EASL Clinical Practice Guidelines: Liver transplantation

1 EASL Clinical Practice guidelines : Liver transplantationqEuropean Association for the Study of the Liver IntroductionThe first human orthotopic Liver transplantation (LT) in Europewas performed by Sir Roy Calne in Cambridge in 1968[1], onlyone year after the first successful human Liver transplantationreported by Thomas Starzl in the United States[2]. Since thenLT has evolved rapidly, becoming the standard therapy for acuteand chronic Liver failure of all aetiologies, with more than 80,000procedures performed to date. Survival rates have improved sig-nificantly in the last 25 years, achieving rates of 96% and 71% at 1and 10 years after LT respectively[3].This great success is mostly attributable to several advancessuch as the introduction of new immunosuppressive agentsand preservation solutions, to the improvements in surgicaltechniques and to the early diagnosis and management of com-plications after LT[4].

2 As a consequence of these achievements,indications for LT have been expanded resulting in a growingdemand for transplantable grafts and in a dramatic organ short-age. Therefore, one of the main ongoing challenges the transplantcommunity is facing is to expand the donor pool in order to min-imize the rate of patient death on the waiting list[5]. On theother hand, Liver transplanted patients are surviving longer afterthe operation and long-term outcomes are becoming the mainconcern for clinicians, who have to deal with direct and indirectside effects of immunosuppressive Clinical Practice Guideline (CPG) has been developed toassist physicians and other healthcare providers during the eval-uation process of candidates for LT and to help them in the cor-rect management of patients after evidence and recommendations in these guidelines havebeen graded according to the Grading of RecommendationsAssessment Development and Evaluation (GRADE) system[6].

3 The strength of recommendations reflects the quality of underly-ing evidence. The principles of the GRADE system have beenenunciated. The GRADE system offers two grades of recommen-dation: strong (1) or weak (2) (Table 1). The CPGs thus considerthe quality of evidence: the higher the quality of evidence, themore likely a strong recommendation is warranted; the greaterthe variability in values and preferences, or the greater the uncer-tainty, the more likely a weaker recommendation is candidate to Liver transplantationIndications to Liver transplantationLT should be considered in any patient with end-stage Liver dis-ease, in whom the LT would extend life expectancy beyond whatthe natural history of underlying Liver disease would predict or inwhom LT is likely to improve the quality of life (QoL). Patientsshould be selected if expected survival in the absence of trans-plantation is one year or less, or if the patient had an unaccept-able QoL because of Liver disease.

4 A detailed medical evaluationis performed to ensure the feasibility of is indicated in patients with end-stage Liver disease, inpatients with the development of hepatocellular carcinoma(HCC) and in patients with acute Liver failure. The most commonindication to LT for end-stage Liver disease in adults is should be referred to transplant centres when majorcomplications of cirrhosis, such as variceal haemorrhage, ascites,hepatorenal syndrome and encephalopathy , acute Liver failure represents an urgent indicationto LT[7]. Viruses (especially hepatitis viruses A and B), drugs(acetaminophen), and toxic agents are the most common causesof acute Liver failure, with the proportions varying between coun-tries. Seronegative hepatitis is also an important cause of LT foracute Liver failure, being the most common indication for LT inacute Liver failure in the UK[8].

5 Prognosis is essentially deter-mined by neurological status, but is also rapidly affected by dam-age to other organs. LT has revolutionized the prognosis of acuteliver failure, causing survival to increase from 10 20% (all causescombined) to 75 80% at 1 year and 70% at 5 years. Indications forLT in Europe are summarized inFig. recent years, an extension of indications has been observed,but in contrast, the transplant community is currently facingorgan shortages. Actually, limited organ availability and anincreasing demand for organ transplantation has extended trans-plant waiting times and thus increased morbidity and mortalityfor potential recipients on these waiting lists. This has led toincreased pressure on organ allocation programs. Since a success-ful outcome requires optimal patient selection and timing, theissue of which patients to list for LT and when to transplant cir-rhotic patients has generated great interest as well as consider-able of Hepatology2015vol.

