      ]. In Child-Pugh A patients, data from this study show SVR12 rates above 95%, both in treatment-naïve and treatment-experienced individuals, independent of treatment duration. In patients with decompensated cirrhosis, preliminary analysis showed SVR12 rates above 85% both in Child-Pugh B and C patients, independent of treatment duration. At week 4 post-treatment, the MELD scores had improved by 1 to 8 points in two thirds of decompensated cirrhotic patients. The safety profile of this combination was good and most serious adverse events, including death, were unrelated to the study drugs. Data on the efficacy and safety of the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir with RBV in compensated cirrhotic patients infected with genotype 1 have shown SVR12 rates around 95% [
      • Poordad F.
      • Hezode C.
      • Trinh R.
      • Kowdley K.V.
      • Zeuzem S.
      • Agarwal K.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
      ], with slightly lower efficacy (around 85–90%) in those individuals with lower platelet counts (<100,000 cells/ml) and low albumin levels (<35 g/dl). Thus, this combination can be considered in individuals with compensated cirrhosis and HCC who are on the waiting list. The combination of sofosbuvir and simeprevir, with or without RBV, has been assessed in large real-life cohorts including a significant number of patients with cirrhosis [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ]. In patients with HCV genotype 1 infection and compensated cirrhosis, the SVR4 rates were in the order of 90%. Preliminary data in 81 genotype 1-infected patients with decompensated cirrhosis showed an SVR4 rate of 75%, with a good safety profile. The combination of sofosbuvir, daclatasvir and RBV has also shown a high efficacy in phase II studies including a small number of patients with compensated cirrhosis, and can be used in all genotypes [
      • Sulkowski M.S.
      • Gardiner D.F.
      • Rodriguez-Torres M.
      • Reddy K.R.
      • Hassanein T.
      • Jacobson I.
      • et al.
      Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.
      ].

      Recommendations:

      Figure thumbnail fx10

      Alcoholic liver disease

      Alcoholic liver disease is one of the most common indications of LT in Western countries []. LT for alcoholic cirrhosis has a favourable outcome, similar to other aetiology of end-stage liver disease [
      • Burra P.
      • Senzolo M.
      • Adam R.
      • Delvart V.
      • Karam V.
      • Germani G.
      • et al.
      Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).
      ]. Several centres developed an evaluation process based on medical and psychiatric criteria to better determine patients that would mostly benefit from the procedure. Alcohol abstinence of at least 6 months, in order to evaluate the need and timing of LT and obtain a better control of alcoholism, is usually required. This interval is neither a consensus nor an absolute requirement. The risk of recidivism is estimated between 15 to 40% depending on the series and how recurrence of alcoholism is defined. The risk of recurrence of alcohol consumption seems related to the duration of follow-up after LT, to the duration of abstinence before transplantation; however, this remains controversial [
      • Pfitzmann R.
      • Schwenzer J.
      • Rayes N.
      • Seehofer D.
      • Neuhaus R.
      • Nussler N.C.
      Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease.
      ]. The interest of the 6-month abstinence rule is double: a) abstinence can lead to significant improvement of liver function avoiding the need for transplantation; and b) this period of abstinence is an opportunity to assess the patient compliance. However, there are strong limitations to this rule: a) the duration of abstinence prior transplantation was not found to be related to the risk of recidivism in many studies; b) the improvement in liver function occurred mainly during the first three months of abstinence; c) during this period some patients with no risk of recidivism will die; d) several authors consider that the risk of recidivism is more related to psychosocial factors than to the duration of abstinence and these factors can be evaluated prior to transplantation. Therefore several groups have advocated breaking this 6-month abstinence rule [
      • Yates W.R.
      • Martin M.
      • LaBrecque D.
      • Hillebrand D.
      • Voigt M.
      • Pfab D.
      A model to examine the validity of the 6-month abstinence criterion for liver transplantation.
      ]. Acute alcoholic hepatitis (AAH) has been considered an absolute contraindication to LT on the grounds that patients with this disorder have been drinking recently and that a period of abstinence will allow many to recover. Unfortunately, many patients die during this time interval. Patients who do not recover within the first three month abstinence are unlikely to survive [
      • Mathurin P.
      • Duchatelle V.
      • Ramond M.J.
      • Degott C.
      • Bedossa P.
      • Erlinger S.
      • et al.
      Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone.
      ]. If the AAH is severe, defined by a Maddrey’s score over 32, treatment with steroids can improve the outcome [
      • Mathurin P.
      • O’Grady J.
      • Carithers R.L.
      • Phillips M.
      • Louvet A.
      • Mendenhall C.L.
      • et al.
      Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.
      ]. The Lille score allows an evaluation at day 7 after therapy introduction, if it is over 0.45, the expected survival is below 30% at 6 months [
      • Louvet A.
      • Naveau S.
      • Abdelnour M.
      • Ramond M.J.
      • Diaz E.
      • Fartoux L.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      ].
      Consequently, LT centres face a dilemma when caring for a patient with alcohol abuse who has developed severe alcoholic hepatitis and whose condition deteriorates despite adherence to abstinence, nutritional support, steroids, and standard medical support [
      • O’Shea R.S.
      • Dasarathy S.
      • McCullough A.J.
      Alcoholic liver disease.
      ]. In a recent multicentre French study, patients with a first episode of severe AAH resistant to steroids, a favourable psychosocial environment and a favourable addiction disease consultation, have been transplanted resulting with a dramatic improvement in survival in comparison to their spontaneous expected survival; a low rate of recidivism at 2 years was also reported [
      • Mathurin P.
      • Moreno C.
      • Samuel D.
      • Dumortier J.
      • Salleron J.
      • Durand F.
      • et al.
      Early liver transplantation for severe alcoholic hepatitis.
      ]. This study needs confirmation before achieving a consensus on the indication of LT in relation with abstinence duration. In all cases it emphasises the importance of psychosocial management of these patients to ensure long-term success of LT.

      Recommendations:

      Figure thumbnail fx11

      Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)

      In the setting of the metabolic or insulin resistance syndrome, NAFLD and NASH are becoming increasingly common medical problems in the developed world. Patients with histological necrotic-inflammatory changes and/or fibrosis may progress to end-stage liver disease and require LT. NAFLD and NASH are increasingly recognised as an indication to LT at the stage of cirrhosis and liver failure [
      • Charlton M.R.
      • Burns J.M.
      • Pedersen R.A.
      • Watt K.D.
      • Heimbach J.K.
      • Dierkhising R.A.
      Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.
      ]. Some patients may have both NAFLD linked to metabolic syndrome and chronic alcohol consumption acting as a cofactor for cirrhosis development. One specific point that should be carefully evaluated is the presence of comorbid factors linked to metabolic syndrome, which might increase the risk of complications during a surgical procedure [
      • Charlton M.
      Evolving aspects of liver transplantation for nonalcoholic steatohepatitis.
      ]. In particular obesity, hypertension, diabetes and dyslipidemia required a specific work-up in the pre-transplant phase or screening and should be addressed in the post-transplant setting as they might exacerbate [
      • Dare A.J.
      • Plank L.D.
      • Phillips A.R.
      • Gane E.J.
      • Harrison B.
      • Orr D.
      • et al.
      Additive effect of pretransplant obesity, diabetes, and cardiovascular risk factors on outcomes after liver transplantation.
      ]. It is likely that many potential LT candidates with NASH are excluded from LT due to comorbid conditions related to metabolic syndrome. In particular, morbid obesity might be a limiting factor to transplantation as it increases infection complications, as well as the length of stay in the intensive care unit (ICU) and hospital [
      • Hakeem A.R.
      • Cockbain A.J.
      • Raza S.S.
      • Pollard S.G.
      • Toogood G.J.
      • Attia M.A.
      • et al.
      Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom.
      ]. Indication to LT in obese patients with a body mass index (BMI) over 35 should be discussed within a multidisciplinary team including dietician, psychologist, hepatologist, anestethist and surgeon.

      Recommendation:

      Figure thumbnail fx12

      Primary biliary cholangitis (PBC)

      The advent of ursodeoxycholic acid as a recognised treatment of PBC has deeply modified the natural history of the disease, improved survival and the number of candidates to LT has dramatically decreased over the last decades. Nevertheless its efficacy in the long-term has yet to be determined [
      • Rudic J.S.
      • Poropat G.
      • Krstic M.N.
      • Bjelakovic G.
      • Gluud C.
      Bezafibrate for primary biliary cirrhosis.
      ].
      The indication to LT should be given when the expected survival is less than one year, in the case of patients with decompensated cirrhosis at any stage and in the case of complicated portal hypertension. Uncontrolled and intolerable pruritus refractory to all medical therapies including MARS, even if isolated, represents an indication to LT, which provides a significant improvement in the QoL [
      • Carbone M.
      • Neuberger J.
      Liver transplantation in PBC and PSC: indications and disease recurrence.
      ].

      Recommendation:

      Figure thumbnail fx13

      Primary sclerosing cholangitis (PSC)

      Specific indications to LT for patients with PSC are long-standing severe jaundice, repeated episodes of cholangitis not controlled by antibiotics, secondary biliary cirrhosis with complications of portal hypertension or decompensation and liver failure. The risk of cholangiocarcinoma is increased in these patients with a prevalence over 10–15% after a 10-year disease course [
      • Boberg K.M.
      • Lind G.E.
      Primary sclerosing cholangitis and malignancy.
      ]. In some cases, discovery of cholangiocarcinoma is detected only during the surgical procedure, in other cases, cholangiocarcinoma is highly suspected on the progression of cholestasis, and increased level of carbohydrate antigen 19–9 (a tumour marker) but not found during surgery. On single centre studies when patients were transplanted for PSC, explant pathology showed an incidence of 10–20% unsuspected cholangiocarcinoma. Thus the diagnosis of cholangiocarcinoma on PSC might be difficult or impossible before the pathological analyses of the biliary and liver explant. A suspicion of cholangiocarcinoma on PSC might be an indication to LT; however, it can be a contraindication if it is at an advanced stage. Patients transplanted with an unsuspected cholangiocarcinoma have usually a high risk of recurrent cholangiocarcinoma and poor long-term prognosis [
      • Ringe B.
      • Weimann A.
      • Lamesch P.
      • Nashan B.
      • Pichlmayr R.
      Liver transplantation as an option in patients with cholangiocellular and bile duct carcinoma.
      ]. Chronic inflammatory bowel disease (IBD) is frequently associated with PSC. IBD can be quiescent at time of LT and is not a contraindication to LT. Active IBD should be controlled before LT. Colon cancer should be searched for in patients with ulcerative colitis. Medical treatment of IBD and IBD surveillance is necessary after LT [
      • Singh S.
      • Loftus Jr., E.V.
      • Talwalkar J.A.
      Inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis.
      ].

      Recommendations:

      Figure thumbnail fx14

      Autoimmune hepatitis (AIH)

      AIH is more common in young woman, but may also affect older women, and in some few cases also men. The clinical presentation of the disease is variable; classically it presents as active chronic hepatitis, but may also present as established cirrhosis and in some rare cases as a fulminant course without chronic hepatic disease. A main characteristic of this disease is a good response to immunosuppressive treatment including steroids [
      • Manns M.P.
      • Czaja A.J.
      • Gorham J.D.
      • Krawitt E.L.
      • Mieli-Vergani G.
      • Vergani D.
      • et al.
      Diagnosis and management of autoimmune hepatitis.
      ]. LT is indicated in AIH in case of end-stage liver disease, or in case of acute liver failure, when immunosuppressive treatment is usually ineffective and potentially deleterious because the risk of sepsis [
      • Ichai P.
      • Duclos-Vallee J.C.
      • Guettier C.
      • Hamida S.B.
      • Antonini T.
      • Delvart V.
      • et al.
      Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis.
      ].

      Recommendation:

      Figure thumbnail fx15

      Genetic diseases

      Genetic diseases represent a heterogeneous group of disorders, which affects 10 out of 1000 births. They could manifest as predominant liver parenchymal damage (genetic cholestatic disorders, Wilson’s disease, hereditary haemochromatosis, tyrosinemia, alpha-1-antitrypsine deficiency) or they could be liver-based genetic disorders characterized by architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid neuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). For the first group, hepatic complications are the main indications to LT while in the second extrahepatic manifestations are the main cause of morbidity and mortality while liver function is preserved [
      • Fagiuoli S.
      • Daina E.
      • D’Antiga L.
      • Colledan M.
      • Remuzzi G.
      Monogenic diseases that can be cured by liver transplantation.
      ].

      Wilson’s disease

      Liver disease can manifest as acute liver failure, accompanied by haemolysis and kidney failure, or subacute or chronic liver failure, which can progress to end-stage liver disease. Treatments are copper-chelating agents (penicillamine, trientine, tetrathiomolybdate) or zinc salts (through the block of intestinal copper absorption) [
      • EASL Clinical Practice Guidelines
      Wilson’s disease.
      ]. LT is indicated in the acute setting or in case of progression of the disease to end-stage liver disease. In case of disease progression under therapy, non-compliance and incorrect drug dosage should be ruled out. In patients with neurological symptoms LT can improve brain damage with a complete recovery in 57–77% of cases [
      • Lui C.C.
      • Chen C.L.
      • Cheng Y.F.
      • Lee T.Y.
      Recovery of neurological deficits in a case of Wilson’s disease after liver transplantation.
      ,
      • Medici V.
      • Mirante V.G.
      • Fassati L.R.
      • Pompili M.
      • Forti D.
      • Del Gaudio M.
      • et al.
      Liver transplantation for Wilson’s disease: the burden of neurological and psychiatric disorders.
      ]. Nevertheless long-standing neurological disease is unlikely to improve, a severe worsening has been also reported in these patients with lower survival compared to patients with liver disease only. Therefore a neuropsychiatric evaluation is mandatory in LT candidates with neuropsychiatric symptoms.

