Should living donor liver transplantation be part of every liver transplant program?

Transcription

1 32 Forum on Liver Transplantation / Journal of Hepatology 43 (2005) [10] Markmann JF, Markmann JW, Markmann DA, Bacquerizo A, Singer J, Holt CD, et al. Preoperative factors associated with outcome and their impact on resource use in 1148 consecutive primary liver transplants. Transplantation 2001;72: [11] Trotter JF, Mackenzie S, Wachs M, Bak T, Steinberg T, Polsky P, et al. Comprehensive cost comparison of adult-adult right hepatic lobe living-donor liver transplantation with cadaveric transplantation. Transplantation 2003;75: [12] van Agthoven M, Metselaar HJ, Tilanus HW, de Man RA, JN IJ, Martin van Ineveld BM. A comparison of the costs and effects of liver transplantation for acute and for chronic liver failure. Transpl Int 2001;14: [13] Gold MR, Russel LB, Weinstein MC. Cost effectiveness in health and medicine. New York, NY: Oxford University Press; [14] Mark DB, Hlatky MA, Califf RM, Naylor CD, Lee KL, Armstrong PW, et al. Cost effectiveness of thrombolytic therapy with tissue plasminogen activator as compared with streptokinase for acute myocardial infarction. N Engl J Med 1995;332: [15] Ouwens JP, van Enckevort PJ, TenVergert EM, Bonsel GJ, van der Bij W, Haagsma EB, et al. The cost effectiveness of lung transplantation compared with that of heart and liver transplantation in the Netherlands. Transpl Int 2003;16: [16] Longworth L, Young T, Buxton MJ, Ratcliffe J, Neuberger J, Burroughs A, et al. Midterm cost-effectiveness of the liver transplantation program of England and Wales for three disease groups. Liver Transpl 2003;9: [17] Sagmeister M, Mullhaupt B, Kadry Z, Kullak-Ublick GA, Clavien PA, Renner EL. Cost-effectiveness of cadaveric and livingdonor liver transplantation. Transplantation 2002;73: [18] Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30: [19] Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness perspective. Hepatology 2001;33: [20] Perin DM. Economic point of view and insurance of the donors. Transplant Proc 2003;35: Should living donor liver transplantation be part of every liver transplant program? Zakiyah Kadry, Lucas Mc Cormack, Pierre-Alain Clavien* Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Raemistrasse 100, Ehoer , Zurich, Switzerland The critical shortage in donor organs is generally proffered as the main impetus behind the development of living donor liver transplantation (LDLT), and although the procedure has significantly impacted since its initial development approximately 17 years ago on the pediatric waiting list mortality and morbidity, the same cannot be stated with reference to the adult population of potential liver transplant recipients [1,2]. The picture which emerges is complex and is affected by a variety of factors such as geographic variability in the availability of deceased donor (DD) organs, differences in institutional commitments, surgical expertise, the availability of ancillary support services, emerging data on donor and recipient outcomes and complications, anatomic as well as psychosocial limiting factors in both potential donors and recipients, * Corresponding author. Tel.: ; fax: address: clavien@chir.unizh.ch (P.-A. Clavien). Abbreviations: ACOT, US Department of Health and Human Services Advisory Committee on Organ Transplantation; DD, deceased donor; ELTR, European Liver Transplant Registry; ESLD, end stage liver disease; LDLT, living donor liver transplantation; MELD, Model for end stage liver disease. Division of Transplantation MCH062, Department of Surgery, The Milton S. Hershey Medical Center, P.O. Box 850, 500 University Drive, Hershey, PA 17033, USA. and ethical considerations as well as conflicting viewpoints within the transplant community. In addressing the question Should LDLT be part of every liver transplant program? all of the issues listed need to be discussed. Although the transplant community has been developing a number of guidelines as to who should or should not perform LDLT, the question of level of need for LDLT and donor/recipient risk are constantly being weighed against the required threshold of surgical and institutional expertise. In addition, to further add complexity to this situation, we are concomitantly re-evaluating and extending our accepted indications for liver transplantation within the context of LDLT, with changes in our perceptions of minimal outcome limits in specific oncologic diseases. Ultimately, the question as to who should be performing LDLT should also enter into the realm of Who oversees innovative practice? and Do we have a structure to monitor the development and