6 Xxxjxxx xxxReceived 8 October 2015; accepted 8 October 2015qContributors. Coordinator:Patrizia Burra;Panel members:Andrew Burroughsy,Ivo Graziadei, Jacques Pirenne, Juan Carlos Valdecasas, Paolo Muiesan, DidierSamuel, Xavier Burroughs passed away during the preparation ofthis chapter. We would like to acknowledge Giacomo Germani and EmmanuelTsochatzis, who contributed to its completion. Correspondence: EASL Office, 7 Rue Daubin, CH 1203 Geneva, Practice GuidelinesPlease cite this article in press as: EASL Clinical Practice guidelines : Liver Hepatol (2015), and prognostic factors for end-stage Liver diseaseThe timing of LT is crucial since patients who should be trans-planted for end-stage Liver disease need to undergo surgerybefore life-threatening systemic complications occur. Theyshould not be transplanted too early since the advantage of trans-plant might be unbalanced by the risk of surgery and immuno-suppression for all on the waiting list was based in the past by the wait-ing time, and severity of Liver disease.

7 The Child-Pugh-Turcotteclassification and since 2002 also the model of end-stage liverdisease (MELD) score (based on objective measures such as crea-tinine, bilirubin and international normalized ratio) are used forpatient priority[9]. The MELD was developed to determine theshort-term prognosis for patients undergoing TIPS after gastroin-testinal bleeding[10], and then proposed for predicting 3-monthmortality in patients with end-stage Liver patients with MELD614, 1-year survival was lower withrather than without transplantation [11]. Consequently, a MELD scoreP15 is recommended to list patients with end-stage liverdisease. However, it does not provide a prediction of mortalityfollowing LT except for those patients with very high MELD scores over 35[12].In very sick patients with MELD >30 the risk of mortality andmorbidity after transplantation should be does not reflect the impact of complications such asrefractory ascites and recurrent encephalopathy in the risk ofmortality without fact, there are several exceptions to MELD, including pul-monary complications of cirrhosis, hepatic encephalopathy,amiloidosis, primary hyperoxaluria, etc.

8 (Table 2). In these cases,extra points could be attributed to patients in order to give thempriority to transplantation [13].Serum sodium (MELD-Na), serum sodium and age (integratedMELD) scores have been proposed to improve the predictivevalue of MELD[14]. Delta MELD (DMELD), meaning the changeof 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 givepriority to patients with HCC. Additional points can be addeddepending on the type of tumour (size, number of nodules, alphafetoprotein [AFP] level, waiting time, response to downstagingprocedures).MELD score is driving the allocation of grafts in many coun-tries in Europe. However, the final decision for allocation is fre-quently based on multiple parameters besides MELD includingthe match with the donor, but also local/regional : Evaluation for LT should be considered when a major complication of cirrhosis occurs (Grade II-2) MELD score is good to predict short-term pre-transplant mortality risk (Grade II-1) MELD is based on objective laboratory tests and can be used in organ allocation (Grade II-1) As the MELD has several limitations, patients with Liver diseases requiring LT, whose severity is not described by the MELD, should be recognised.

9 A different priority needs to be given to these patients by experts (Grade II-3/III) HCC is a particular MELD exception that requires extra points to get access to the transplant. These points have to be standardized in each country and have to take into account size, number of nodules, AFP levels, recurrence after downstaging therapy (Grade II-1)Management of patients with Liver cirrhosis (without HCC)The management of a patient in the waiting list aims at eliminat-ing not only contraindications of surgery, but also contraindica-tions to taking long-term immunosuppressive treatment. Thisassessment is not uniform and should be discussed in each trans-plant centre. Contraindications to LT are dynamic, changing overtime and may vary among Liver transplant centres, depending ontheir local and selecting a good recipient for LT thusrequires the collaboration of several specialists, who accountfor all comorbidities.

10 The final decision should be made,within each expert centre, among a multidisciplinary group ofstaff including transplant hepatologist, transplant surgeon,Table system used in EASL Clinical Practice guidelines [6].Grade evidenceIRandomized, controlled trialsII-1 Controlled trials without randomizationII-2 Cohort or case-control analytic studiesII-3 Multiple time series, dramatic uncontrolled experimentsIIIO pinions of respected authorities, descriptive epidemiologyMetabolic diseases:5430 (6%)Acute hepatic failure:7347 (8%)Others*:3404 (4%)Cancers:14,194 (15%)Cholestatic diseases:9543 (10%)Cirrhosis:53,040 (57%)Fig. 1. Primary diseases leading to Liver transplantation in Europe (01/1988 12/2011)[40]. Others: Budd-Chiari: 792, Bening Liver tumours or polycysticdiseases: 1228, Parasitic diseases: 80, Other Liver diseases: Practice GuidelinesPlease cite this article in press as: EASL Clinical Practice guidelines : Liver Hepatol (2015), of Hepatology2015vol.