      Hereditary haemochromatosis (HH)

      Overall only 1% of patients with HH undergo LT for hepatic decompensation. The risk of developing HCC is increased compared with patients affected by other causes of cirrhosis [
      • Niederau C.
      • Fischer R.
      • Sonnenberg A.
      • Stremmel W.
      • Trampisch H.J.
      • Strohmeyer G.
      Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.
      ]. Therefore another potential indication of LT is the development of HCC on cirrhosis due to HH.
      Therapeutic phlebotomy is the general treatment for HH, which is safe and effective [
      • Powell L.W.
      Hemochromatosis: the impact of early diagnosis and therapy.
      ]. Phlebotomies are recommended if serum ferritin is >1000 ng/ml, usually started at 500 ml/week, and continued until reaching normalized iron store levels (serum ferritin <50 ng/ml) with concomitant follow-up of haematocrit (<20% change between phlebotomies).
      Iron overload affects primarily the liver, but it can also lead to multiple organ damage; heart, pancreas, gonads, skin, and joints. Clinical manifestations are cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism, and skin pigmentation. LT candidates should undergo extensive cardiac work-up taking into account the risk of cardiomyopathy. The outcome after LT for HH is good with 1- and 5-year survival rates of 80.7% and 74% respectively, the main causes of death after LT are infections (45%) and cardiac complications (22%) [
      • Kowdley K.V.
      • Brandhagen D.J.
      • Gish R.G.
      • Bass N.M.
      • Weinstein J.
      • Schilsky M.L.
      • et al.
      Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.
      ].

      Primary hyperoxaluria type 1 (PH1)

      PH1 is an autosomal recessive disease that has been associated with an enzymatic defect of alanine-glyoxylate aminotransferase, resulting in less conversion of glyoxylate into glycine. The increased glyoxylate on its turn is converted into oxalate, which forms insoluble calcium salts that accumulate in the kidney and other organs [
      • Bobrowski A.E.
      • Langman C.B.
      The primary hyperoxalurias.
      ]. The prevalence of PH1 ranges from one to three in 1,000,000. The natural history of PH1 is characterized by the decline of renal function as a result of progressive nephrolithiasis/nephrocalcinosis, with progression to end-stage renal disease (ESRD) and/or complications of systemic oxalosis [
      • Watts R.W.
      The clinical spectrum of the primary hyperoxalurias and their treatment.
      ]. Early diagnosis of PH1 and initiation of therapy may prevent renal failure. Pyridoxine (vitamin B6) stimulates the conversion pathway of glyoxylate to glycine, reducing the conversion to oxalate.
      Approximately 10–30% of individuals with PH1 respond to treatment with pyridoxine. Isolated kidney transplantation restores oxalate excretion to normal, but is associated with a high rate of recurrence and in many cases early graft loss. Pre-emptive LT before ESRD and systemic oxalosis is a possible approach as replacing the liver corrects the metabolic defect and prevents kidney failure. Another possibility is the combined liver-kidney transplantation. The optimal approach and the timing of the transplant is still controversial [
      • Cochat P.
      • Fargue S.
      • Harambat J.
      Primary hyperoxaluria type 1: strategy for organ transplantation.
      ,
      • Hoppe B.
      • Beck B.B.
      • Milliner D.S.
      The primary hyperoxalurias.
      ].

      Familial amyloid polyneuropathy (FAP)

      FAP is a progressive degenerative disorder of autosomal dominant inheritance. It is caused by the mutation of the transthyretin (TTR), one of the prealbumins, which is most commonly due to a single amino acid substitution of valine to methionine at position 30 (Val30Met). Plasma TTR is predominantly synthesized by the liver and mutated forms of TTR are the precursor protein of amyloid fibre and amorphous aggregates in patients’ tissues. It is characterized by extracellular amyloid tissue accumulation. The clinical manifestations are mainly represented by progressive peripheral and autonomic polyneuropathy associated with sensory loss, motor weakness, and autonomic dysfunction. Liver tissue of TTR-FAP patients has normal structure and function, except for the production of amyloidogenic variant TTR. LT must be proposed to the symptomatic patients as early as possible as transplanted patients have significantly prolonged survival compared with the non-transplanted ones [
      • Yamashita T.
      • Ando Y.
      • Okamoto S.
      • Misumi Y.
      • Hirahara T.
      • Ueda M.
      • et al.
      Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy.
      ]. The outcome is generally favourable for those with an early onset of the disease [
      • Herlenius G.
      • Wilczek H.E.
      • Larsson M.
      • Ericzon B.G.
      Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry.
      ]. Outcome after LT in patients with FAP not related to Val30Met mutation are inferior compared with patients transplanted for FAP related to Val30Met mutations [
      • Herlenius G.
      • Wilczek H.E.
      • Larsson M.
      • Ericzon B.G.
      Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry.
      ]. In these patients, overall survival at 5 years is reported to be above 80% [
      • Yamashita T.
      • Ando Y.
      • Okamoto S.
      • Misumi Y.
      • Hirahara T.
      • Ueda M.
      • et al.
      Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy.
      ,
      • Plante-Bordeneuve V.
      • Said G.
      Familial amyloid polyneuropathy.
      ,
      • Okamoto S.
      • Wixner J.
      • Obayashi K.
      • Ando Y.
      • Ericzon B.G.
      • Friman S.
      • et al.
      Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients’ survival.
      ].
      If the disease is in an advanced stage, LT does not improve the symptoms [
      • Ohya Y.
      • Okamoto S.
      • Tasaki M.
      • Ueda M.
      • Jono H.
      • Obayashi K.
      • et al.
      Manifestations of transthyretin-related familial amyloidotic polyneuropathy: long-term follow-up of Japanese patients after liver transplantation.
      ]. The pre-transplant work-up should take into account the cardiomyopathy due to TTR fibril deposit, which could impair the post-LT outcome [
      • Gustafsson S.
      • Ihse E.
      • Henein M.Y.
      • Westermark P.
      • Lindqvist P.
      • Suhr O.B.
      Amyloid fibril composition as a predictor of development of cardiomyopathy after liver transplantation for hereditary transthyretin amyloidosis.
      ]. Owing to the fact that the mutation is in the liver, but without liver injury, LT is often done as domino transplantation. The explanted liver of the FAP patient will then be transplanted into another patient with end-stage liver disease. The patient receives a FAP liver with the production of the mutant TTR protein, but the process of amyloid deposition is slow.
      Domino LT has mainly been used in patients with a shorter life expectancy or higher chance of recurrence of liver disease. So far some cases of de novo polyneuropathy have been reported 7 to 9 years after domino LT with proven amyloid deposits [
      • Adams D.
      • Lacroix C.
      • Antonini T.
      • Lozeron P.
      • Denier C.
      • Kreib A.M.
      • et al.
      Symptomatic and proven de novo amyloid polyneuropathy in familial amyloid polyneuropathy domino liver recipients.
      ]. Nevertheless amyloid polyneuropathy acquired after a domino LT can be reversible after liver retransplantation [
      • Antonini T.M.
      • Lozeron P.
      • Lacroix C.
      • Mincheva Z.
      • Durrbach A.
      • Slama M.
      • et al.
      Reversibility of acquired amyloid polyneuropathy after liver retransplantation.
      ].

      Management of patients with liver cirrhosis and hepatic malignancies

      Hepatocellular carcinoma

      HCC is the most common primary malignancy of the liver. LT is a suitable therapeutic option for early, unresectable HCC particularly in the setting of chronic liver disease. When Milan criteria (solitary HCC with diameter <5 cm or up to 3 nodules with diameter <3 cm) are applied for patient selection excellent results after LT can be achieved, with a 5-year survival exceeding 70% [
      • Mazzaferro V.
      • Regalia E.
      • Doci R.
      • Andreola S.
      • Pulvirenti A.
      • Bozzetti F.
      • et al.
      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      ]. More recently, Yao et al. [
      • Yao F.Y.
      • Ferrell L.
      • Bass N.M.
      • Watson J.J.
      • Bacchetti P.
      • Venook A.
      • et al.
      Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.
      ] have shown that patients with one nodule <6.5 cm in diameter or with several nodules with the largest <4.5 cm in diameter and the total sum of all diameters <8 cm, named as UCSF criteria, have a recurrence-free survival not significantly different from patients within the Milan criteria. Other criteria have been described including poor prognosis criteria such as AFP over 500 ng/ml or an increase of 15 ng/ml/month [
      • Vibert E.
      • Azoulay D.
      • Hoti E.
      • Iacopinelli S.
      • Samuel D.
      • Salloum C.
      • et al.
      Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor.
      ]. Recently Duvoux et al. [
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria.
      ] have described a new model called “AFP model” which takes into account the number, the size of nodules, and the AFP level. A patient with an AFP score ⩽2 has a little risk of recurrence after the transplant with a 5-year survival of 70%. This can allow patients who are outside the Milan criteria to undergo transplantation resulting in a very good outcome. However, the Milan criteria remain the benchmark for the selection of HCC patients for LT and the basis for comparison with other proposed criteria. Considering the role of downstaging, LT after successful downstaging should achieve a 5-year survival comparable to that of HCC patients who meet the criteria for LT without requiring downstaging [
      • Clavien P.A.
      • Lesurtel M.
      • Bossuyt P.M.
      • Gores G.J.
      • Langer B.
      • Perrier A.
      Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report.
      ]. Moreover, since the drop-out rate from transplant waiting list is about 15–30% because of HCC progression, downstaging and bridging treatment should be offered to all patients with an estimating waiting time for transplant over 6 months [
      • Aloia T.A.
      • Adam R.
      • Samuel D.
      • Azoulay D.
      • Castaing D.
      A decision analysis model identifies the interval of efficacy for transarterial chemoembolization (TACE) in cirrhotic patients with hepatocellular carcinoma awaiting liver transplantation.
      ,
      • Llovet J.M.
      • Mas X.
      • Aponte J.J.
      • Fuster J.
      • Navasa M.
      • Christensen E.
      • et al.
      Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation.
      ].
      HCC arising in a non-cirrhotic patient is rare and Milan criteria are not applicable to evaluate the suitability for LT. In general, non-cirrhotic patients with non-resectable HCC and patients who were treated by resection and have intrahepatic recurrence of HCC may be considered as appropriate candidates for LT if the absence of macrovascular invasion and extrahepatic spread has been shown. A recent analysis of the European Liver Transplant Registry (ELTR) showed 5-year survival rates at 50–70% in well-selected patients. Important determinants of poor outcome are macrovascular invasion, lymph node involvement, and time interval of <12 months when LT is used as rescue therapy for intrahepatic recurrence after a previous partial liver resection [
      • Mergental H.
      • Porte R.J.
      Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis.
      ].

      Cholangiocarcinoma

      Cholangiocarcinoma is the second most common cancer among the primary hepatic neoplasm, accounting for 5 to 20% of liver malignancies. LT for cholangiocarcinoma remains a controversial issue due to a high risk of recurrence [
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • Llovet J.M.
      • Park J.W.
      • Patel T.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      ]. A protocol combining neoadjuvant chemoradiation and LT was first used in patients with unresectable hilar cholangiocarcinoma [
      • Rosen C.B.
      • Heimbach J.K.
      • Gores G.J.
      Liver transplantation for cholangiocarcinoma.
      ]. Results have confirmed that this approach leads to significantly lower recurrence rates and higher long-term survival rates than other existing treatment modalities [
      • Rana A.
      • Hong J.C.
      Orthotopic liver transplantation in combination with neoadjuvant therapy: a new paradigm in the treatment of unresectable intrahepatic cholangiocarcinoma.
      ]. For the extrahepatic cholangiocarcinoma the treatment of choice is surgical resection, LT can be effective for perihilar cholangiocarcinoma with 65% rate of disease-free 5-year survival in highly selected patients [
      • Darwish Murad S.
      • Kim W.R.
      • Harnois D.M.
      • Douglas D.D.
      • Burton J.
      • Kulik L.M.
      • et al.
      Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.
      ]. Despite this, protocols to treat patients with cholangiocarcinoma are not widespread and are available at only a handful of transplant programs.

      Other hepatic malignancies

      Others hepatic malignancies, without metastatic spread outside the liver, are succesfully treated by LT, as fibrolamellar carcinoma and epithelioid haemangioendothelioma. The results of the largest reported transplant series in the treatment of haemangioendothelioma showed excellent results with disease-free survival rates at 1, 5, and 10 years post-LT of 90%, 82%, and 64% [
      • Lerut J.P.
      • Orlando G.
      • Adam R.
      • Schiavo M.
      • Klempnauer J.
      • Mirza D.
      • et al.
      The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry.
      ].

