Liver Transplantation in the United Kingdom

TRANSPLANT INTERNATIONAL Liver Transplantation in the United Kingdom James Neuberger Organ Donation and Transplantation, National Health Service Blood and Transplant, Bristol, UK; and Queen Elizabeth Hospital, Birmingham, UK Liver transplantation (LT) services in the United Kingdom are provided by 7 designated transplant centers for a population of approximately 64 million. The number of deceased organ donors has grown, and in 2014-2015 it was 1282 (570 donation after circulatory death and 772 donation after brain death). Donor risk is increasing. In 2014-2015, there were 829 LTs from deceased and 38 from living donors. The common causes for transplantation are liver cell cancer, viral hepatitis, and alcohol-related liver disease. Livers are allocated first nationally to super-urgent listed patients and then on a zonal basis. The United Kingdom will be moving toward a national allocation scheme. The median interval between listing and transplantation is 152 days for adults awaiting their first elective transplant. Of the adults listed for the first elective transplant, 68% underwent transplantation at < 1 year; 17% are waiting; and 4% and 11% were removed or died, respectively. The 1- and 5-year adult patient survival rate from listing is 81% and 68%, respectively, and from transplantation is 92% and 80%, respectively. The transplant program is funded through general taxation and is free at the point of care to those who are eligible for National Health Service (NHS) treatment; some have to pay for medication (up to a maximum payment of US $151/year). The competent authority is the Human Tissue Authority which licenses donor characterization, retrieval, and implantation; transplant units are commissioned by NHS England and NHS Scotland. National Health Service Blood and Transplant (NHSBT) promotes organ donation, maintains the organ donor register, obtains consent, and undertakes donor characterization and offering. NHSBT also maintains the national waiting list, develops and applies selection and allocation policies, monitors outcomes, and maintains the UK National Transplant Registry and commissions a national organ retrieval service. Liver Transplantation 22 1129-1135 2016 AASLD. Received January 5, 2016; accepted April 8, 2016. The first successful liver transplantation (LT) in Europe was done by Sir Roy Calne and Roger Williams in Cambridge in 1968. Since then, the number of transplants Abbreviations: CUMSUM, cumulative sum; DBD, donation after brain death; DCD, donation after circulatory death; EU, European Union; HTA, Human Tissue Authority; ITU, intensive therapy unit; LT, liver transplantation; NHS, National Health Service; NHSBT, National Health Service Blood and Transplant; ODR, organ donor register; SNOD, specialist nurse in organ donation; UKELD, United Kingdom Model for End-Stage Liver Disease. Address reprint requests to James Neuberger, Ph.D., Organ Donation and Transplantation, National Health Service Blood and Transplant, Fox Den Road, Bristol, BS34 8RR UK. Telephone: Tel.: 44 117 975 7488; FAX: 44 121 627 2414; E-mail: james.neuberger@ nhsbt.nhs.uk Copyright VC 2016 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/lt.24462 Potential conflict of interest: Nothing to report. has grown (Fig. 1), and there are now 7 designated transplant units covering the United Kingdom. In this paper, the provision of LT services is described, together with the outcomes. Burden of Liver Disease The burden of liver disease in the United Kingdom is high and increasing as recently summarized by the Lancet Commission (1) ; this reported that standardized mortality rates from liver disease have increased 4-fold since 1970 and nearly 5-fold in those aged less than 65 years. Indeed, liver disease is the third most common cause of premature death in those aged between 18 and 65 years, accounting for 62,000 life-years lost each year (ischemic heart disease 74,000 life-years and selfharm 71,000 life-years). In 2012, there were an estimated 60,000 people with cirrhosis, who had 57,682 hospital admissions and 10,948 deaths. The great majority of these (around three-quarters) are due to alcohol, and most of the rest are associated with obesity and viral hepatitis. TRANSPLANT INTERNATIONAL 1129

