Clinical Practice Guidelines EASL Clinical Practice Guidelines: Liver transplantationq ⇑ European Association for the Study of the Liver Introduction the variability in values and preferences, or the greater the uncer- tainty, the more likely a weaker recommendation is warranted. The first human orthotopic liver transplantation (LT) in Europe was performed by Sir Roy Calne in Cambridge in 1968 [1], only one year after the first successful human liver transplantation The candidate to liver transplantation reported by Thomas Starzl in the United States [2]. Since then LT has evolved rapidly, becoming the standard therapy for acute Indications to liver transplantation and chronic liver failure of all aetiologies, with more than 80,000 procedures performed to date. Survival rates have improved sig- LT should be considered in any patient with end-stage liver dis- nificantly in the last 25 years, achieving rates of 96% and 71% at 1 and 10 years after LT respectively [3]. ease, in whom the LT would extend life expectancy beyond what the natural history of underlying liver disease would predict or in This great success is mostly attributable to several advances such as the introduction of new immunosuppressive agents whom LT is likely to improve the quality of life (QoL). Patients should be selected if expected survival in the absence of trans- and preservation solutions, to the improvements in surgical techniques and to the early diagnosis and management of com- plantation is one year or less, or if the patient had an unaccept- plications after LT [4]. As a consequence of these achievements, able QoL because of liver disease. A detailed medical evaluation indications for LT have been expanded resulting in a growing is performed to ensure the feasibility of LT. demand for transplantable grafts and in a dramatic organ short- LT is indicated in patients with end-stage liver disease, in age. Therefore, one of the main ongoing challenges the transplant patients with the development of hepatocellular carcinoma community is facing is to expand the donor pool in order to min- (HCC) and in patients with acute liver failure. The most common imize the rate of patient death on the waiting list [5]. On the indication to LT for end-stage liver disease in adults is cirrhosis. other hand, liver transplanted patients are surviving longer after Patients should be referred to transplant centres when major the operation and long-term outcomes are becoming the main complications of cirrhosis, such as variceal haemorrhage, ascites, concern for clinicians, who have to deal with direct and indirect hepatorenal syndrome and encephalopathy occur. side effects of immunosuppressive therapy. Conversely, acute liver failure represents an urgent indication This Clinical Practice Guideline (CPG) has been developed to to LT [7]. Viruses (especially hepatitis viruses A and B), drugs assist physicians and other healthcare providers during the eval- (acetaminophen), and toxic agents are the most common causes uation process of candidates for LT and to help them in the cor- of acute liver failure, with the proportions varying between coun- rect management of patients after LT. tries. Seronegative hepatitis is also an important cause of LT for The evidence and recommendations in these guidelines have acute liver failure, being the most common indication for LT in been graded according to the Grading of Recommendations acute liver failure in the UK [8]. Prognosis is essentially deter- Assessment Development and Evaluation (GRADE) system [6]. mined by neurological status, but is also rapidly affected by dam- age to other organs. LT has revolutionized the prognosis of acute The strength of recommendations reflects the quality of underly- ing evidence. The principles of the GRADE system have been 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 enunciated. The GRADE system offers two grades of recommen- dation: strong (1) or weak (2) (Table 1). The CPGs thus consider LT in Europe are summarized in Fig. 1. In recent years, an extension of indications has been observed, the quality of evidence: the higher the quality of evidence, the more likely a strong recommendation is warranted; the greater but in contrast, the transplant community is currently facing organ shortages. Actually, limited organ availability and an increasing demand for organ transplantation has extended trans- plant waiting times and thus increased morbidity and mortality Received 8 October 2015; accepted 8 October 2015 for potential recipients on these waiting lists. This has led to q Contributors. Coordinator: Patrizia Burra; Panel members: Andrew Burroughsy, increased pressure on organ allocation programs. Since a success- Ivo Graziadei, Jacques Pirenne, Juan Carlos Valdecasas, Paolo Muiesan, Didier ful outcome requires optimal patient selection and timing, the y Samuel, Xavier Forns. Andrew Burroughs passed away during the preparation of issue of which patients to list for LT and when to transplant cir- this chapter. We would like to acknowledge Giacomo Germani and Emmanuel rhotic patients has generated great interest as well as consider- Tsochatzis, who contributed to its completion. ⇑ Correspondence: EASL Office, 7 Rue Daubin, CH 1203 Geneva, Switzerland. able controversy. E-mail address: easloffice@easloffice.eu. Journal of Hepatology 2015 vol. xxx j xxx–xxx Please cite this article in press as: EASL Clinical Practice Guidelines: Liver transplantation.J Hepatol (2015), http://dx.doi.org/10.1016/j.jhep.2015.10.006 Clinical Practice Guidelines Table 1. GRADE system used in EASL Clinical Practice Guidelines [6]. In fact, there are several exceptions to MELD, including pul- monary complications of cirrhosis, hepatic encephalopathy, Grade evidence amiloidosis, primary hyperoxaluria, etc. (Table 2). In these cases, I Randomized, controlled trials extra points could be attributed to patients in order to give them II-1 Controlled trials without randomization priority to transplantation [13]. II-2 Cohort or case-control analytic studies Serum sodium (MELD-Na), serum sodium and age (integrated II-3 Multiple time series, dramatic uncontrolled MELD) scores have been proposed to improve the predictive experiments value of MELD [14]. Delta MELD (DMELD), meaning the change III Opinions of respected authorities, descriptive of MELD over time, might also be a better predictor of mortality epidemiology [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 Others*: procedures). 3404 (4%) Cancers: Acute hepatic failure: 14,194 (15%) MELD score is driving the allocation of grafts in many coun- 7347 (8%) tries in Europe. However, the final decision for allocation is fre- Metabolic diseases: Cholestatic diseases: 5430 (6%) 9543 (10%) quently based on multiple parameters besides MELD including the match with the donor, but also local/regional priorities. Recommendations: • Evaluation for LT should be considered when a major complication of cirrhosis occurs (Grade II-2) Cirrhosis: 53,040 (57%) • MELD score is good to predict short-term pre- transplant mortality risk (Grade II-1) Fig. 1. 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. • 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 Score and prognostic factors for end-stage liver disease diseases requiring LT, whose severity is not described by the MELD, should be recognised. A different priority The timing of LT is crucial since patients who should be trans- needs to be given to these patients by experts (Grade planted for end-stage liver disease need to undergo surgery II-3/III) before life-threatening systemic complications occur. They • HCC is a particular MELD exception that requires extra should not be transplanted too early since the advantage of trans- points to get access to the transplant. These points plant might be unbalanced by the risk of surgery and immuno- have to be standardized in each country and have to suppression for all life. take into account size, number of nodules, AFP levels, Priority on the waiting list was based in the past by the wait- recurrence after downstaging therapy (Grade II-1) ing 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 crea- tinine, 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 gastroin- Management of patients with liver cirrhosis (without HCC) testinal bleeding [10], and then proposed for predicting 3-month mortality in patients with end-stage liver disease. The management of a patient in the waiting list aims at eliminat- In patients with MELD 614, 1-year survival was lower with ing not only contraindications of surgery, but also contraindica- rather than without transplantation [11]. Consequently, a MELD tions to taking long-term immunosuppressive treatment. This score