      Hepatic metastases

      Classically, metastatic tumours of the liver have been considered a poor indication for LT, although some centres performed this procedure in parallel with other therapies, such as chemotherapy and radiotherapy. In metastases from neuroendocrine tumours, LT could be indicated for patients with symptoms related to massive hepatomegaly, hormone production, unavailability of effective therapeutic alternatives, diffuse metastases of the liver, slow growing tumour and patients with no extrahepatic disease [
      • Hoti E.
      • Adam R.
      Liver transplantation for primary and metastatic liver cancers.
      ]. Main advantages of LT in this setting would be a significant improvement of the QoL in many patients with a palliative therapeutic alternative and a possible cure in some cases. Other causes of liver metastasis are currently considered as contraindication to LT.
      LT for colorectal cancer unresectable metastases is still controversial. A single centre study from Norway reports a 5-year survival of 60% with no long-term disease-free survival [
      • Hagness M.
      • Foss A.
      • Line P.D.
      • Scholz T.
      • Jorgensen P.F.
      • Fosby B.
      • et al.
      Liver transplantation for nonresectable liver metastases from colorectal cancer.
      ]. These results should be viewed with caution; moreover, organ use in this respect during a period of donor shortage is highly questionable.
      There is an ongoing European randomized controlled trial (RCT) to explore whether LT in selected patients with liver metastases from colorectal cancer can obtain significant life extension and better health related QoL compared to patients receiving surgical resection (NCT01479608).

      Management of comorbidities

      All potential candidates of LT should undergo an extensive work-up before their registration on the waiting list. Usually there is no formal age limit of potential LT recipient, but patients over 65 years of age need a multidisciplinary evaluation to exclude comorbidities. LT has been successfully performed in patients older than 70 years, although they have an increased risk of cardiovascular complications [
      • Aduen J.F.
      • Sujay B.
      • Dickson R.C.
      • Heckman M.G.
      • Hewitt W.R.
      • Stapelfeldt W.H.
      • et al.
      Outcomes after liver transplant in patients aged 70 years or older compared with those younger than 60 years.
      ]. The trend in LT is an increase rate of recipients older than 65 years as the results are comparable to those for younger patients. The trend of increasing age of transplant candidates is related both to the changing demographics, with an aging society, but also to changing epidemiology of liver disease. Some teams consider that the physiologic age is more important than the chronologic age [
      • Cross T.J.
      • Antoniades C.G.
      • Muiesan P.
      • Al-Chalabi T.
      • Aluvihare V.
      • Agarwal K.
      • et al.
      Liver transplantation in patients over 60 and 65 years: an evaluation of long-term outcomes and survival.
      ,
      • Garcia C.E.
      • Garcia R.F.
      • Mayer A.D.
      • Neuberger J.
      Liver transplantation in patients over sixty years of age.
      ]. The final decision for listing a patient aged 65–70 or older than 70 years should be taken after a thorough multidisciplinary discussion.

      Cardiovascular function

      In patients with cirrhosis, increased cardiac output has been described. Moreover, the presence of a latent cardiac dysfunction, which includes a combination of reduced cardiac contractility with systolic and diastolic dysfunction and electrophysiological abnormalities are noticed. This syndrome is termed cirrhotic cardiomyopathy [
      • Moller S.
      • Henriksen J.H.
      Cirrhotic cardiomyopathy.
      ].
      Although cardiac evaluation is very prominent in the assessment process, there is no ideal way to assess it and a lot of resources are being wasted in attempting to do so. Traditional cardiovascular risk factors are related to coronary artery disease (CAD) in patients with liver disease, and they might be used as indicators for careful preoperative evaluation of coronary risk [
      • An J.
      • Shim J.H.
      • Kim S.O.
      • Lee D.
      • Kim K.M.
      • Lim Y.S.
      • et al.
      Prevalence and prediction of coronary artery disease in patients with liver cirrhosis: a registry-based matched case-control study.
      ]. Electrocardiogram and transthoracic echocardiography should be performed in all liver transplant candidates to rule out underlying heart disease. If the patient has multiple cardiovascular risk factors, and is older than 50 years, a cardiopulmonary exercise test should be done in order to uncover asymptomatic ischaemic heart disease. Aerobic capacity is markedly impaired in many patients with chronic liver disease. In patients undergoing LT, the anaerobic threshold measured during cardiopulmonary exercise testing is related to post-operative hospitalization and survival [
      • Bernal W.
      • Martin-Mateos R.
      • Lipcsey M.
      • Tallis C.
      • Woodsford K.
      • McPhail M.J.
      • et al.
      Aerobic capacity during cardiopulmonary exercise testing and survival with and without liver transplantation for patients with chronic liver disease.
      ]. If coronary disease is suspected during the evaluation in high risk patients, coronary angiography should be performed.
      When CAD is treated effectively before LT, survival after LT is not significantly different between patients with and without obstructive CAD [
      • Wray C.
      • Scovotti J.C.
      • Tobis J.
      • Niemann C.U.
      • Planinsic R.
      • Walia A.
      • et al.
      Liver transplantation outcome in patients with angiographically proven coronary artery disease: a multi-institutional study.
      ]. To date there are no multicentre studies examining the impact of CAD on LT outcome.

      Recommendations:

      Figure thumbnail fx18

      Respiratory function

      To evaluate the respiratory function, lung function tests and a chest X-ray are recommended in all candidate patients to LT. When hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PPHTN) are suspected, further investigations should be performed [
      • Umeda N.
      • Kamath P.S.
      Hepatopulmonary syndrome and portopulmonary hypertension.
      ].
      HPS is found in 10–17% of patients with cirrhosis and is characterized by intrapulmonary vascular dilatations especially in the basal parts of the lung. It results in hypoxemia and oxygenotherapy could be required. Because it could reverse HPS through closure of the shunts, LT is the only curative treatment. HPS can be diagnosed by calculating the alveolar-arterial oxygen gradient and by performing a contrast echocardiography [
      • Koch D.G.
      • Fallon M.B.
      Hepatopulmonary syndrome.
      ]. The severity of HPS is not related to the severity of liver disease and can be an isolated indication for LT. It is important to properly assess the severity of HPS, since patients with PaO2 <50 mmHg and no reversibility to 100% oxygen may have a risk of irreversible respiratory failure in the post-transplant period and a high risk of perioperative mortality [
      • Arguedas M.R.
      • Abrams G.A.
      • Krowka M.J.
      • Fallon M.B.
      Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation.
      ]. It should also be remembered that in most patients with HPS, there is a deterioration of the respiratory function in the first days after LT due to the surgical procedure itself, and that improvement and reversibility of HPS may take months [
      • Pastor C.M.
      • Schiffer E.
      Therapy Insight: hepatopulmonary syndrome and orthotopic liver transplantation.
      ].
      PPHTN occurs in 2–8% of the patients with cirrhosis. An imbalance between vasodilating and vasoconstrictive agents may be responsible for misguided angiogenesis and pulmonary hypertension [
      • Ashfaq M.
      • Chinnakotla S.
      • Rogers L.
      • Ausloos K.
      • Saadeh S.
      • Klintmalm G.B.
      • et al.
      The impact of treatment of portopulmonary hypertension on survival following liver transplantation.
      ]. The diagnosis of PPHTN is suspected when systolic pulmonary artery pressure is higher than 30 mmHg on echocardiography and should be confirmed by right heart catheterization. Moderate (mean pulmonary artery pressure [MPAP] ⩾35 mmHg) and severe PPHTN (MPAP ⩾45 mmHg) are associated with increased mortality after LT. In a series of 12 patients with MPAP between 34 and 60 mmHg who underwent LT, five died, all within one month post-LT [
      • 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.
      ]. The pre-LT management of patients with PPHTN requires early diagnosis and therapy with pulmonary vasodilators. Recently, pharmacological treatments such as epoprostenol (prostacycline), or prostacyclin analogues (iloprost, treprostinil), or endothelin receptor antagonist, or phosphodiesterase inhibitor type 5 (sildenafil) have been shown to improve pulmonary haemodynamics. Some cases of transplantation in patients treated with these agents have been reported to be efficacious; however, long-term results are pending [
      • Hoeper M.M.
      • Krowka M.J.
      • Strassburg C.P.
      Portopulmonary hypertension and hepatopulmonary syndrome.
      ]. Therefore LT could be considered in patients with PPHTN responding to medical therapy with pulmonary vasodilators and with MPAP ⩽35 mmHg.
      Careful perioperative attention to avoid right ventricular failure from acutely elevated pulmonary artery pressure or sudden increase in right ventricular preload is key to the management of PPHTN. With increased surgical and anaesthetic expertise, patients with PPHTN can be considered for LT [
      • Fix O.K.
      • Bass N.M.
      • De Marco T.
      • Merriman R.B.
      Long-term follow-up of portopulmonary hypertension: effect of treatment with epoprostenol.
      ].

      Recommendations:

      Figure thumbnail fx19

      Renal function

      Cirrhotic patients with renal failure have a 7-fold increased risk of death, with 50% of patients dying within one month [
      • Fede G.
      • D’Amico G.
      • Arvaniti V.
      • Tsochatzis E.
      • Germani G.
      • Georgiadis D.
      • et al.
      Renal failure and cirrhosis: a systematic review of mortality and prognosis.
      ], therefore the assessment of renal function is essential when evaluating a patient for LT. The hepatorenal syndrome, usually a reversible cause of renal failure, has to be differentiated from other causes of acute kidney injury, such as sepsis, hypovolemia and parenchymal renal disease.
      Acute kidney injury is defined as a reduction in kidney function manifested by an absolute rise of serum creatinine of at least 0.3 mg/dl or the equivalent to a percentage increase of 50% (1.5-fold) from baseline, occurring within 48 h. Chronic kidney disease is defined as an estimated glomerular filtration rate (GFR) of <60 ml/min, calculated using the Modification of Diet in Renal Disease 6 (MDRD6) formula, [
      • Wong F.
      • Nadim M.K.
      • Kellum J.A.
      • Salerno F.
      • Bellomo R.
      • Gerbes A.
      • et al.
      Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.
      ] for more than three months.
      The evaluation of renal clearance can be difficult in patients with cirrhosis [
      • Francoz C.
      • Glotz D.
      • Moreau R.
      • Durand F.
      The evaluation of renal function and disease in patients with cirrhosis.
      ], therefore performing inulin or other exogenous marker’s clearance and renal biopsies might help in decision-making.
      Patients with end-stage liver disease and with GFR less than 30 ml/min, or hepatorenal syndrome requiring renal replacement therapy more than 8–12 weeks, and patients with renal biopsy revealing more than 30% fibrosis and glomerulosclerosis would benefit from receiving both liver and kidney grafts [
      • Eason J.D.
      • Gonwa T.A.
      • Davis C.L.
      • Sung R.S.
      • Gerber D.
      • Bloom R.D.
      Proceedings of consensus conference on simultaneous liver kidney transplantation (SLK).
      ]. There is a debate regarding the need for combined liver-kidney transplantation in patients with creatinine clearance between 30 ml/min and 60 ml/min. It should be balanced between the risk of deterioration of renal function after LT alone as a consequence of surgery and of drug toxicity, and the shortage of kidney grafts.

      Recommendations:

      Figure thumbnail fx20

      Nutritional assessment

      Liver cirrhosis is associated with malnutrition, and cachexia is present in nearly 70% of patients with end-stage liver disease [
      • Cruz Jr., R.J.
      • Dew M.A.
      • Myaskovsky L.
      • Goodpaster B.
      • Fox K.
      • Fontes P.
      • et al.
      Objective radiologic assessment of body composition in patients with end-stage liver disease: going beyond the BMI.
      ]. Malnutrition is associated with lower survival rate after LT, patients with BMI <18.5 are the group at highest risk of poor outcome [
      • 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.
      ]. The general condition and nutritional status are sometimes difficult to assess in patients with end-stage liver disease. The clinical and biological parameters classically used (BMI, prealbumin, etc.) may not apply in cases of severe hepatic insufficiency. Several authors have recently pointed out the role of sarcopenia assessed by a CT scan evaluation of the transversal psoas muscle thickness on the post-transplant morbidity and mortality [
      • Durand F.
      • Buyse S.
      • Francoz C.
      • Laouenan C.
      • Bruno O.
      • Belghiti J.
      • et al.
      Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.
      ]. More studies are needed to develop specific nutritional scores in cirrhosis. Nutrition intervention prior to transplantation may play an important role, nevertheless it is extremely difficult to achieve. To date, studies have been unable to identify a nutritional intervention that offers convincing benefits [
      • Langer G.
      • Grossmann K.
      • Fleischer S.
      • Berg A.
      • Grothues D.
      • Wienke A.
      • et al.
      Nutritional interventions for liver-transplanted patients.
      ], and no nutritional protocol in cirrhotic patients waiting for LT has been established [
      • Ferreira L.G.
      • Anastacio L.R.
      • Correia M.I.
      The impact of nutrition on cirrhotic patients awaiting liver transplantation.
      ]. Considering patients with high BMI, outcomes after LT seem to be worse in patients with a BMI >40 compared with normal weight patients [
      • 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.
      ]. Moreover, diabetes mellitus is often present in obese patients and in patients with features of metabolic syndrome. Therefore, they are at higher risk of developing post-transplant diabetes mellitus and of cardiovascular events. Pre-transplant diabetes and dyslipidaemia should be managed as in the general population.

      Evaluation of bone abnormalities

      Osteoporosis is a common complication among patients with cirrhosis and most particularly in those with chronic cholestasis disease [
      • Wibaux C.
      • Legroux-Gerot I.
      • Dharancy S.
      • Boleslawski E.
      • Declerck N.
      • Canva V.
      • et al.
      Assessing bone status in patients awaiting liver transplantation.
      ]. Bone densitometry could predict the risk of pathological fracture and prevention could be initiated. Female gender, lower BMI, and tobacco consumption are major risk factors for bone disease in cirrhotic patients. Bone densitometry must be included in the LT evaluation of all patients [
      • Alcalde Vargas A.
      • Pascasio Acevedo J.M.
      • Gutierrez Domingo I.
      • Garcia Jimenez R.
      • Sousa Martin J.M.
      • Ferrer Rios M.T.
      • et al.
      Prevalence and characteristics of bone disease in cirrhotic patients under evaluation for liver transplantation.
      ].