LIVER TRANSPLANTATION, August 2016 1000 Number 900 800 700 600 500 611 Donors Transplants Transplant list 572 636 640 632 633 676 657 706 679 712 675 510 782 739 553 825 784 492 932 880 549 924 842 611 400 300 365 314 338 371 200 268 100 0 2005-2006 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011 2011-2012 2012-2013 2013-2014 2014-2015 Year FIG. 1. The number of donors, transplants, and patients registered for a LT on the UK National Transplant Registry. Access to Health Care The United Kingdom consists of 4 nations, England, Scotland, Wales, and Northern Ireland, with a combined population of approximately 64 million. Health care is free at the point of delivery to those who are ordinarily resident in all countries. There is a small private health care system. Spending on health care accounts for 9.4% of the United Kingdom s gross national product (compared with Germany, 11.3%; France, 11.6%; Netherlands, 11.9%; and the United States, 17.7%). (2) Patients do not pay for the treatment, and some may be eligible for reimbursement for travel costs. Prescriptions are free to those in Northern Ireland, Scotland, and Wales. In England, there is a charge of 8.20 (US $12) per chargeable item. Delivery of Liver Transplantation In England, the provision of health care is through NHS Trusts, which will include those hospital trusts that deliver LT services. In the other nations, health care is delivered though Health and Social Care in Northern Ireland, NHS Scotland, and NHS Wales. While there are differences in funding and staffing levels across the 4 nations, the standard of care is broadly similar. Delivery of Liver Transplantation in the United Kingdom COMPETENT AUTHORITY The competent authority in the United Kingdom is thehumantissueauthority(hta).thisisan executive, nondepartmental public body acting, in the context of organ donation, retrieval, and transplantation, across the United Kingdom. The HTA also oversees the legal requirements for consent for organ donation: in Scotland, the legal framework is covered by the Human Tissue (Scotland) Act 1130 TRANSPLANT INTERNATIONAL

LIVER TRANSPLANTATION, Vol. 22, No. 8, 2016 2006, and the term authorization is used. There are separate specific regulations for obtaining consent for donation from children and adults with incapacity. NATIONAL HEALTH SERVICE BLOOD AND TRANSPLANT National Health Service Blood and Transplant (NHSBT) is a UK-wide NHS arms-length body, funded by all 4 Departments of Health. Its statutory obligations (3) include maintaining the national transplant waiting list, the provision of an organ and tissue matching an allocation service, the development and implementation of selection and allocation of deceased donor organs, supporting organ donation, donor characterization, and transport. Clinical advice to NHSBT is provided through the Liver Advisory Group comprised of representation from all LT units and includes donor and recipient coordinators, clinical scientists, and lay members (appointed independently). ORGAN DONATION Organ Donor Register NHSBT maintains the Organ Donor Register (ODR) which invites people to register their wishes to donate 1 or more organs. Awareness of the ODR is increased by local and national advertising and support from some companies using their loyalty card programs and through some government portals (such as the Driving Vehicle Licensing Authority). At present, there are over 21 million registrants. Joining the ODR is considered legal evidence for consent/authorization for donation and cannot, in theory at least, be overridden by family members. People can also record their wish not to donate. The United Kingdom has one of the highest rates of refusal for organ donation (approximately 40% of families decline). This refusal rate is higher when the potential donor is not on the ODR and is higher for DCD than DBD donors. In 2014-2015, the consent rates were 67% for families of DBD donors and 52% for DCD donors. When the potential donor was registered on the ODR or their wishes were known, the consent rates were 92% for DBD and 84% for DCD compared with 56% and 41%, respectively, when the wishes were not known; 111 families overrode the potential donor s wish to donate. Until this year, the United Kingdom had an opt-in approach to consent. The Welsh government introduced a soft opt-out system for consent to organ donation. (4) From December 2015, all those normally resident in Wales will be considered to have given consent unless they have opted out by indicating their wishes on the ORD. This process of deemed consent was implemented after widespread discussion and a national publicity campaign. It is too early to determine the impact of this change. Specialist Nurses in Organ Donation NHSBT employs approximately 200 specialist nurses in organ donation (SNODs) across the United Kingdom. Their roles include working with intensive care units and emergency departments to be aware of donation and approaching families of potential donors when either brain stem death has been declared or when the decision to withdraw treatment has been made. The SNOD is also responsible for arranging donor characterization, ensuring all relevant and available information is available to the recipient team through the electronic offering system, arranging the retrieval process and the transport of organs, and providing support for the donor s family. TRANSPLANT UNITS There are 7 designated LT units in the United Kingdom, 6 of which are in England and 1 is