evolution of innovative techniques such as LDLT? The dichotomy which has developed with LDLT between our rule as physicians to primum non nocere : first do no harm, and our desire to help an ever-increasing population of patients with end stage liver disease places us in urgent need of structure and guidelines /$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 1. Variability in the need for LDLT Forum on Liver Transplantation / Journal of Hepatology 43 (2005) Looking at cadaveric organ donation rates in various countries, there is a recognized diversity in the percentage of organ donors per million population. Geographic variability in the availability of DD and social acceptance of cadaveric organ donation, in conjunction with the stimulus of the growing mortality of patients with end stage liver disease (ESLD) in need of liver transplantation, appear to play a crucial role in the development of LDLT [3 5]. In spite of the 1997 approval in Japan of the law for organ retrieval from brain dead donors, the low popular acceptance of cadaveric donation that has ultimately resulted in an extreme paucity of DD organs, has caused LDLT to remain as the main technique of liver transplantation performed in that country [3]. Trotter et al. found that LDLT centres in the United States had significantly fewer (46% less) DD liver grafts available per listed patient compared to non-ldlt centres [4]. In Latin America, where cadaveric donation rates vary between countries in the range of 4.5 to 11.8 per million population per year, LDLT is performed in most countries for pediatric recipients and in 3 Latin American countries for adult patients [5]. In Switzerland, faced with a non patient based liver allocation system where donor hepatic allografts originating from non transplant centres are distributed into a national pool rotated between liver transplant centres, the University of Zurich initiated their LDLT program in the year 2000 to address their low local donor rates, high waiting list numbers and significant mortality and drop out of patients due to progressive advancement of liver disease [6]. The donation rates from deceased donors are lowest in the German part of Switzerland despite numerous efforts from the Swiss transplant community to change this cultural barrier [7]. In Europe, data relating to LDLT activity can be obtained from the European Liver Transplant Registry (ELTR). Although the number of adult LDLT procedures began to exponentially increase as of 1999 until the present time, LDLT is only performed by 48% of European liver transplant centres (nz61/126) and forms only 2.9% of all liver transplantations recorded in the ELTR database (nz1468/50577) [8] (Figs. 1 and 2). This same trend can be seen in the USA where LDLT only makes up approximately 5 9% of all liver transplantations performed, even at the time of its peak in 2001 when 506 LDLT were recorded by UNOS [9]. The initial enthusiasm as well as the projected major increase in LDLT procedures has not occurred in countries where cadaveric organ donation is present despite the availability of LDLT for a number of years [4]. Reasons for this are multiple and complex. From the perspective of donor suitability, approximately O50% of potential liver transplant recipients do not have at the outset an identifiable potential donor based on either a lack of family members or other significant person willing to donate, or based on general Fig. 1. Evolution of the number of centers performing living donor liver transplantation in Europe, (European Liver Transplant Registry). donor medical contra-indications such as cumulative comorbidities, age, obesity and psychosocial reasons [10 12]. After further detailed evaluation of those living donors who appear to be initially suitable, stringent exclusion criteria based on liver anatomy, degree of hepatic steatosis and graft volume size, only 11 45% eventually proceed with liver donation [4,10 13] (see previous article by HP Tan, K Patel-Tom, and A Marcos in this forum). In other examples of how social acceptance of LDLT and availability of DD organs can impact to some extent on the degree to which donor restrictions apply, Morimoto et al. evaluated 135 patients for living donation and only 11% of cases were rejected, whereas Renz et al. describe an acceptance rate of 13% of the 75 potential donors who underwent evaluation in their institution. Other liver transplant centers have published acceptance rates ranging between these two extremes, generally w30% [4,10 14]. Fig. 2. Average number of LDLT per center in Europe, (European Liver Transplant Registry). No data available in the UNOS registry website (USA).