      Recommendations:

      Figure thumbnail fx21

      Immunological evaluation

      The role of the donor-specific human leukocyte antigen alloantibodies (DSA) on acute and chronic antibodies-mediated rejection and also on different histological damage such as fibrosis, disease recurrence, biliary complications etc. has been recently raised. The correlation between the cut-off of DSA and liver damage, and moreover, the LT outcome, is still not clear [
      • O’Leary J.G.
      • Demetris A.J.
      • Friedman L.S.
      • Gebel H.M.
      • Halloran P.F.
      • Kirk A.D.
      • et al.
      The role of donor-specific HLA alloantibodies in liver transplantation.
      ]. DSA is an important tool but more research needs to be done in order to understand their usefulness.

      Recommendation:

      Figure thumbnail fx22

      Infection screening

      Patients with cirrhosis are prone to develop infections that could result in the development of multiple organ failure and death [
      • Gustot T.
      • Durand F.
      • Lebrec D.
      • Vincent J.L.
      • Moreau R.
      Severe sepsis in cirrhosis.
      ]. A screening of latent infections is required in order to treat a potentially lethal infection before LT and to prevent an exacerbation after LT under immunosuppressive regimens. A correct evaluation of the presence of acute or chronic infections in the recipient is crucial. The infectious screening in liver transplant recipients should be graduated in different levels as follows: a) first level to be performed in all LT candidates; b) second level to be performed only in patients eligible to LT at the time of listing; and c) third level to be performed in patients with risk factors or who are from a geographic area with specific endemic infections [
      • 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.
      ].
      The first level of screening consists of screening for human immunodeficiency virus (HIV) 1 and 2 antibodies, HBV serology, HCV antibodies, HAV antibodies, cytomegalovirus (CMV) and completing a chest X-ray [
      • 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.
      ].
      The second level of screening consist of screening for: Mycobacterium tuberculosis (history + PPD-Mantoux + IFN-Gamma Release Assays), Epstein-Barr virus (EBV), human herpes virus 8 (HHV-8), varicella zoster virus (VZV), herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), urine culture, parasitological exam and stool culture (Strongyloides stercoralis serology, Toxoplasma gondii IgG, Treponema pallidum serology), immunoenzymatic assay with venereal disease research laboratory (VDRL), Staphylococcus aureus nasal/axillary swab, and dentist review. [
      • 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.
      ].
      The third level screening should be performed to a subset of patients according to the clinical history, comorbidities and to endemic diseases and local epidemiology [
      • 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.
      ].
      Regarding vaccination, it is important to make sure that transplant candidates are immunised against HAV and HBV, varicella, Pneumococcus, influenza and tetanus.

      Infections exposure that require monitoring

      Dust exposure requires monitoring for aspergillosis. Recipients living in West Nile virus (WNV) endemic areas require specific monitoring with WNV serology and PCR.

      Exposure to infections that require routine intervention

      A chest radiograph should be performed to essentially search for indirect signs of bacterial or fungal lung infection, including tuberculosis. Some teams recommend conducting a skin test. The search for the tubercle bacillus is not systematic in the absence of other risk factors and with a normal chest radiograph.
      Patients with positive PPD test results should be considered for prophylactic therapy with isoniazid, according to standard guidelines, after a careful evaluation to exclude active disease that would require combination therapy [
      • 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.
      ].
      Serological screening and secondary prophylaxis for coccidioidomycosis in transplant recipients have been recommended for transplant candidates and recipients in areas where these diseases are endemic.

      Infections that delay LT

      Chronic oedema and increased bacterial translocation predispose cirrhotic patients to develop soft tissue infections, which represent nearly 11% of infections [
      • Liu B.M.
      • Chung K.J.
      • Chen C.H.
      • Kung C.T.
      • Ko S.F.
      • Liu P.P.
      • et al.
      Risk factors for the outcome of cirrhotic patients with soft tissue infections.
      ] and which can be caused by both Gram-positive (S. aureus, Streptococci) and Gram-negative bacteria (Klebsiella spp.). Cellulitis is the most frequent skin infection in cirrhotic patients and it has a recurrence rate of 20% [
      • Lin M.N.
      • Tsai C.C.
      • Hung T.H.
      • Tsai C.C.
      The risk of cellulitis in cirrhotic patients: a nationwide population-based study in taiwan.
      ].

      Infections that contraindicate LT

      In cirrhotic patients, bacteremia can occur spontaneously or as consequences of skin, lung or urinary infections. Although transient bacteremia, associated with therapeutic invasive procedures such as transarterial chemoembolization (TACE) and percutaneous sclerotherapy is relatively common, the risk of a relevant clinical impact does not warrant antibiotic prophylaxis [
      • Cheruvattath R.
      • Balan V.
      Infections in Patients With End-stage Liver Disease.
      ].
      Pneumonia is the third leading cause of infections in patients with cirrhosis [
      • Tandon P.
      • Garcia-Tsao G.
      Bacterial infections, sepsis, and multiorgan failure in cirrhosis.
      ,
      • Caly W.R.
      • Strauss E.
      A prospective study of bacterial infections in patients with cirrhosis.
      ], with an increased risk of bacteremia compared with the general population [
      • Falguera M.
      • Trujillano J.
      • Caro S.
      • Menendez R.
      • Carratala J.
      • Ruiz-Gonzalez A.
      • et al.
      A prediction rule for estimating the risk of bacteremia in patients with community-acquired pneumonia.
      ]. Community-acquired pneumonia is often caused by S. pneumonia and H. influenza [
      • Niederman M.S.
      • Mandell L.A.
      • Anzueto A.
      • Bass J.B.
      • Broughton W.A.
      • Campbell G.D.
      • et al.
      Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention.
      ]. Pneumococcal vaccination is recommended in patients with cirrhosis.
      Candidemia represent a frequent infection in patients with chronic liver disease and in particular in patients with PSC, identified in up to 44% of bile samples in PSC patients, especially those with dominant strictures [
      • Lenz P.
      • Conrad B.
      • Kucharzik T.
      • Hilker E.
      • Fegeler W.
      • Ullerich H.
      • et al.
      Prevalence, associations, and trends of biliary-tract candidiasis: a prospective observational study.
      ,
      • Kulaksiz H.
      • Rudolph G.
      • Kloeters-Plachky P.
      • Sauer P.
      • Geiss H.
      • Stiehl A.
      Biliary candida infections in primary sclerosing cholangitis.
      ].
      The presence of invasive fungal infection, such as aspergillosis, represents a contraindication to LT and the recipient should be treated at least until there is radiographic, clinical and microbiologic resolution [
      • Fischer S.A.
      • Avery R.K.
      Screening of donor and recipient prior to solid organ transplantation.
      ].
      HIV infection has been considered as a contraindication for LT before the era of antiretroviral therapies. This was due to the poor spontaneous prognosis of HIV infection. The advent of highly active antiretroviral drugs has been a therapeutic breakthrough, and the prognosis has been dramatically improved. The progression of chronic HBV and HCV seems more rapid in coinfected patients, and a high number of patients will develop life-threatening liver cirrhosis. Patients with a controlled HIV disease, absence of AIDS related event, and CD4 over 100–150/mm3 can be considered for transplantation. While HBV/HIV coinfection is considered as a good indication for transplantation, the indication for transplantation in patients with HCV/HIV coinfection is more controversial due to the severity of HCV recurrence in these coinfected patients [
      • Samuel D.
      • Weber R.
      • Stock P.
      • Duclos-Vallee J.C.
      • Terrault N.
      Are HIV-infected patients candidates for liver transplantation?.
      ]. In a recent prospective, multicentre study patient and graft survival after LT were evaluated in 89 HCV/HIV-coinfected patients and were compared with 235 HCV-monoinfected liver transplanted patients, along with all US transplant recipients who were 65 years old or older. Among the HCV/HIV patients, older donor age, renal dysfunction requiring combined kidney-liver transplantation, and a BMI <21 kg/m2 were independent predictors of graft loss [
      • Terrault N.A.
      • Roland M.E.
      • Schiano T.
      • Dove L.
      • Wong M.T.
      • Poordad F.
      • et al.
      Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection.
      ]. The use of highly efficacious IFN-free regimens to treat HCV infection (both before and after LT) will most likely change the outcomes of these patients and HCV/HIV coinfection will become a standard indication for LT.

      Recommendations:

      Figure thumbnail fx23

      Anatomical evaluation

      The surgeon must be warned about the type of vascularization of the recipient regarding the hepatic artery and the main portal system. The presence of portacaval shunts, which should be suture-ligated during surgery or arcuate ligament are routinely searched. It has replaced hepatic arteriography, which is indicated in cases of variant anatomy or previous hepatic surgery.
      In the past, portal vein thrombosis (PVT) was considered an absolute contraindication for LT. As a result of improvements in medical care, surgical techniques and radiological interventions, PVT by itself can represent an indication for LT. Several studies showed that surgical thrombectomy, thromboendovenectomy with venous reconstruction, interposition of vein graft, porto-caval hemitransposition, and radiological endovascular interventions can resolve venous obstruction in liver transplant recipients. Interestingly, PVT patients’ survival rates at 1- and 5-years after LT are equal [
      • Francoz C.
      • Valla D.
      • Durand F.
      Portal vein thrombosis, cirrhosis, and liver transplantation.
      ]. An isolated thrombosis of the portal vein is not a surgical contraindication, an anticoagulant is used to prevent thrombus extension; however, in some case a thrombosis of the whole portal system (including portal vein, superior mesenteric vein, splenic vein) can be a contraindication to LT.
      Evaluation of the biliary tree anatomy is particularly important in patients who will receive living donor LT, and it can be achieved non-invasively with magnetic resonance tomography or magnetic resonance cholangiopancreatography or invasively with endoscopic retrograde cholangiopancreatography.
      An overall surgical and anaesthesia consultations are mandatory at the end of the evaluation process to assess operational and post-operational risks.

      Recommendations:

      Figure thumbnail fx24

      Screening for neoplastic lesions

      A past history of cancer already treated should not disqualify candidates for LT. In accordance, the survival and the risk of recurrence at 1-, 5-, and 10-years under a long-term immunosuppressive treatment should be estimated, case by case, with an oncologist. Common practice is to consider the patient suitable for LT if the risk of recurrence is estimated to be less than 10%. Moreover, usually an interval time of 5 years free-of-recurrence is often required to exclude potential recurrence, but this may vary considerably with the type of malignancy. However, to date no consistent data have been published on the optimal management of patients candidated to LT and with a previous extrahepatic malignancy.
      Screening for neoplastic lesions should always be performed, when evaluating a patient for LT, taking into account age, gender, alcohol consumption and smoking status of the recipient.
      Colorectal cancer screening is mandatory for candidates older than 50 years. If a colonoscopy under general anaesthesia is too risky, CT colonography may be an alternative, although its usefulness in cirrhotic patients with ascites has never been demonstrated. The search for pulmonary neoplasia, ear-nose-throat, stomatology, oesophageal and bladder is mandatory in cases of alcohol and smoking addiction. An ear-nose-throat examination associated with a nasofibroscopy, an examination of the oral cavity, and upper gastrointestinal endoscopy are recommended. Upper gastrointestinal endoscopy is commonly performed in all candidates, for both cancer screening and evaluation of the presence of oesophageal or gastric varices.
      Women should have regular gynaecological care including Pap smear and mammogram if needed. Screening for prostate disease should be done according to the urologist indication.
      An examination of the skin is important, taking into account that non-melanotic skin cancers rarely contraindicates LT. A special screening for hepatic malignancy is based on preoperative baseline metastatic work-up which includes bone scan and chest CT. Recently, positron emission tomography (PET) scan also tends to be included because of the usefulness to find otherwise undetected neoplastic lesions [
      • Asman Y.
      • Evenson A.R.
      • Even-Sapir E.
      • Shibolet O.
      [18F]fludeoxyglucose positron emission tomography and computed tomography as a prognostic tool before liver transplantation, resection, and loco-ablative therapies for hepatocellular carcinoma.
      ].