in Scotland. These units are commissioned by NHS England and NHS Scotland, respectively. The designated transplant units are as follows: Queen Elizabeth Hospital and Birmingham Children s Hospital, Birmingham; Addenbrooke s Hospital, Cambridge; Royal Infirmary in Edinburgh, Edinburgh; St. James s Hospital, Leeds; Royal Free Hospital, London; King s College Hospital, London; and Freeman Hospital, Newcastle. Potential candidates for transplantation may be referred to any one of these units, regardless of where they live. Eligibility to a LT under the NHS is determined by the Directions to NHSBT (3) which defines 2 groups of patients: group 1 includes those who are persons ordinarily resident in the United Kingdom or the Channel Islands, members of Her Majesty s UK Forces serving abroad, Crown servants, and those citizens of EU member states who are entitled to receive transplant services in the United Kingdom; TRANSPLANT INTERNATIONAL 1131

LIVER TRANSPLANTATION, August 2016 and group 2 patients include everyone else. Organs from deceased donors must be allocated first to those ingroup1andcanbeofferedtothoseingroup2 only if the offer has been declined for all group 1 patients. Selection and Allocation Policies Selection policies are reviewed regularly and published on the NHSBT Web site. (5) Patients are reviewed by the center s multidisciplinary team, which determines whether the patient meets the nationally agreed upon criteria. Patients can be listed when the risk of death without transplant at 1 year exceeds the risk of death after transplant. The United Kingdom Model for End-Stage Liver Disease (UKELD) score (6) is used to assess prognosis, and a UKELDscoreof49orhigherisrequiredforliver cell cancer (serum alpha-fetoprotein < 1000 IU/L and a single tumor <5 cm in diameter, or up to 5 tumors all < 3cm or a single tumor >5cm and <7 cm where there is no evidence of tumor progression over 6 months) or a variant syndrome (such as diuretic-resistant ascites, chronic hepatic encephalopathy, intractable pruritus, familial amyloid polyneuropathy, or polycystic liver disease). Candidates are expected to have a greater than 50% probability of surviving at least 5 years after transplant with a quality of life acceptable to the patient. There is no upper age limit. There are clear criteria for those with a history of alcohol and other substance abuse: the United Kingdom does not and has never required a minimum period of abstinence. Patients must be reviewed by a specialist in alcohol and substance abuse, must be abstinent since first advised, and must agree to maintain lifelong abstinence. At present, cessation of smoking is not a requirement. There is a pilot program for transplanting those who present for the first time with acute alcoholic hepatitis, but at the time of writing, only 1 patient has been enrolled who was delisted following improvement. Patients with nonend-stage liver disease (such as chronic encephalopathy, intractable pruritus, or hepatopulmonary syndrome) can be listed as exemptions. All patients have a right to a second opinion from another center, and there is a national appeals process if the unit feels that transplantation is indicated but does not fulfill nationally agreed upon criteria. NHSBT reviews each registration and refers back those that do not meet agreed listing criteria; NHSBT also undertakes an occasional audit of reference data. The United Kingdom maintains a super-urgent scheme, for those patients who meet agreed upon criteria and are expected to live less than 7 days. Criteria for this category include fulminant hepatic failure and early posttransplant graft failure; those with acute-onchronic liver failure are not eligible. Allocation Donated organs from deceased donors are offered to those on the super-urgent list nationally; if there is no suitable super-urgent patient, then the liver is offered to a center, and each center has a designated zone. If the zonal center has no suitable recipient, then the organ is offered sequentially to other centers, and if not accepted, it is offered to Europe or may be used for a group 2 patient. To ensure equity of access, the size of the designated zone is reviewed and adjusted annually to ensure that the proportion of deceased donors allocated to each unit mirrors the proportion of patients on the transplant waiting list. In November 2015, a review showed the difference between the percentage share of registrations in the previous 12- month period and donors in the previous 3-year period ranged from 2.9 to 1 3.4. Because this difference was not significant, there were no changes in the allocation zones. No adjustments have been required in the previous 3 years, but before that, adjustment required transferring no more than 3 hospitals to adjacent zones. The Liver Advisory Group has proposed a national allocation scheme that is being prepared for implementation. Modeling suggests a national allocation scheme may reduce up to 40 deaths each year. GOVERNANCE AND MONITORING OF OUTCOMES NHSBT is responsible for monitoring outcomes after transplantation and does this through cumulative sum (CUSUM) monitoring and use of Funnel plots. (7) When a center signals, NHSBT will seek an explanation from the unit. The response is assessed by the associate medical director in NHSBT, the Chair of the Advisory group (or deputy if there is a conflict of interest) and a representative, which forms the commissioners. If the response is not acceptable or there is evidence of an ongoing problem that has not been resolved, the relevant commissioners may undertake a formal review and suspension of the center. 