EASL Clinical Practice Guidelines

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 [7]. 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 [8]. 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.

Fig. 2
Primary diseases leading to liver transplantation in Europe (01/1988–12/2011) [40]. ∗Others: Budd-Chiari: 792, Bening liver tumours or polycystic diseases: 1228, Parasitic diseases: 80, Other liver diseases: 1304.

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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 [9]. The MELD was developed to determine the short-term prognosis for patients undergoing TIPS after gastrointestinal bleeding [10], 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 [11]. 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 [12].

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 [13].

Table 2
Exceptions to MELD score.

Serum sodium (MELD-Na), serum sodium and age (integrated MELD) scores have been proposed to improve the predictive value of MELD [14]. Delta MELD (ΔMELD), meaning the change of MELD over time, might also be a better predictor of mortality [[15], [16]].

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 [17]. 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 [18]. Since interferon (IFN) is contraindicated in patients with decompensated cirrhosis, the only choice for these patients is treatment with NUCs. Lamivudine first and adefovir [19] 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 [17]. 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 [[20], [21], [22]]. Lactic acidosis has been reported in some patients with MELD score >20, particularly when treated with entecavir [23]. 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 [[19], [24]].

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 [25], 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 [26].



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 [[27], [28]]. The advent of IFN-free antiviral therapy has modified this approach [29]. 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 [30] (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 [[31], [32]]. 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) [[31], [32]].

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) [33]. 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) [34]. 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 [35].


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) [36]; 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 [30]. 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% [37], 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 [38]. 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 [39].


Alcoholic liver disease

Alcoholic liver disease is one of the most common indications of LT in Western countries [40]. LT for alcoholic cirrhosis has a favourable outcome, similar to other aetiology of end-stage liver disease [41]. 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 [42]. 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 [43]. 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 [44]. If the AAH is severe, defined by a Maddrey’s score over 32, treatment with steroids can improve the outcome [45]. 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 [46].

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 [47]. 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 [48]. 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.


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 [49]. 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 [50]. 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 [51]. 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 [52]. 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.


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 [53].

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 [54].


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 [55]. 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 [56]. 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 [57].


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 [58]. 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 [59].


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 [60].

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) [61]. 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 [[62], [63]]. 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 [64]. 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 [65]. 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%) [66].

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 [67]. 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 [68]. 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 [[69], [70]].

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 [71]. The outcome is generally favourable for those with an early onset of the disease [72]. Outcome after LT in patients with FAP not related to Val30Met mutation are inferior compared with patients transplanted for FAP related to Val30Met mutations [72]. In these patients, overall survival at 5 years is reported to be above 80% [[71], [73], [74]].

If the disease is in an advanced stage, LT does not improve the symptoms [75]. The pre-transplant work-up should take into account the cardiomyopathy due to TTR fibril deposit, which could impair the post-LT outcome [76]. 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 [77]. Nevertheless amyloid polyneuropathy acquired after a domino LT can be reversible after liver retransplantation [78].


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% [79]. More recently, Yao et al. [80] 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 [81]. Recently Duvoux et al. [82] 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 [83]. 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 [[84], [85]].

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 [86].


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 [87]. A protocol combining neoadjuvant chemoradiation and LT was first used in patients with unresectable hilar cholangiocarcinoma [88]. Results have confirmed that this approach leads to significantly lower recurrence rates and higher long-term survival rates than other existing treatment modalities [89]. 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 [90]. 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% [91].

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 [92]. 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 [93]. 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 [94]. 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 [[95], [96]]. 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 [97].

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 [98]. 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 [99]. 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 [100]. To date there are no multicentre studies examining the impact of CAD on LT outcome.


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 [101].

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 [102]. 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 [103]. 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 [104].

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 [105]. 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 [106]. 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 [107]. 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 [108].


Renal function

Cirrhotic patients with renal failure have a 7-fold increased risk of death, with 50% of patients dying within one month [109], 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, [110] for more than three months.

The evaluation of renal clearance can be difficult in patients with cirrhosis [111], 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 [112]. 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.


Nutritional assessment

Liver cirrhosis is associated with malnutrition, and cachexia is present in nearly 70% of patients with end-stage liver disease [113]. Malnutrition is associated with lower survival rate after LT, patients with BMI <18.5 are the group at highest risk of poor outcome [114]. 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 [115]. 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 [116], and no nutritional protocol in cirrhotic patients waiting for LT has been established [117]. Considering patients with high BMI, outcomes after LT seem to be worse in patients with a BMI >40 compared with normal weight patients [114]. 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 [118]. 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 [119].


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 [120]. DSA is an important tool but more research needs to be done in order to understand their usefulness.


Infection screening

Patients with cirrhosis are prone to develop infections that could result in the development of multiple organ failure and death [121]. 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 [122].

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 [122].

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. [122].

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 [122].

Regarding vaccination, it is important to make sure that transplant candidates are immunised against HAV and HBV, varicella, Pneumococcus, influenza and tetanus.

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

Patients with cirrhosis are prone to develop infections that could result in the development of multiple organ failure and death [121]. 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 [122].

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 [122].

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. [122].

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 [122].

Regarding vaccination, it is important to make sure that transplant candidates are immunised against HAV and HBV, varicella, Pneumococcus, influenza and tetanus.

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 [122].

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 [123] 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% [124].

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 [125].

Pneumonia is the third leading cause of infections in patients with cirrhosis [[126], [127]], with an increased risk of bacteremia compared with the general population [128]. Community-acquired pneumonia is often caused by S. pneumonia and H. influenza [129]. 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 [[130], [131]].

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 [132].

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 [133]. 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 [134]. 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.


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 [135]. 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.


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 [136].


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 [137]. 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 [138].

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 [[139], [140]]. 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 [141].

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 [142].

Pre- and post-transplant smoking rates are high and cause significant morbidity and mortality due to cardiovascular events [143], increased incidence of hepatic artery thrombosis [144] and increased incidence of malignancies such as oropharyngeal [145]. Therefore smoking cessation should be mandatory in all transplant candidates.