      Recommendations:

      Figure thumbnail fx25

      Social assessment, psychiatric and addiction

      It is important to assess social network, psychiatric illness and addiction in order to evaluate adherence of the recipient. In case of hepatic encephalopathy, neuropsychological testing, CT brain scan or NMR and electroencephalography could help to determine reversibility of neuropsychiatric conditions. Active drug or alcohol abuse is considered to be a contraindication to LT for many reasons: the risk of recidivism, the risk of non-compliance and the risk of injury to the graft.
      Stably abstinent, methadone-maintained, opiate-dependent patients are generally good candidates for LT and show low relapse rates [
      • Lucey M.R.
      • Weinrieb R.M.
      Alcohol and substance abuse.
      ]. However, there are no conclusive evidence showing that patients with end-stage liver failure using methadone have poorer outcomes after transplantation compared with patients not using methadone. Moreover, nearly one third of liver transplant centres in the US require patients to be weaned off of methadone before they can become eligible for LT [
      • Jiao M.
      • Greanya E.D.
      • Haque M.
      • Yoshida E.M.
      • Soos J.G.
      Methadone maintenance therapy in liver transplantation.
      ].
      Current methods in toxicology screening can provide a positive result when screening for cannabinoids up to two months after the patient’s last use. Patients who tested positive for marijuana had similar survival rates compared to those with negative test results. Whether patients who regularly use marijuana should be excluded from the waiting list remains a controversial issue [
      • Weinrieb R.M.
      • Lucey M.R.
      Treatment of addictive behaviors in liver transplant patients.
      ,
      • Coffman K.L.
      The debate about marijuana usage in transplant candidates: recent medical evidence on marijuana health effects.
      ]. In a recent survey among 102 adult liver transplant centres in the US, 46.7% of centres considered the daily consumption of marijuana as an absolute contraindication, whereas 43% a relative contraindication and 10.3% as no contraindication [
      • Secunda K.
      • Gordon E.J.
      • Sohn M.W.
      • Shinkunas L.A.
      • Kaldjian L.C.
      • Voigt M.D.
      • et al.
      National survey of provider opinions on controversial characteristics of liver transplant candidates.
      ].
      When patients with polysubstance abuse disorders undergo LT the rate of recidivism is nearly 27%, but this does not seem to influence post-transplant survival [
      • Nickels M.
      • Jain A.
      • Sharma R.
      • Orloff M.
      • Tsoulfas G.
      • Kashyap R.
      • et al.
      Polysubstance abuse in liver transplant patients and its impact on survival outcome.
      ].
      Pre- and post-transplant smoking rates are high and cause significant morbidity and mortality due to cardiovascular events [
      • Leithead J.A.
      • Ferguson J.W.
      • Hayes P.C.
      Smoking-related morbidity and mortality following liver transplantation.
      ], increased incidence of hepatic artery thrombosis [
      • Pungpapong S.
      • Manzarbeitia C.
      • Ortiz J.
      • Reich D.J.
      • Araya V.
      • Rothstein K.D.
      • et al.
      Cigarette smoking is associated with an increased incidence of vascular complications after liver transplantation.
      ] and increased incidence of malignancies such as oropharyngeal [
      • van der Heide F.
      • Dijkstra G.
      • Porte R.J.
      • Kleibeuker J.H.
      • Haagsma E.B.
      Smoking behavior in liver transplant recipients.
      ]. Therefore smoking cessation should be mandatory in all transplant candidates.

      Organ donation

      Organ donation

      Consent systems

      In the EU, organs cannot be procured without the consent of donors and/or their relatives. However, the establishment of consent differs between Member States. National provisions usually foresee that citizens (donors or relatives) can “opt-in” (explicit consent) or “opt-out” for donation (presumed consent). Mixed solutions also exist, with or without central databases that register the wishes expressed by citizens. The ACTOR study found that most European countries have “opt-out”, i.e. presumed consent systems, according to which no explicit consent is required for a person to become a potential donor. In practice, and in the absence of such explicit consent, most laws require the deceased’s next of kin to consent to post-mortem organ removal. Though to date the majority of European countries have transplant laws based on the presumed consent principle, the practical application of national legislation particularly, with regard to the role of next of kin in objecting or consenting to organ donation, varies substantially between countries, regions, hospitals, and even individual requestors and thus may impact on ultimate efficiency of national laws. Regardless of the consent system, the opinion of relatives or “next of kin” is almost always asked and respected in almost all European countries.
      A combination of legislation, potential of medically suitable donors, investments in health care and infrastructure, education, public attitudes, culture and religion may all play a role in determining the number of deceased organ donors in a country or region. Donation figures within the Eurotransplant area, however, seem to show a rather direct effect of legislative measures: donation rates per million population are nearly twice as high in Austria and Belgium (presumed consent) compared to those in Germany and the Netherlands [
      • Roels L.
      • Rahmel A.
      The European experience.
      ].

      Deceased and living donation

      It is also the Member States’ decision on whether they organise their transplant systems based purely on deceased donation or whether they also encourage living donation. While deceased donation is highly developed in several Southern European countries, some Northern European countries are more advanced in the area of living donation.

      Brain death and circulatory death

      A further distinction can also be made between different types of deceased donation that are allowed and organised within a country. Donation after brain death (DBD) is the most common type of deceased donation, while donation after circulatory death (DCD) is increasingly used as an additional source of organs for transplantation. These two kinds of deceased donation raise different ethical concerns and require different organisational set-ups.

      Bilateral and multilateral agreements

      Some countries have chosen to take part in multilateral “European organ exchange organisations”, such as Eurotransplant (Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands and Slovenia) or Scandiatransplant (Sweden, Finland, Denmark, Norway and Iceland), and manage waiting lists and allocation criteria (at least partially) together. The recently created Southern Alliance for Transplantation foresees a similar collaboration. Bilateral organ exchange agreements have been set up by some countries, e.g. just focusing on the exchange of a specific type of organ with a neighbouring country. Examples include:
      • -
        Italy and Malta 2008–2010: 20 organs (kidney, heart, liver, split liver) from Malta were transplanted in Italy.
      • -
        Spain and Portugal 2009: 41 organs offered to Spain from Portugal.
      Such organ exchanges need, for being fully operational, to be supported by a wide set of organisational and practical agreements, aimed also at ensuring compliance with Article 3(2) c) of the EU Charter of Fundamental rights and excluding any risk of organ trafficking.

      Waiting lists

      The management of waiting lists is a national competence (which can partially be delegated to and co-managed with a “European Organ Exchange Organisation”). It includes the definition of criteria to place patients on the list or exclude patients from a waiting list. The lists are usually specific to the types of organ and transplant needed (kidney, liver, lung, heart, pancreas, small bowel, combined transplants) and are also specific for paediatric transplants.

      Indirect effect of legislation on transplantation

      Some legislation has had an indirect but significant effect on LT, for example the law restricting over-the-counter paracetamol pack sizes, introduced in the UK in September 1998. This was because of the large number of people taking paracetamol overdoses, and increasing numbers of deaths and liver transplants due to paracetamol induced hepatotoxicity. Such legislation was introduced following recommendations by the UK government agency currently known as Medicines and Healthcare Products Regulatory Agency, and restricted pack sizes of paracetamol to a maximum of 32 tablets in pharmacies and to 16 tablets for non-pharmacy sales.
      These measures were followed by persistent significant reductions in deaths due to paracetamol overdose, with some indication of fewer registrations for transplantation at liver units during the 11 years after the legislation [
      • Hawton K.
      • Bergen H.
      • Simkin S.
      • Dodd S.
      • Pocock P.
      • Bernal W.
      • et al.
      Long term effect of reduced pack sizes of paracetamol on poisoning deaths and liver transplant activity in England and Wales: interrupted time series analyses.
      ].
      A similar but much amplified effect may be expected in the future as a consequence of legislation on the funding of new direct-acting antiviral agents (DAA) against hepatitis C. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, have the potential to lead to viral eradication in most if not all HCV patients who undergo treatment. This is an area of vertiginously rapid basic sciences and clinical development, but the costs of DAA are currently prohibitive for funding of treatment on a large-scale. The implication of near-eradication of HCV in Europe in the next decades is that of a significant reduction of patients needing a liver transplant for HCV and HCC in the future.

      Organ allocation

      Liver allocation in Europe

      Data from LT activity in Europe is collected by the ELTR [], which is a service of the European Liver and Intestine Transplant Association (ELITA), with the following objectives:
      • Registry of all LT procedures in Europe.
      • Link between European liver transplant centres.
      • Scientific use and publications.
      Between 1968 and December 2012, the ELTR has collected data regarding 112,554 liver transplant procedures performed in 153 centres from 27 European countries.
      Within Europe the LT activity and organ donation rates vary in the different countries and regions reflecting different organ allocation systems and organisations. Further differences in legislation, organ donation rates, indications for LT, and traditions in the practice of medicine exist in different countries and regions of Europe.
      There are no uniform rules or systems for organ allocation in Europe or within the European Union. There are several organ exchange organisations for different countries and geographical areas, including:
      • Organización Nacional de Trasplantes (ONT) in Spain.
      • NHS Blood & Transplant (NHSBT) for the United Kingdom and Ireland.
      • Scandiatransplant (Sweden, Norway, Finland, Denmark, and Iceland).
      • Eurotransplant (Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands and Slovenia) for a total population of over 112 million.
      • Centro Nazionale Trapianti (CNT) in Italy.
      • Agence de la biomedécine in France.
      Most organisations have similar rules with an urgent priority group that includes acute hepatic failure and early retransplantation following primary-non-function (PNF) as well as hepatic artery or PVT. There are also similarities in allocation for children and rules to favour splitting of the best liver grafts. There are, however, important differences as well. Organ allocation can be patient-directed, as is the case in the US and some European countries, or centre-directed, which is the case of other European countries including the UK, Spain and Scandiatransplant. There is an increasing collaboration between the organ procurement organisations.

      ONT – Spain

      Liver transplant activity started in Spain in 1984 and has a mean activity of more than a 1000 liver transplants performed yearly []. There are 25 liver transplant teams, four of which are paediatric. The ONT provides essential support for organ procurement, allocation support, and management of waiting list at a national level [
      • Matesanz R.
      Organ procurement in Spain.
      ]. Spain has one of the highest organ donation rates in the world thanks to the outstanding donor detection and organ procurement organisation, which is often referred to as the Spanish model. In 2013, deceased donor organ donation rate reached 35.12 donors per million population []. The ONT has set a large-scale, comprehensive strategy to achieve and sustain an important improvement in donation and transplantation in Spain [
      • Matesanz R.
      • Marazuela R.
      • Dominguez-Gil B.
      • Coll E.
      • Mahillo B.
      • de la Rosa G.
      The 40 donors per million population plan: an action plan for improvement of organ donation and transplantation in Spain.
      ].
      Liver allocation in Spain is centre-oriented as all available organs are referred to the national coordinating office.
      National priority is given to liver emergencies. Livers are allocated sequentially to the hospital, city or region in the effort to reduce cold ischaemia time. The decision about the donor-recipient matching is made by the transplant team of the accepting unit with the aid of consensus guidelines developed with the support of the Spanish Liver Transplant Society [
      Consensus document of the Spanish Society of Liver Transplantation.
      ,
      Consensus document of the Spanish Society of Liver Transplantation. Waiting lists, liver transplantation and quality indicators.
      ,
      III Consensus Meeting of the Spanish Society of Liver Transplantation. Hepatitis C, living-donor liver transplantation, quality of liver grafts and of liver transplantation programs.
      ].
      Emergency LT in Spain is considered in two situations: 1) acute liver failure in the absence of any previous liver disease; or 2) retransplantation within seven days after transplantation (up to 30 days in paediatric recipients).
      Clearance of candidates from the liver transplant waiting list in Spain has not changed in the last five years with a waiting list ranging from 103 to 124 days.

      NHSBT – United Kingdom

      An organ donation taskforce was recently set up in the UK to improve the poor donation rates. The taskforce recommendations were implemented, which were followed by an increase in the number of DBD of 7% over the last 4 years. Since 2007, the numbers of DCD have rapidly increased by 118%. The total number of deceased organ donors reached a record total of 1320 in 2013. Of these, 780 were DBD and 540 were DCD [].
      In 2013, 871 liver transplants were performed. There are seven transplant units in the UK. Three of which also have a paediatric liver transplant program. In April 2014 there were 512 patients registered on the liver transplant waiting list. Currently, on average, adult patients wait 142 days for a liver transplant while paediatric patients wait on average 78 days.
      The key players in regulating organ donation, allocation and transplantation in the UK include NHSBT, a special health authority of the National Health Service (NHS) and the Human Tissue Authority (HTA). The latter is an independent watchdog that protects public confidence by licensing and inspecting organisations that store and use tissue for transplantation and other purposes. Liver allocation in the UK is centre-oriented, though there is a plan to change the system to a patient-oriented, national allocation scheme. Donor zones are allocated to each centre based on the number of new registrations of prospective candidates to match the scale of the centre’s waiting list. If the organ is declined, it will be offered, according to a rotation system, to the second in line centre through the liver allocation sequence.
      The allocation priority at each centre is decided by a multidisciplinary meeting, which includes liver transplant professionals, following a UKELD-based prioritisation system.
      There are nine categories of patients suitable for listing on the super urgent national list and these are divided into paracetamol overdose and non-paracetamol overdose [].
      In summary for adult (age >16 years or weight >35 kg) and paediatric (age <16 years or weight <35 kg) liver donors the sequence for allocating liver grafts is similar and as follows:
      • Super urgent list.
      • Combined liver and small bowel adult recipients.
      • Patients with hepatoblastoma.
      • Designated zonal retrieval centre.
      • Other designated UK and Ireland liver transplant centres.
      • Designated zonal retrieval centres for adults.

      Scandiatransplant

      Scandiatransplant is a collaboration of all organ transplant centres in the Nordic countries—Sweden, Norway, Finland, Denmark and Iceland. There are currently five liver transplant centres within Scandiatransplant (two in Sweden and one in each other Nordic country except for Iceland). In 2013, out of a total of 421 actual deceased donors, 362 liver transplants were performed in the Scandiatransplant network [,
      • Fosby B.
      • Karlsen T.H.
      • Melum E.
      Recurrence and rejection in liver transplantation for primary sclerosing cholangitis.
      ].
      There is no common waiting list in Scandinavia. Centre-oriented allocation is used and each transplant centre has its own waiting list and the right to transplant livers procured from a defined geographical area. The MELD score and/or the Child-Pugh scores are used in conjunction with clinical and non-clinical parameters (e.g. waiting time) to select patients to be transplanted.
      Patients with acute hepatic failure (urgent call status) have priority to receive a liver from the next available deceased donor in the Scandiatransplant region for 72 h. The high urgent status is based solely on the diagnosis and clinical status. All livers that were received on urgent call status or as a kind request have to be paid back to the sending centre within a 6-month period.
      High urgent status also applies for patients in need of an acute retransplantation within 14 days of the transplant due to PNF, hepatic artery or PVT.
      Paediatric LTs represent 5% of all LTs performed in Scandinavia. In 2011, a common waiting list for paediatric patients in need of a left lateral segment liver graft was established in order to improve organ availability for children.
      DCD donation is not practiced among the Scandiatransplant countries with the exception of Norway.