3 34 Forum on Liver Transplantation / Journal of Hepatology 43 (2005) Donor issues Donor safety, emphasized after the highly publicized death of a living liver donor in New York in 2001 as well as other data either published or communicated at international transplant meetings relating to instances of donor morbidity and mortality, has played a major role in the reticence of the transplant community to adopt the widespread use of LDLT [8,15 17]. To date, there have been three reported donor deaths in the USA, four in Europe, and one in Japan, India, Egypt and South America, respectively. Three other donors have required liver transplantation and one donor is in a persistent vegetative state due to complications from right hemi liver donation [15,16,18,19]. This data is difficult to translate into an accurate overall operative mortality since the exact number of living liver donor operations performed worldwide have not been recorded in all countries. Estimated living donor mortality risk has been quoted to range from 0.04% in Japan to 0.11% in the USA and 0.27% in Europe [8,9,15]. 3. Recipient issues Although the recipient indications for LDLT have been described as being the same as for cadaveric liver transplantation, the reality of the situation is that only a limited fraction of patients suffering from ESLD can undergo LDLT. Certain urgent situations such as fulminant liver failure have brought into question the clarity and freedom with which the potential donor can base his or her decision to donate. In the USA, both the New York State Health Department and the UNOS Ad Hoc Committee on Live Donation have recommended against live donation in this acute situation [4,20,21]. Also critically ill patients with acute severe decompensation of an underlying cirrhosis have been shown to have an associated high postoperative mortality with LDLT which some consider to be excessive for a healthy living donor to be placed at risk [12,22,23]. This trend can be seen when examining the data pertaining to LDLT and DD liver transplantation in the USA: 79% of LDLT recipients were reported to have been not hospitalized at the time of transplantation compared to 69% of DD recipients [24]. Additionally 8% were ICU bound compared to 15% of DD liver recipients, and MELD scores (Model for End Stage Liver Disease) were more frequently in the range (41%) than in the higher 21 to 30 score (3.9%) [24]. Technical issues do seem to play a role in these trends, since severity of recipient disease and degree of portal hypertension have been reported to impact on graft outcome particularly if the graft to body weight ratio is in the lower range [25 27]. Data from the ELTR shows an overall lower LDLT graft survival in adults, especially when a lower graft volume such as a left hemiliver is used [8]. Right hemiliver LDLT is also associated with anatomic variations in the biliary anatomy in up to 53% of cases, which has been shown to result in a higher incidence of postoperative biliary complications and a higher risk of graft loss [4, 12,28] (see previous article by S Todo, H Furukawa and T Kamiyama in this forum). In essence all of this translates into important technical and physiologic issues in LDLT which impact on the overall successful outcome of this procedure. It also questions the concept of relief in the size of the waiting list since patients in acute decompensation of their liver disease probably cannot benefit from LDLT and, in situations of LDLT graft failure this may actually worsen the competition within the allocation system. Suggested implementation of extended criteria specific to LDLT such as advanced stage hepatocellular cancer or other primary liver malignancies such as hemangioendothelioma or cholangiocarcinoma [29 32] may also create new groups of candidates for liver transplantation [33]. These are strong arguments to limit LDLT to academic centers with a wide experience in this procedure, and in cases where extended indications to liver transplantation apply, to direct patients to specific study protocols, rather than have a widespread implementation of LDLT. 4. Criteria for a LDLT program The question as to whether LDLT should be part of every liver transplant program was partly addressed in an interesting survey of 100 liver transplant surgeons published in 2003 [34]. In this survey 72% of responders considered that transplant programs have a duty to their patients to offer adult LDLT [34]. There is general agreement however that requirements need to go further with LDLT. This is a procedure, which should be performed in institutions with surgical teams having an established experience in liver transplantation, where there is appropriate ongoing oversight. LDLT centers should have a solid basis in academic surgery and clinical and scientific research: efforts to reduce donor risk will involve research and development of safe use of smaller volume grafts and in depth examination of the process of liver regeneration. The necessary multidisciplinary approach with medical, radiological and surgical alternatives to transplantation and a wide range of ancillary services are a central adjunct, which can be best provided by an academic liver transplant center. True institutional support will require a willingness to invest in LDLT, as well as the provision of a safe environment through the establishment of dedicated staff for the LDLT process and donor/recipient care, the presence of an adequate operating room space, instrumentation and staff, the inclusion of a donor advocate or a donor evaluation team that is separate to the physicians involved in the LDLT recipient s care as well as a functioning ethical committee. Centers preparing to