1132 TRANSPLANT INTERNATIONAL

LIVER TRANSPLANTATION, Vol. 22, No. 8, 2016 DATA AND STATISTICS Donors In the year up to March 31, 2015, there were 36,145 audited deaths. There were 1282 deceased organ donors, of which 772 were DBD (donors after neurological determination of death). In addition, there were 639 people from whom consent was obtained but donation did not proceed. Indications for Liver Transplant Of the 630 adults receiving a first elective transplant between April 1, 2013 and March 31, 2014, hepatocellular carcinoma accounted for 25%; alcoholassociated liver disease accounted for 23%; viral hepatitis B and C alone accounted for 12%; primary sclerosing cholangitis accounted for 11%; primary biliary cirrhosis accounted for 9%; and autoimmune hepatitis accounted for 7%. Other indications account for the remainder. HCV infection was implicated in 21% of recipients (primarily alcohol-associated liver disease and hepatocellular carcinoma). The median unadjusted Model for End-Stage Liver Disease score of adults listed for a primary elective transplantation was 18. Waiting List As of March 31, 2015, there were 611 people (45 aged under 18 years) on the waiting list, compared with 548 the year before. The median waiting time from listing is 152 days with some variation between centers. Outcomes After Registration Of the 860 new adult elective registrants between April 1, 2012 and March 31, 2013, within 1 year, 68% had been transplanted; 17% were still waiting; 4% were removed (usually as too unwell or outside criteria); and 11% died awaiting a graft. Transplants In the years 2014-2015, there were 882 LTs of which 844 were from deceased donors, which is a slight reduction compared with 912 in 2013-2014. Of these, there were 621 adult elective first transplants and 69 adult super-urgent transplants. Survival ADULT ELECTIVE The 1-year survival rate for adult elective first transplants was 92% (95% confidence intervals, 91.2-93.5), and the 5-year survival rate was 80%. Unadjusted 5-year patient survival varies between indication, ranging from 73% for cancer and 86% for those grafted for alcohol and for autoimmune liver disease. In comparison, 1- and 5-year patient survival rates from listing for adults listed for their first elective transplant were 81% and 68%, respectively. ADULT SUPER-URGENT The 1- and 5-year patient survival rates after transplant were 90% and 80%, respectively. INTERACTIONS WITH CONTINENTAL EUROPE Sixteen people who were non-uk resident EU patients had a LT in the United Kingdom: 14 had a DBD liver (2 split-liver), 1 DCD whole liver, and 1 living donor. Forty-three group 2 patients underwent a LT, and all but 1 had a living donor liver. In 2014-2015, livers donated by UK deceased donors were grafted into 14 recipients from the EU, and there were 5 UK recipients who received livers donated in EU member countries. Challenges In the last 6 years, the number of donors has increased by over 60%, and the number of LTs increased by a smaller amount. (8) The increase in organ donors can be attributed to a combination of many factors, the most influential of which was implementation of the recommendations of the Organ Donor Task Force. (9) The discrepancy between the increase in donors and in LT reflects the increased risk of donors: donors are becoming older and with greater body mass index values. A further challenge is the increase in DCD donors: in the year to April 2015, for adult recipients, there were 667 DBD and 232 DCD donors which resulted in 607 and 132 LTs, respectively. The ratios of donors to transplants were, therefore, 91% and 57% for DBD and DCD, respectively. In the early days of the program, patient and graft outcomes were inferior to recipients of DCD livers, but with increasing experience and improved techniques this difference is decreasing. The DCD program was developed to TRANSPLANT INTERNATIONAL 1133

LIVER TRANSPLANTATION, August 2016 100 90 80 % of all organs 85% 82% Transplanted: % of all organs meeting age criteria 1 85% 82% 70 Percentage 60 50 40 30 20 10 0 100 90 Kidney Liver Pancreas Bowel Heart Lungs Organs from actual DBD donors Donor age criteria met 1 Consent for organ donation Organs offered for donation Organs retrieved for transplant Organs transplanted 23% 22% 17% 31% 27% 21% 3% 7% % of all organs Transplanted: % of all organs meeting age criteria 80 80% 80% 70 Percentage 60 50 40 30 35% 35% 20 10 0 Kidney Liver Pancreas Lungs Organs from actual DCD donors Donor age criteria met Consent for organ donation Organs offered for donation Organs retrieved for transplant Organs transplanted 12% 7% 21% 10% FIG. 2. The outcome of potential donors from donors after (A) brain death and (B) circulatory death. ensure that the organ donation and transplantation occurs whenever appropriate, but a prospective audit showed no evidence that the presence of an active DCD program results in a switch of donors from DBD to DCD. (10) The wider use of effective treatments for hepatitis C virus, the increase in the number of patients with nonalcoholic fatty liver disease, and more effective therapies for the treatment of liver cell cancer will variously affect the waiting list. 1134 TRANSPLANT INTERNATIONAL

LIVER TRANSPLANTATION, Vol. 22, No. 8, 2016 CURRENT DEVELOPMENTS AND PRIORITIES The greatest priority is to increase the number of transplants and improve the quality and length of life of patients who would benefit from LT. As shown in Fig. 2, there is room for improvement across the entire donation and transplantation pathway. The 2 areas for improving outcomes are reducing decline rates and increasing usage rates. There is clearly no single measure that will increase donation and transplant rates. Measures adopted to improve consent rates include changing public behavior to support organ donation, removing actual or perceived objections to donation, and ensuring that every potential donor is identified and that the family is approached by personnel who are trained to seek consent whenever appropriate. The lack of intensive therapy unit (ITU) beds remains an issue: for example, a study in 2010 showed the United Kingdom has 3 ITU beds per 100,000 population compared with 25 beds per 100,000 population in Germany. (10) The shortage of beds has significant implications on donation because this may affect how end-of-life care is administered. Work is continuing to assess organ donation from uncontrolled deceased donors in emergency departments. Increasing organ utilization requires supporting surgeons and patients to take appropriate risks, improving donor optimization, developing biomarkers that will help the surgeon decide whether the liver should be used, and using new technologies such as donor hypothermia, normothermic regional perfusion, and normothermic and hypothermic machine perfusion, which are being evaluated. (11) Acknowledgments: The work presented here represents the contribution of all those involved in the donation, retrieval, and transplant pathways, including clinicians and scientists, managers and others in UK hospitals, NHSBT Organ Donation and Transplantation Directorate and the UK Registry, the 4 national Departments of Health, NHS England, and the HTA. REFERENCES 1) Williams R, Aspinall R, Bellis M, Camps-Walsh G, Cramp M, Dhawan A, et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet 2014;384:1953-1997. 2) The World Bank. Health expenditure per capita (current US$). www.data.worldbank.org/indicator/sh.xpd.pcap. Accessed November 27, 2015. 3) NHSBT. (Gwaed a Thrawsblaniadau r GIG) (England) Directions 2005. www.nhsbt.nhs.uk/download/nhsbt_directions_2005. pdf. Accessed April 21, 2016. 4) Organ Donation Wales. Deemed consent. www.organdonationwales. org. Accessed April 21, 2016. 5) Neuberger J, Gimson A, Davies M, Akyol M, O Grady J, Burroughs A, Hudson M; for Liver Advisory Group; UK Blood and Transplant. Selection of patients for liver transplantation and allocation of donated livers in the UK. Gut 2008;57:252-257. 6) Barber K, Madden S, Allen J, Collett D, Neuberger J, Gimson A; for United Kingdom Liver Transplant Selection and Allocation Working Party. Elective liver transplant mortality: development of a United Kingdom end-stage liver disease score. Transplantation 2011;92:469-476. 7) Neuberger J, Madden S, Collett D. Review of methods for measuring and comparing center performance after organ transplantation. Liver Transpl 2010;16:1119-1128. 8) Johnson RJ, Bradbury LL, Martin K, Neuberger J; for UK Transplant Registry. Organ donation and transplantation in the UK the last decade: a report from the UK national transplant registry. Transplantation 2014;97(suppl 1):S1-S27. 9) Organ Donation Task Force 2008. www.odt.nhs.uk. Accessed April 21, 2016. 10) Broderick AR, Manara A, Bramhall S, Cartmill M, Gardiner D, Neuberger J. A donation after circulatory death program has the potential to increase the number of donors after brain death. Crit Care Med 2016;44:352-359. 11) Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet 2010;376:1339-1346. TRANSPLANT INTERNATIONAL 1135