      Eurotransplant

      Eurotransplant is responsible for the allocation of donor organs in eight European countries: Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands and Slovenia. This international collaborative framework includes all donor and transplant hospitals and tissue-typing laboratories. In Eurotransplant, allocation is governed by the different national laws on transplantation, resulting in a standard allocation algorithm; the Eurotransplant Liver Allocation System (ELAS) based on medical and logistical criteria with modifications according to the different national laws [
      • De Meester J.
      • Persijn G.G.
      • Wujciak T.
      • Opelz G.
      • Vanrenterghem Y.
      The new Eurotransplant Kidney Allocation System: report one year after implementation. Eurotransplant International Foundation.
      ].
      The allocation system for LT in Eurotransplant was changed in 2006 for elective recipients from a waiting time based allocation to an urgency-based system using the MELD scoring. Patient-oriented allocation according to MELD is effective in four Eurotransplant countries (Germany, Belgium, the Netherlands, and Luxembourg), whereas a centre-oriented allocation system is effective in Austria, Slovenia and Croatia. On the Eurotransplant matching list all patients have to be registered with a lab MELD which must be updated by the transplant centres at scheduled intervals. Patients whose disease severity is not adequately reflected by lab MELD can be requested for an exceptional MELD. Some diseases have been identified as standard exceptions and are comprised in a country-specific list.
      Besides allocation in elective recipients, some urgency categories within Eurotransplant are given priority based on their respective medical urgency:
      • 1.
        High urgency, which is the highest priority internationally.
      • 2.
        Approved combined organ, which is a multiorgan liver transplant with exception of liver-kidney.
      Urgency status is granted only after approval by Eurotransplant, and patients in these categories are ranked by the time they have spent in their current urgency [
      • Neuberger J.
      • Ubel P.A.
      Finding a place for public preferences in liver allocation decisions.
      ]. A pay-back system ensures that the donor centre is re-offered the next available liver of the same blood group.
      In contrast to adult recipients ranked by their calculated MELD, paediatric recipients are automatically assigned an initial paediatric MELD equivalent depending on age that is upgraded each 90 days until transplantation.
      In conclusion different systems are used, ranging from centre-oriented to patient-oriented. Some systems are constructed using rigorous rules based on points and scores, whereas others are based on the clinical judgment of the responsible transplant surgeon. The current diversity makes it unlikely that we will manage to produce a uniform organ allocation system in Europe in the near future.

      Extended criteria donors

      The success of LT has resulted in a growing demand for transplantable grafts. The discrepancy between supply and demand and the increased morbidity and mortality of patients on the waiting list has led to a search for alternatives to the standard pool of organs from DBD. In the past 20 years the paediatric waiting lists have been successfully reduced due to the introduction of segmental LT including reduced/split LT and living donor LT (LDLT). These techniques have only marginally increased the organ pool for adults in the Western world. The most immediate source of organs capable of expanding the donor pool is that of extended criteria donors (ECD) also called marginal donors. These, although not universally defined, include a wide range of donors with unfavourable characteristics, historically associated with poorer graft and patient survival. These include advanced age, steatosis, hypernatremia, DCD and others. DCD is associated with severe ischaemia-reperfusion injury, which is responsible for PNF or delayed graft function and biliary ischaemia. However, if carefully selected and matched with appropriate recipients, livers from DCD donors can be used safely and effectively [
      • Muiesan P.
      • Girlanda R.
      • Jassem W.
      • Melendez H.V.
      • O’Grady J.
      • Bowles M.
      • et al.
      Single-center experience with liver transplantation from controlled non-heartbeating donors: a viable source of grafts.
      ].
      Scores have been developed to quantify the risk of graft failure of ECD donors, including the donor risk index (DRI), and more recently the Balance of Risk score (BAR score) (see chapters Donor risk index and Balance of risk score).
      Protocols have been developed for the selection of ECD and DCD livers to allow a safer utilisation and an effective expansion of the donor pool.

      Definition of ECD donors

      The ECD graft represents an organ with unfavourable characteristics associated with suboptimal post-transplant outcomes that fall into two main risk categories: poor graft function and potential for disease transmission. Within the poor graft function category it is possible to differentiate two groups, the DCDs and the non-DCDs.
      The Eurotransplant definition refers to the category of graft dysfunction [

      Eurotransplant Manual. 5th Ed. 2010. 18.

      ]. According to this definition the following criteria defines a liver donor marginal:
      • Donor age >65 years.
      • ICU stay with ventilation >7 days.
      • BMI >30.
      • Steatosis of the liver >40%.
      • Serum sodium >165 mmol/L.
      • Transaminases: ALT >105 U/L, AST >90 U/L.
      • Serum bilirubin >3 mg/dl.

      DCD

      In recent years, renewed interest in DCD has emerged as a strategy to increase the number of viable grafts, and to decrease the mortality on the waiting list. According to the setting in which circulatory death occurs, DCD can be classified using the Maastricht criteria [
      • Kootstra G.
      • Daemen J.H.
      • Oomen A.P.
      Categories of non-heart-beating donors.
      ,
      • Morrissey P.E.
      • Monaco A.P.
      Donation after circulatory death: current practices, ongoing challenges, and potential improvements.
      ] (Table 3). In Europe, the United Kingdom, the Netherlands, Spain, Belgium, and France have the highest DCD activity. DCD is based on the type III category in most countries; type II DCD is predominant in Spain and in France. DCD may be also divided into two main categories: controlled (CDCD) and uncontrolled (UDCD). The ethics, assessment, logistics, techniques of retrieval, and outcomes of transplant are very different with controlled and uncontrolled liver DCD.
      Table 3Categories of donation after circulatory death (modified from
      • Kootstra G.
      • Daemen J.H.
      • Oomen A.P.
      Categories of non-heart-beating donors.
      ,
      • Morrissey P.E.
      • Monaco A.P.
      Donation after circulatory death: current practices, ongoing challenges, and potential improvements.
      ).
      Controlled donors (Maastricht type III) are generally victims of a catastrophic brain injury of diverse aetiology, deemed incompatible with meaningful recovery, but whose condition does not meet formal criteria for brain death and whose cardiopulmonary function ceases before organs are retrieved. The procedure of withdrawal of life support therapy (WLST) is planned by the medical team in agreement with the family of the injured patient. It is important to emphasise that this decision precedes, and is independent from the one to donate. In category III, circulatory arrest is induced by WLST and occurs either in the ICU or in the operating room. In type IV, a brain dead donor suffers an unpredicted cardiac arrest prior to the donation procedure or the latter is delayed after cardiac arrest if the family wishes so for religious or cultural reasons.
      CDCD occurs in the presence of organ retrieval teams and limits the ischaemic injury associated with death. The process of dying in type III DCD; however, may be associated with a prolonged agonal period of hypotension and/or hypoxia, which are ultimately responsible for ischaemic injury that may prevent organ donation, or be accountable for graft dysfunction or non-function of the transplanted organ. In this respect it is crucial that we recognise that there is a total lack of arterial and portal blood flow through the liver long before the time of cardio-circulatory arrest [
      • Hernandez-Alejandro R.
      • Caumartin Y.
      • Chent C.
      • Levstik M.A.
      • Quan D.
      • Muirhead N.
      • et al.
      Kidney and liver transplants from donors after cardiac death: initial experience at the London Health Sciences Centre.
      ].
      UDCD occurs following the unanticipated cardiac arrest of a patient; due to logistical reasons and the associated degree of ischaemic injury only deaths occurring at a centre with established organ retrieval teams and pathways are suitable for donation of liver grafts (category II). It is possible to overcome some of these logistical challenges by directing intensive medical care resources outside of the hospital. In Madrid and Barcelona a network of mobile ICU teams are tasked to patients in out-of-hospital cardiac arrest. The subsequent effect is that this also maximises rates of UDCD.
      Several groups have reported excellent results with the use of CDCD grafts for LT. In this sense, 1- and 3-year graft survivals are 80% and 70%. Regarding the development of intrahepatic biliary strictures also defined as ischaemic-type biliary lesions (ITBL) or ischaemic cholangiopathy (IC), groups with specific expertise including King’s College Hospital in London have reported less than a 3% rate of ITBL. It is important to remark that this is not only a reliable graft source for the adult population; in the paediatric population, where graft scarcity is even greater than among adults, CDCD grafts achieve excellent results. Results from the UDCD programs are excellent as well. With a median follow-up between 20 and 34 months, Spanish groups have reported graft and patient survivals between 70% and 87.5% with rates of PNF and ITBL around 10%. Grafts obtained from DCD are not optimal; graft and patient survival comparisons with standard DBD generally show a lower performance. On an intention-to-treat basis though DCD may compare better with DBD grafts as there may be an advantage with an earlier transplant accepting a DCD liver rather than deteriorating and possibly dying, waiting for a DBD organ.
      Moreover, recipients of DCD grafts show mortality rates comparable to other well-established, accepted risk predictors such as advanced age, hepatitis C or HCC, in recipients and older donor age. As recently suggested, combining DCD grafts with these risk factors must be carefully considered as it may create an unacceptable risk. For this reason, physicians should not shy away from using DCD grafts. Perhaps the optimal environment for a DCD graft is a low risk recipient. Malignancy seems to be a good indication as the risk of dropping out of the HCC criteria on the waiting list may outweigh that of receiving a graft from a DCD. In conclusion, both controlled and uncontrolled programs have a huge potential to clearly expand the pool of donors for the adult and paediatric populations. Future advances in the fields of in situ donor recirculation and ex situ perfusion will surely not only add but also rescue grafts. The process to obtain a valid consent is probably the most important legal requirement associated with DCD programs. In this sense, legislation can be based on either the opting out (presumed consent) or the opting in (explicit consent) principle. From an ethical point of view, two problems may arise in UDCD and CDCD programs. In the first group, there is an urgent need to start preservation to ensure organ viability. This commonly happens when the family is not present. In an opt-out system, the next of kin have the right to object to organ donation, even when the deceased themselves have not declined the option. In an opt-in system, the family can decide whether to donate when the deceased has not made a choice. From a legal point of view, this means that when the next of kin are not available to consent or to object, there is no legal basis to start manoeuvres, and the organs would be lost. An optimal example of a legal pathway to gain sufficient time for proper consent and to avoid unnecessary conflicts may be the one proposed by Dutch legislation: “The necessary measures to maintain the organ in a suitable condition for transplantation may be taken after death, so long as the procedure for obtaining the necessary consent in accordance with this law has not been completed”.
      In the CDCD group, the ethical conflict will emerge in the context of decisions regarding WLST or ending of resuscitation efforts. Teams should ensure that there are no conflicts of interest; thus, transplant team members cannot be involved in decisions related to patient prognosis, withdrawal of ventilatory or organ perfusion support or determination of death.

      Non-DCD

      Older donors, usually deceased from cerebrovascular disease, are generally affected by a number of medical comorbidities including, diabetes, hypertension, previous history of malignancy and obesity. The latter, now pandemic in the Western world, is responsible for steatotic transformation of a large proportion of potential donor livers.

      Older donor age

      Utilisation of livers from older donors represents a logical means to expand the donor pool. In the non-transplant setting, the liver’s physiologic function remains well preserved throughout life, likely a result of its unique regenerative capacity. However, patients transplanted with livers from older donors are at increased risk of developing graft failure and mortality due to an increased vulnerability to ischaemia/reperfusion and a diminished regenerative ability of older livers [
      • Schmucker D.L.
      • Sanchez H.
      Liver regeneration and aging: a current perspective.
      ]. A further mechanism could be the increased burden of comorbidities in older donors such as, hypertension, diabetes, dyslipidaemia and obesity, which may lead to atherosclerotic vessels and steatotic grafts. Several studies have shown that older donor livers are associated with PNF [
      • Ploeg R.J.
      • D’Alessandro A.M.
      • Knechtle S.J.
      • Stegall M.D.
      • Pirsch J.D.
      • Hoffmann R.M.
      • et al.
      Risk factors for primary dysfunction after liver transplantation–a multivariate analysis.
      ], hepatic artery thrombosis [
      • Park Y.
      • Hirose R.
      • Coatney J.L.
      • Ferrell L.
      • Behrends M.
      • Roberts J.P.
      • et al.
      Ischemia-reperfusion injury is more severe in older versus young rat livers.
      ] and ischaemia-reperfusion injury.
      Although increasing donor age adversely affects survival after LT [], liver grafts have been used from selected deceased donors older than 70 years. While there are reports of excellent short-term results, long-term follow-up with septuagenarian and octogenarian deceased donors showed no differences in long-term patient or graft survival between hepatitis C negative recipients of livers from older compared with younger donors. In contrast, the 7-year survival for HCV positive recipients of older donor livers was less than half that of HCV negative recipients. Transplantation of livers from septuagenarian and octogenarian donors can achieve excellent long-term patient and graft survival for selected HCV negative patients [
      • Chedid M.F.
      • Rosen C.B.
      • Nyberg S.L.
      • Heimbach J.K.
      Excellent long-term patient and graft survival are possible with appropriate use of livers from deceased septuagenarian and octogenarian donors.
      ].
      There is consistent evidence of an interaction between older donor age and positive recipient HCV status that predisposes patients to fibrosing cholestatic hepatitis, post-transplant infections, graft failure and mortality [
      • Uemura T.
      • Nikkel L.E.
      • Hollenbeak C.S.
      • Ramprasad V.
      • Schaefer E.
      • Kadry Z.
      How can we utilize livers from advanced aged donors for liver transplantation for hepatitis C?.
      ].