4 Forum on Liver Transplantation / Journal of Hepatology 43 (2005) perform LDLT should undergo careful institutional planning and have an internal peer review mechanism. A prepared disaster plan already in place in case of donor death has also been suggested and an additional outside institutional review mechanism or outside expert available for particular controversial cases has been recommended [35,36]. In the USA, guidelines have been published regarding the regulation and oversight of adult LDLT by both the US Department of Health and Human Services Advisory Committee on Organ Transplantation (ACOT) and the New York State Committee on Quality Improvement in Living Liver Donation [36]. Furthermore, the UNOS ad Hoc Living Donor Committee has developed requirements which institutions and their transplant teams must fulfill in order to be eligible for submission of verification and to ultimately qualify as a UNOS-certified LDLT center [37]. In terms of surgical experience, there is general agreement that experience in both hepatobiliary surgery and cadaveric liver transplantation is essential in the creation of a LDLT center, even though the living donor hepatectomy technically somewhat differs from an oncologic hepatic resection. Optimal suggested minimum prerequisites for LDLT teams have included a yearly volume of 50 orthotopic liver transplants, 20 to 50 hepatectomies, 20 pancreatico-duodenectomies and 10 complicated biliary reconstructions [31,35 37]. In setting guidelines however, one must not lose sight of the fact that the greatest need for LDLT has been seen by institutions lacking in deceased donor organs, that probably are unable to reach the suggested annual rate of 50 cadaveric liver transplants. Mortality on the waiting list is an important prerequisite to justify establishment of LDLT programs in countries and transplant centers where DD are scarce. It varies widely however between centers and may be underestimated if patients are removed from the transplant waiting list based upon clinical deterioration. In an intention to treat analysis, patients removed from the waiting list due to deterioration should be included in a waiting list mortality analysis. Centers having a waiting list mortality O10% despite all efforts to increase the decreased donor pool, including the use of marginal donors, could consider initiating a LDLT program. Not all transplant physicians have embraced LDLT as manifested by the fact that by 2003 only 41% of US and 48% of European liver transplant centers were offering this procedure to their patients [8,9]. This could be due to personal physician choice, lack of institutional resources, insufficient technical expertise, few potential LDLT recipients and donors as well as perceived adequate numbers of DD. The issue of donor safety is probably an excellent dissuasive factor for the initiation of a LDLT program. However, both institutional and peer reviewed oversights and self-regulation within the liver transplant community are necessary to maintain high standards, patient/donor safety as well as public trust. With the cumulating data on donor morbidity and mortality and recipient outcomes in LDLT, the presence of an appropriate consent process is essential. There have been guidelines published relating to this question in a consensus meeting organized by the American Society of Transplant Surgeons in 2000 and ACOT has recommended in the USA that the document be accessible to all educational levels and be aimed at 8th or 9th grade level of education to facilitate understanding [36,38]. The ability to speak the language and to communicate appropriately with both potential donor and recipient is of utmost importance if informed consent is to be obtained. In addition to international published data relating to morbidity and mortality rates, each center should give information on the local experience by providing the number of cases performed by the surgical team and by comparing outcomes to published data on the procedure. Information should include details pertaining to the operative technique, hospital stay, complications experienced, and documented mortality risk within the local transplant center. Short and long term results of LDLT should undergo continuous and prospective reporting to intra and extra institutional committees, authorities or societies. In fact, Table 1 Recommended requirements for a living donor liver transplant program Medical requirements Institutional requirements (1) Established need for LDLT (1) Adequate resources O10% annual waiting list mortality and/or drop out in spite of efforts (2) Donor advocate team (a) To increase local cadaveric donation rate (3) Ongoing internal and external oversight (b) To expand donor pool (marginal donors, domino and split) (4) Local and national LDLT date registry (2) Active liver transplant program (5) Presence of a disaster plan in case of LDLT donor death (a) cadaveric liver transplantation/year (b) Commitment to research (3) Wide experience in hepatobiliary surgery (a) liver resections per year (b) 20 pancreato-duodenectomies per year (c) complex biliary reconstructions per year