      Liver grafts from donors with diabetes

      A retrospective analysis of the Scientific Registry of Transplant Recipients database (2004–2008) (25,413 patients) showed that recipients from diabetes mellitus donors experienced worse 1- and 5-year graft survival than recipients from non-diabetes mellitus donors and this was particularly lower for recipients from donors with diabetes mellitus duration >5 years. However, in patients without HCV infection, using diabetes mellitus donors was not independently associated with worse post-transplantation graft survival. Matching these diabetes mellitus donors to recipients without HCV may be safe [
      • Zheng J.
      • Xiang J.
      • Zhou J.
      • Li Z.
      • Hu Z.
      • Lo C.M.
      • et al.
      Liver grafts for transplantation from donors with diabetes: an analysis of the Scientific Registry of Transplant Recipients database.
      ].

      Steatotic liver grafts

      Hepatic steatosis is defined as the accumulation of droplets of fat in the hepatocytes and is associated with a range of post-transplant complications and poor graft function in particular. The key to this dysfunction is the ischaemia-reperfusion injury. The reported incidence of steatosis in the liver graft is between 9–26% among the liver donor population [
      • Karayalcin K.
      • Mirza D.F.
      • Harrison R.F.
      • Da Silva R.F.
      • Hubscher S.G.
      • Mayer A.D.
      • et al.
      The role of dynamic and morphological studies in the assessment of potential liver donors.
      ].
      Steatosis is classified as mild (10–30%), moderate (30–60%), or severe (>60%) [
      • D’Alessandro A.M.
      • Kalayoglu M.
      • Sollinger H.W.
      • Hoffmann R.M.
      • Reed A.
      • Knechtle S.J.
      • et al.
      The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation.
      ], but it is believed that steatosis will disappear after LT. There are two patterns of hepatic steatosis, microvescicular and macrovescicular. Microvescicular steatosis refers to the accumulation of tiny lipid droplets measuring <1 mm giving a foamy appearance of the cytoplasm and it is associated with rare conditions including drug toxicity, acute fatty liver in pregnancy and Reye disease. Macrovescicular steatosis is defined by the presence of small to large droplets that may end up occupying the whole cytoplasm; it is typically associated with alcohol, obesity and diabetes. Small fat droplets seem not to be involved with poor graft function. The volume of large droplet macrosteatosis in the liver graft is closely linked to its suitability for transplantation.
      Mild macrosteatosis (<30% volume) is considered suitable for transplantation. Livers with moderate macrovescicular steatosis (30–60%) may result in acceptable outcomes in select donor-recipient combinations. Severe macrosteatosis (>60%) is linked with unacceptable risks of graft failure, acute kidney injury, biliary complications and mortality [
      • Deroose J.P.
      • Kazemier G.
      • Zondervan P.
      • Ijzermans J.N.
      • Metselaar H.J.
      • Alwayn I.P.
      Hepatic steatosis is not always a contraindication for cadaveric liver transplantation.
      ,
      • Verran D.
      • Kusyk T.
      • Painter D.
      • Fisher J.
      • Koorey D.
      • Strasser S.
      • et al.
      Clinical experience gained from the use of 120 steatotic donor livers for orthotopic liver transplantation.
      ].
      Low-grade macrosteatotic liver grafts (⩽30% macrosteatosis) resulted in a 5-year graft survival rate of 60% or more up to BAR 18, comparable to non-steatotic grafts [
      • 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.
      ]. Microsteatotic or ⩽30% macrosteatotic liver grafts can be used safely up to BAR score of 18 or less, but liver grafts with more than 30% macrosteatotis should be used with risk adjustment, that is, up to BAR score of 9 or less. Microvescicular steatosis does not preclude the use of grafts.
      Current developments of extracorporeal normothermic machine perfusion devices may allow in the near future to assess moderately and severely steatotic grafts prior to implantation, furthermore it is foreseeable that normothermic machine perfusion-based defatting protocols may be developed to allow further expansion of the donor pool.

      HBcAb positive donor grafts

      One of the current efforts to overcome the organ shortage is based on the use of grafts from anti-HBV core antigen (anti-HBc) positive donors. These grafts are common in countries with high prevalence of HBV infection, such as Asia and the Mediterranean countries. This is despite the risk of HBV transmission to the recipient after LT [
      • Angelico M.
      • Nardi A.
      • Marianelli T.
      • Caccamo L.
      • Romagnoli R.
      • Tisone G.
      • et al.
      Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: evidence from the Liver Match cohort study.
      ].
      HBcAb positive donor grafts have better outcomes when transplanted into HBsAg positive than HBsAg negative recipients. These findings suggest that donor HBcAb positivity requires more stringent allocation strategies.
      Anti-HBc positive liver donors frequently have occult HBV infection, i.e. persistent liver and/or serum HBV DNA without serologic evidence of active HBV infection so that viral replication may increase with the use of post-transplant immunosuppression and in particular with corticosteroids. The liver grafts from anti-HBc positive donors are currently the main sources of de novo HBV infection after LT [
      • Joya-Vazquez P.P.
      • Dodson F.S.
      • Dvorchik I.
      • Gray E.
      • Chesky A.
      • Demetris A.J.
      • et al.
      Impact of anti-hepatitis Bc-positive grafts on the outcome of liver transplantation for HBV-related cirrhosis.
      ]. Many centres now use grafts from anti-HBc positive donors for HBsAg negative recipients. Since the probability of such de novo HBV infection is substantially lower in anti-HBc and/or anti-HBs positive compared to HBV naïve recipients (15% vs. 48%), it is reasonable to recommend that liver grafts from anti-HBc positive donors should be preferentially directed to HBV-exposed liver transplant candidates. The presence of anti-HBs seems to protect from de novo HBV infection and both anti-HBc and anti-HBs positive recipients can safely receive anti-HBc positive liver grafts without any post-transplant HBV prophylaxis (probability of de novo HBV infection <2%). Pre-transplant vaccination alone does not appear to be an effective strategy, as de novo HBV infection after LT developed in 10% of successfully vaccinated recipients without any post-transplant prophylaxis. However, HBV vaccination should be offered to all naïve HBV patients early in the course of non-HBV chronic liver disease (i.e. in the pre-cirrhotic stage), even though additional anti-HBV prophylaxis will be needed in cases of LT with grafts from anti-HBc positive donors.
      If de novo post-LT HBV infection develops, antiviral treatment is needed and it is reasonable to think that the efficacy of treatment is similar to that of post-transplant HBV recurrence. Given the poor resistance profile of long-term lamivudine monotherapy and the low potency of adefovir, both entecavir and tenofovir may be the agents of choice at present, despite the current lack of data.
      In summary, liver grafts from anti-HBc positive donors can be safely used, preferentially in HBsAg positive or anti-HBc/anti-HBs positive recipients. HBsAg negative recipients should receive prophylaxis with lamivudine, while both anti-HBc and anti-HBs positive recipients may need no prophylaxis at all [
      • Cholongitas E.
      • Papatheodoridis G.V.
      • Burroughs A.K.
      Liver grafts from anti-hepatitis B core positive donors: a systematic review.
      ,
      • Yu S.
      • Yu J.
      • Zhang W.
      • Cheng L.
      • Ye Y.
      • Geng L.
      • et al.
      Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation.
      ].
      Lastly, a series of eight cases of LT using grafts from deceased HBsAg positive in HBsAg positive recipients showed that it is feasible, and may provide further expansion of the pool of organ donors with appropriate antiviral management and monitoring [
      • Choi Y.
      • Choi J.Y.
      • Yi N.J.
      • Lee K.
      • Mori S.
      • Hong G.
      • et al.
      Liver transplantation for HBsAg-positive recipients using grafts from HBsAg-positive deceased donors.
      ].

      HCV positive donors

      Chronic donor shortages, made it necessary to consider HCV positive donors as an alternative organ source. While the use of HCV antibody–positive grafts in recipients with HCV infection is a common practice and is generally considered safe [
      • Alvaro E.
      • Abradelo M.
      • Fuertes A.
      • Manrique A.
      • Colina F.
      • Alegre C.
      • et al.
      Liver transplantation from anti-hepatitis C virus-positive donors: our experience.
      ,
      • Saab S.
      • Chang A.J.
      • Comulada S.
      • Geevarghese S.K.
      • Anselmo R.D.
      • Durazo F.
      • et al.
      Outcomes of hepatitis C- and hepatitis B core antibody-positive grafts in orthotopic liver transplantation.
      ], LT of HCV positive grafts in HCV negative recipients is avoided. The transplantation of HCV positive donor livers into HCV positive recipients has not been associated with greater disease progression or graft loss [
      • Northup P.G.
      • Argo C.K.
      • Nguyen D.T.
      • McBride M.A.
      • Kumer S.C.
      • Schmitt T.M.
      • et al.
      Liver allografts from hepatitis C positive donors can offer good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis.
      ] and has shown similar graft and patient survival to HCV positive recipients who received HCV negative livers. Superinfection with a different donor genotype from that of the recipient may occur with all genotypes. HCV positive donors (whose genotype may not be known at the time of procurement) are often avoided for candidates with non-type 1 infection, since there is a reduced ability to treat type 1 genotype superinfection. However, the newer generation DAAs may change the recommendation in the future [
      • Coilly A.
      • Furlan V.
      • Roche B.
      • Barau C.
      • Noel C.
      • Bonhomme-Faivre L.
      • et al.
      Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence.
      ,
      • Coilly A.
      • Roche B.
      • Dumortier J.
      • Leroy V.
      • Botta-Fridlund D.
      • Radenne S.
      • et al.
      Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.
      ].
      The use of HCV antibody–positive grafts in recipients with HIV and HCV co-infections has been associated with poorer graft and patient survival [
      • Terrault N.A.
      • Roland M.E.
      • Schiano T.
      • Dove L.
      • Wong M.T.
      • Poordad F.
      • et al.
      Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection.
      ,
      • Miro J.M.
      • Montejo M.
      • Castells L.
      • Rafecas A.
      • Moreno S.
      • Aguero F.
      • et al.
      Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study.
      ]. Optimal strategies for donor and recipient selection have not been fully defined in this population to date.
      It is important to note that stored fresh arterial and venous grafts from HCV- and HBV-infected donors used for different types of vascular reconstruction during LT, were recently found to be the route of transmission of infection from donor to uninfected recipients [
      Potential transmission of viral hepatitis through use of stored blood vessels as conduits in organ transplantation-Pennsylvania, 2009.
      ]. In order to avoid these problems the HTA in England has set rules and a registry to avoid wastage of these vessels, the American Organ Procurement and Transplantation Network (OPTN) policy was amended to preclude their storage for use in recipients other than the recipients of the corresponding organ [].

      Donors with previous or current malignancy

      Livers from a donor with previous history of malignancy can be used in selected situations, as donor tumour transmission through LT has been rare. Between 1965 and 2003, thirty-eight such cases have been reported by the Israel Penn International Transplant Tumour Registry.
      Transmission of donor-related malignancy by organ transplantation may occur and is often a fatal complication in immunosuppressed transplant recipients. Acceptance of livers from donors with a current or past history of cancer is a challenging decision for both surgeons and patients.
      Primary intracranial malignancy have generally a low risk of spread outside the central nervous system, hence the relatively low risk of transmission to transplant recipients [
      • Watson C.J.
      • Roberts R.
      • Wright K.A.
      • Greenberg D.C.
      • Rous B.A.
      • Brown C.H.
      • et al.
      How safe is it to transplant organs from deceased donors with primary intracranial malignancy? An analysis of UK Registry data.
      ].
      However, case reports describe transmission of malignancy has occurred from donors with primary malignancy of the central nervous system. These cases are typical of donors with high-grade malignant tumours and who have undergone debulking surgery, radiotherapy and ventricular-systemic shunt interventions that compromise the blood brain barrier. Advice from the Council of Europe in 1997 stated that while the use of organs from donors with low-grade primary malignancy was safe, organs from potential donors with high-grade malignant tumours of the central nervous system, especially where the integrity of the blood brain barrier is compromised, should no longer be considered safe for transplantation. In 2003 a monothematic ASTS meeting issued recommendations about the use of organs from donors with a history of malignancy. Glioblastoma multiforme, along with melanoma, choriocarcinoma and lung cancer were considered absolute contraindications to liver donation [
      • Feng S.
      • Buell J.F.
      • Chari R.S.
      • DiMaio J.M.
      • Hanto D.W.
      Tumors and transplantation: the 2003 Third Annual ASTS State-of-the-Art Winter Symposium.
      ].
      A retrospective analysis of UK registry data has shown that none of the 448 recipients of organs from 177 donors with primary intracranial malignancy developed a transmitted tumour. Among donors with high-grade tumours, there were 23 grade IV gliomas (glioblastoma multiforme) and nine medulloblastomas. Despite the reassuring study there remains a small but definite risk of transmitting cancer from donors with primary intracranial malignancy. The surgeon should be aware of all the relevant donor information, including tumour histology and treatment, including radiotherapy and surgery. At the time of organ retrieval a thorough examination of the thoracic and abdominal cavities for metastatic tumour should be undertaken.
      In terms of non-central nervous system tumours, as previously mentioned, melanoma, choriocarcinoma and lung cancer constitute absolute contraindications to donation. More common tumours such as colorectal and breast cancers are absolute contraindications to donation if in advanced stage (CRC >T3 or breast cancer >T1c). Organ donation needs careful consideration depending on the exact tumour stage and the disease-free interval.
      Finally, it is paramount to counsel potential recipients regarding the small but definite risk of transmission of malignancy, as well as their chance of survival if they choose to remain on the waiting list.

      Use of liver grafts from infected donors

      Organ transplantation is not without risk of microbial infections, since in contrast to the US CDC principle of ‘zero’ risk, the European philosophy is that risk cannot be eliminated, but must be put in a clinical context (Table 4). In general, a risk classification has been used to evaluate the safety and the acceptability of donors according to the type of infection.
      Table 4Organ-donor-derived infectious transmissions (Adapted from
      • Fishman J.A.
      • Grossi P.A.
      Donor-derived infection–the challenge for transplant safety.
      ).
      *Including multi-drug resistant gram-negative infections.

      Unacceptable risk

      This classification includes absolute contraindication. An example of a donor with unacceptable infections is the positivity for HIV-1 or HIV-2. Despite the important progress in the treatment of this infection, which have led to a significant increase in the survival and to an important improvement in the QoL of patients with HIV, the absence of definitive therapies makes this infection an absolute contraindication for accepting a donor.
      The same principle has to be applied to all the systemic infections due to micro-organisms, such as multidrug-resistant bacterial infections or WNV, for whom a practical therapeutic option does not exist. Donors with proven WNV infections of the central nervous system should not be considered eligible because of the risk of recipient transmission [
      • Kusne S.
      • Smilack J.
      Transmission of West Nile virus by organ transplantation.
      ]. The detection of IgM occurs approximately 4 days after viremia, and seroconversion to IgG occurs at approximately 8 days. Nonetheless, WNV serum IgM may persist for up to 500 days after acute infection. Thus, neither the presence of WNV serum IgM nor its absence is sufficient to exclude active infection; donor screening requires the use of nucleic acid test to identify acutely infected donors [
      • Nett R.J.
      • Kuehnert M.J.
      • Ison M.G.
      • Orlowski J.P.
      • Fischer M.
      • Staples J.E.
      Current practices and evaluation of screening solid organ donors for West Nile virus.
      ]. Transmission from infected donors to transplant recipients has not occurred in every instance, and pre-existing immunity in recipients may limit transmission. Once an infection occurs, symptomatic disease is more common among immunocompromised patients, and significant persistent neurological morbidity or mortality may ensue. There are no proven treatments for WNV at this time.
      In general, encephalitis, particularly with fever, without a documented source is typically associated with viral infectious disease transmission. In many instances of transmission, encephalitis is not initially suspected in the donor. Therefore, most experts believe that donors with clinical encephalitis without a proven cause should likely be avoided [].
      Donors with evidence of active tuberculosis should not be considered as organ donors; if donors with untreated latent Mycobacterium tuberculosis infections are used, the recipients should be treated following the recently published guidelines [
      • Morris M.I.
      • Daly J.S.
      • Blumberg E.
      • Kumar D.
      • Sester M.
      • Schluger N.
      • et al.
      Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report.
      ]. Isoniazid seems to be effective and its hepatotoxicity occurs in 6% of treated recipients. Donor-derived tuberculosis infections usually become symptomatic less than 3 months after transplantation. It is important to note that symptoms, particularly in liver recipients, may be atypical and include fever, sepsis, and elevated liver enzymes. If recognised early, recipient with active tuberculosis have a better chance of survival [
      • Holty J.E.
      • Gould M.K.
      • Meinke L.
      • Keeffe E.B.
      • Ruoss S.J.
      Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data.
      ].

      Increased, but acceptable risk

      This classification includes cases where transmissible organisms or diseases are identified during the evaluation process of the donor, but organ utilisation is justified by the specific health situation of the recipient or the severity of their clinical condition. Specifically, this category includes those cases in which the risk of death of the recipient without transplantation is higher compared with the risk of transplantation [
      • Ison M.G.
      • Grossi P.
      Donor-derived infections in solid organ transplantation.
      ]. An example is the use of HCV or HBsAg positive donors in HCV or HBV negative recipients.
      Although the transmission of syphilis from an infected donor has been rarely reported, the prophylactic treatment of recipients who receive organs from donors with positive syphilis serology generally prevents transmission. Typically, recipients are treated for late latent syphilis (i.e., 3 doses of intramuscular penicillin G benzathine (2.4 million units) [
      • Sifri C.D.
      • Ison M.G.
      Highly resistant bacteria and donor-derived infections: treading in uncharted territory.
      ]. Donors with a positive non-treponemal serology (i.e., rapid plasma reagin or VDRL test) should have confirmatory testing performed even if these results become available after transplantation because the rate of false positivity among organ donors is high [

      Theodoropoulos N, Jaramillo A, Penugonda S, Wasik C, Brooks K, Carrera JD, et al. Comparison of syphilis screening tests in deceased organ donors. <https://idsa.confex.com/idsa/2012/webprogram/Handout/id472/POSTER64_521.pdf>. Accessed March, 2013.

      ]. Confirmed positive syphilis serology is considered a marker for risk behaviours that place the donor at an increased risk for HIV, HBV, and HCV, as stated by the US Public Health Service guidelines.

      Calculated risk

      This classification includes all cases where, even in the presence of transmissible diseases, transplantation is allowed for recipients with the same disease or with a protective serological status; this risk applies also to donors with documented bacteremia and/or bacterial meningitis provided that the donor was on targeted antimicrobial treatment for a minimum duration of 24–48 h [
      • Ison M.G.
      • Grossi P.
      Donor-derived infections in solid organ transplantation.
      ]. Donors with HCV or HBV infection belong to this category (see previous sections).
      The transmission of bacterial infections is frequently mitigated by the common use of perioperative antibiotics. Much has been learned about the risk of bacterial infections in donors: donors with select bacterial infections can be safely used as long as appropriate therapy is provided to both the donor before procurement and the recipient after transplantation. Available information suggests that organs from a donor with a bacteremia who has received active antibacterial treatment for at least 48 h can be safely used as long as the same effective antibiotic therapy is continued in the recipients [
      • Cerutti E.
      • Stratta C.
      • Romagnoli R.
      • Serra R.
      • Lepore M.
      • Fop F.
      • et al.
      Bacterial- and fungal-positive cultures in organ donors: clinical impact in liver transplantation.
      ]. Although the ideal duration of antimicrobial therapy in the recipient has not been prospectively studied, most experts recommend treating the recipient with active therapy directed against the cultured bacteria for at least 14 days [
      • Cerutti E.
      • Stratta C.
      • Romagnoli R.
      • Serra R.
      • Lepore M.
      • Fop F.
      • et al.
      Bacterial- and fungal-positive cultures in organ donors: clinical impact in liver transplantation.
      ,
      • Gonzalez-Segura C.
      • Pascual M.
      • Garcia Huete L.
      • Canizares R.
      • Torras J.
      • Corral L.
      • et al.
      Donors with positive blood culture: could they transmit infections to the recipients?.
      ]. The donor should be assessed for disseminated foci of infection because this may represent a higher risk of transmission, which is especially high if the organ to be retrieved has evidence of involvement. The strongest data come from donors with documented bacterial meningitis who received effective antimicrobial therapy for at least 24 to 48 h: the risk of transmission was exceptionally low with the active treatment of the donor and the recipient. Infection at sites other than the liver or the biliary tree (e.g., sputum and urine), without demonstration of disseminated infections, do not typically require treatment of recipients. Bacteremia with virulent organisms such as Staphylococcus aureus and Pseudomonas aeruginosa in particular, may result in early post-transplant sepsis or mycotic aneurysm formation at the site of allograft vascular anastomoses. The standard of care is to administer longer courses of therapy in the recipient (e.g., two weeks) if the donor is known to have been bacteremic with a virulent organism [
      • Fischer S.A.
      • Lu K.
      Screening of donor and recipient in solid organ transplantation.
      ].
      EBV is of particular concern because of its association with post-transplant lymphoproliferative disorder, especially in the paediatric population. Donor and recipient screening should be performed, and there should be consideration of pre-emptive monitoring in high risk situations (i.e. D+/R−). A concomitant reduction in immunosuppression is a mainstay of treatment. Early graft dysfunction should prompt an evaluation for hepatic involvement of post-transplant lymphoproliferative disorder; later presentations of post-transplant lymphoproliferative disorder are more likely to present with disseminated disease.
      Livers from donors who are seropositive for the parasite T. cruzi, responsible for Chagas disease, can be considered for transplantation [
      • Altclas J.D.
      • Barcan L.
      • Nagel C.
      • Lattes R.
      • Riarte A.
      Organ transplantation and Chagas disease.
      ]. T. cruzi can remain asymptomatic for a prolonged period of time after infection. Symptoms include fever, often associated to a painful, erythematous rash. Recipients whose donors have proven T. cruzi seropositivity should be screened regularly after transplantation for parasitemia and, if found positive, should undergo treatment [
      • Chin-Hong P.V.
      • Schwartz B.S.
      • Bern C.
      • Montgomery S.P.
      • Kontak S.
      • Kubak B.
      • et al.
      Screening and treatment of chagas disease in organ transplant recipients in the United States: recommendations from the chagas in transplant working group.
      ]. Donors with proven Naegleria meningoencephalitis, can be used with a low risk of transmission [
      • Bennett W.M.
      • Nespral J.F.
      • Rosson M.W.
      • McEvoy K.M.
      Use of organs for transplantation from a donor with primary meningoencephalitis due to Naegleria fowleri.
      ].

      Non-assessable risk

      This classification includes cases where the evaluation process does not allow an appropriate risk assessment for transmissible diseases [
      • Ison M.G.
      • Grossi P.
      Donor-derived infections in solid organ transplantation.
      ]. Organs from donors infected with highly resistant bacteria (i.e., vancomycin-resistant Enterococcus, Acinetobacter baumannii, carbapenemase-producing Klebsiella pneumonia) have rarely been used safely and such offers should be discussed with an experienced infectious diseases physician, given the high risk of graft loss and mortality in case of transmission of infection to the recipient [
      • Sifri C.D.
      • Ison M.G.
      Highly resistant bacteria and donor-derived infections: treading in uncharted territory.
      ].
      Turning to fungal infections, the most commonly transmitted from donors to recipients include Candida species, endemic mycoses (particularly Coccidioides immitis), and Cryptococcus. When transmitted, these mycoses are associated with significant morbidity in addition to frequent graft and/or recipient loss. Contamination of the organ during procurement and preservation appears to occur more commonly than transmissions of infection. Positive cultures for Candida species of the preservation fluid should prompt for treatment. Most centres include azole antifungals in their post-transplant prophylaxis regimen. Appropriate dosing and close monitoring of drug levels is necessary as azoles interact with calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors [
      • Singh N.
      • Huprikar S.
      • Burdette S.D.
      • Morris M.I.
      • Blair J.E.
      • Wheat L.J.
      Donor-derived fungal infections in organ transplant recipients: guidelines of the American Society of Transplantation, infectious diseases community of practice.
      ].

      Standard risk

      This classification includes cases where the evaluation process did not identify a transmissible disease [
      • Ison M.G.
      • Grossi P.
      Donor-derived infections in solid organ transplantation.
      ].

      Recommendations:

      Figure thumbnail fx27

      Donor risk index

      Feng et al. [
      • 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.
      ] developed, in 2006, a DRI with the aim to quantify the effect of specific donor characteristics on the risk of post-transplant graft failure. The value of such information is heightened by the life-saving and life-threatening potential of every decision to either accept or reject a particular opportunity for transplantation. The characteristics of the donor that independently predict and significantly increase risk of graft failure are 5: age (>40 years), race (African American vs. White), cause of death (cardiovascular accidents, others, DCD), partial/split liver graft and height (per 10 cm decrease). Two independent transplant factors, cold ischaemia time and donor location respect to recipient location, are also significantly associated with increased risk of graft loss. To note, a limitation of the DRI is that it does not include liver steatosis.

      Balance of risk score

      The BAR score was calculated on 37,255 patients in the UNOS (United Network for Organ Sharing) database and identifies the six strongest predictors of post-transplantation patient survival [
      • 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.
      ]. Partial transplants (split and living donor LT), DCD and combined liver transplants were excluded to reduce confounding variables. Six strongest predictors of post-transplant survival included: recipient MELD score, cold ischaemia time, recipient and donor age, previous transplantation, and dependence from life support prior to transplantation. With increasing BAR points, patient survival decreases. However, while mortality is linearly increasing with higher MELD or SOFT scores, mortality remains stable in the BAR up to 16, and then increases exponentially at BAR 18.
      The BAR seems appropriate to define the threshold when the risk of LT is too high. This threshold was determined at 18 BAR score points, being the sum of several independent risk factors. Interestingly, high MELD situations can be balanced in BAR system by accepting only a low donor and recipient age and short cold ischaemia. In regards to steatosis, liver grafts with microsteatosis or 30% or less macrosteatosis could be used safely up to a BAR score of 18 or less, but liver grafts more than 30% macrosteatotic should be used with risk adjustment, that is, up to BAR score of nine or less [
      • 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.
      ].

      Liver transplantation

      Different types of liver transplantation

      The shortage of available grafts and the large number of indications for LT have led to the research for alternative strategies in order to obtain organs for as many patients as possible []. In Europe and the US, the most common type of LT is the so-called “conventional” or “standard”, that uses whole liver grafts [, ]. However, in Asian countries, where deceased donation is scarce, the most common type of transplantation is partial grafts from living donors [