5 36 Forum on Liver Transplantation / Journal of Hepatology 43 (2005) some regulation by government agencies has been suggested [12,18,22]. In Europe, the ELTR maintains a database on both cadaveric and living donor liver transplant activity and outcomes from information supplied by participating centers [8]. In the USA, the National Institute of Health (NIH) is setting up a database panel of peer experts to assess and provide quality control in all the LDLT centers [12,13,39,40]. In conclusion: Should LDLT be part of every liver transplant program? The answer is definitely no. Although it is likely that families of patients on the waiting list will continue to want to donate due to the restricted cadaveric donor pool, LDLT programs can only be justified when all the necessary institutional resources and surgical expertise are in place, and when every effort continues to be made to enhance cadaveric organ donation rates (Table 1). The reality of donor deaths and published donor morbidity highlight the importance of a continuous and obligatory oversight of LDLT programs worldwide. There is an urgent need for national and international registries with mandatory reporting requirements to collect the real donor and recipient outcomes after living donation. The combined extensive surgical experience in hepatobiliary surgery and liver transplantation should be today a limiting factor to the performance of LDLT in some centers regardless of the mortality in the waiting list. On the other hand, the sentiment that just because you can do something does not mean that you have to do it should be part of the thought process of every surgical team examining the possibility of offering LDLT to their patients. The establishment of an adequate network of referral centers will allow transplant teams, who do not fulfill the criteria required for a LDLT program, to refer potential donors and patients who would like to proceed with living donation to recognized LDLT centers. Continued quality control by the transplant community through a self-regulation process with the development of necessary guidelines for the implementation of LDLT can only serve to reduce donor risk and improve LDLT outcomes. References [1] Raia SNJ, Mies S. Liver transplantation from live donors. Lancet 1989;2:497. [2] Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA. Successful liver transplantation from a living donor to her son. N Engl J Med 1990;322: [3] Tanaka K, Yamada T. Living donor liver transplantation in Japan and Kyoto University: what can we learn? J Hepatol 2005;42: [4] Trotter JF. Living donor liver transplantation: is the hype over? J Hepatol 2005;42: [5] Hepp J, Innocenti FA. 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6 Forum on Liver Transplantation / Journal of Hepatology 43 (2005) [29] Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240: [30] Kadry Z, Cintorino D, Foglieni CS, Fung J. Living donor liver transplantation and tolerance: a potential strategy in cholangiocarcinoma. Transplantation 2003;76: [31] Malago M, Testa G, Marcos A, Fung JJ, Siegler M, Cronin DC, et al. Ethical considerations and rationale of adult-to-adult living donor liver transplantation. Liver Transpl 2001;7: [32] Hassoun Z, Gores GJ, Rosen CB. Preliminary experience with liver transplantation in selected patients with unresectable hilar cholangiocarcinoma. Surg Oncol Clin N Am 2002;11: [33] Shaw Jr BW. Where monsters hide. Liver Transpl 2001;7: [34] Cotler SJ, Cotler S, Gambera M, Benedetti E, Jensen DM, Testa G. Adult living donor liver transplantation: perspectives from 100 liver transplant surgeons. Liver Transpl 2003;9: [35] Miller, C.M., Who should and who should not do LDLT? in AASLD/AHPBA Surgical Forum; Boston, Massachusetts; [36] Miller CM. Regulation and oversight of adult living donor liver transplantation. Liver Transpl 2003;9:S69 S72. [37] UNOS, Transplant Programs Appendix B, Attachment 1 (XII). Accessed 22 February at bylaws.asp. [38] American Society of Transplant Surgeons position paper on adult-toadult living donor liver transplantation. Liver Transpl; : [39] Neuberger JM, Lucey MR. Living-related liver donation: the inevitable donor deaths highlighted the need for greater transparency. Transplantation 2004;77: [40] Shiffman ML, Brown RS, Jr., Olthoff KM, Everson G, Miller C, Siegler M, et al. Living donor liver transplantation: summary of a conference at The National Institutes of Health. Liver Transpl 2002; 8: