Liver allocation: Can we ever get it right and should we ever get it right?
Authors: James Neuberger, David Mulligan
Journal: Hepatology (2014)

The problem is easy to define but the ideal solution difficult to find. How should livers from deceased donors be allocated and distributed to create fairness? The success of liver transplantation as an effective therapeutic intervention to increase both the quality and quantity of people's lives has resulted in a demand for livers that has not been matched by the availability of livers from deceased donors. The numbers of medically eligible donors has remained fairly static while the waitlist for these life-saving transplants continues to grow significantly.1, 2 To overcome this shortfall, a variety of approaches have been used to maximize the supply of organs: national and local strategies to maximize organ donation have had some, albeit limited, success, yet all too often families refuse to support donation, even sometimes against the stated wishes of the potential donor.3 Patients and families have responded to the shortfall by a variety of approaches, some legal (such as living donation), some of questionable legality (such as advertising for donors), and some illegal (such as paid or coerced donation, organ trafficking, and transplant tourism). Surgeons have responded by straining at the boundary of what is possible, using innovative techniques such as liver splitting, taking more marginal grafts, and using devices and perfusion solution combinations to improve the negative impact of ischemia/reperfusion injury. Newer technologies, such as xenografts, use of livers grown from stem cell technologies, or using scaffolds, have yet to reach the clinical arena.4 The concept of marginal grafts needs closer examination: organs from humans are second-hand or previously enjoyed and therefore carry risk. Risks may be related to the organ (such as steatosis or fibrosis) or to the donor (such as transmission of cancer, infection, or metabolic or autoimmune disease). Donor risk indexes developed to give some objective measures of risk are useful but simplistic: they are developed from retrospective data and use carefully matched donor-recipient pairings, and so may fail to include relevant factors that cannot or have not been quantified or have not been collected.5, 6 They are based on current behaviors, biased by the judgments of the surgeons choosing to use them for particular patients under specific conditions (such as ischemia times, biopsy findings, comorbidities, and so on). Therefore, such models cannot simply be extrapolated to prospective pairings. Factors that predict short-term survival may be different from those that predict longer-term outcomes: some risk factors relate to the logistics (such as steatotic and/or older [>60 years] livers may be more likely to fail if there is a longer cold ischemic time) or recipient factors (livers from donors with hepatitis C virus [HCV] infection may be low risk for a recipient also infected with HCV).7, 8 Thus, donor risk indexes, while useful, are simplistic. This is further compounded by the challenges faced by the surgeons, who may show a systematic bias towards inaccurately low estimates of graft failure.9 If organs from higher-risk donors are used, then it is the patient who takes the risk and so must give suitably informed consent. The major justification for use of higher-risk organs is the higher risk of death on the waiting list, which can be significant in several regions.10 Livers (and other organs) donated by deceased donors are considered a national resource and therefore it is logical that the process of allocation should be decided at a national level. It is axiomatic that the process should meet all the appropriate ethical and legal criteria: the process should be agreed upon by all interested parties, be transparent, evidence-based where possible, meet ethical and legal requirements, be seen as fair, equitable, and just, and simple to follow and audit. Easy to state but hard to put into practice. It is fundamentally important to distinguish allocation from distribution. The former allows prioritization of listed patients based on their disease process, or in the case of endstage liver disease, the 90-day risk of waitlist mortality that is represented by the Model for Endstage Liver Disease (MELD) score. Distribution is the mechanism that these life-saving organs are given to the patients in need in order to be most equitable and fair so that waitlist mortality can be the lowest possible and access to these vital organs can be similar regardless of where a patient resides. The US has, since February 2001, adopted an approach of allocating organs according to need, with the stated aim of reducing deaths on the waiting list. The MELD score was adopted to quantify the risks of death: there are many well-rehearsed criticisms of the MELD approach and many modifications proposed.11, 12 The approach is simple to administer, objective, and auditable. MELD has been studied heavily over the past decade and continues to be a proven and accurate predictor of waitlist mortality.13, 14 It has been long recognized that the MELD score does not reflect prognosis in all cases, as it is based on hepatic function and there are other circumstances which require some prioritization that do not share similar waitlist mortalities, but demonstrate issues like progression of disease as a driving factor: notably, for patients with hepatocellular carcinoma (HCC), the prognosis (whether to death or removal from the list) may be determined by the HCC rather than the parenchymal disease, reflected by the MELD score. To allow for this, additional points are allocated to the MELD score so that the adjusted MELD score, or MELD exception, reflects the survival. There have been several modifications to the adjustment. Other groups of patients, disadvantaged by the MELD score, are those whose quality of life is grim but who are not at immediate risk of death (such as those with intractable pruritus or encephalopathy consequent to their cirrhosis) or other associated problems, such as hepatopulmonary syndrome or metabolic disease or those with polycystic liver disease. To overcome these problems and access transplantation, there are the two options: being awarded additional points15 or finding a living donor—an option open to less than half of transplant candidates.16 Therefore, MELD and MELD exception scores are successful methods to stratify patients with liver disease based on their need for transplant, whether it be waitlist mortality or morbidity due to progression of disease. So far, so good: a system that prioritizes the sickest patient and is based on objective data: But how well does it work in practice? Overall, despite the concerns, the approach has been highly effective in achieving its goal in reducing waiting list mortality without adversely affecting survival after transplant, although hospital stay and resources may be increased.17 Furthermore, this approach has been adopted in many countries with usually, but not invariably, similar outcomes.18 Issues such as gender and ethnic differences in the normal ranges and variations in laboratory measurement of some of the variables in the calculation of the MELD score and possible distortion by, for example, hemolysis resulting in potentially misleading levels of serum bilirubin, are all well recognized. The model gives a number and that number is used to prioritize the offering sequence. However, it is often forgotten that the MELD score is an estimate of survival over a relatively short time frame and that survival estimate has a relatively wide confidence interval, so one candidate with a MELD score of, say, 25 may actually have a greater chance of death within 3 months than another with a score of 28. Furthermore, access to healthcare for a patient with a MELD score of 25 in one region of the country or the world may represent a different waitlist mortality than in another, more medically sophisticated area where access to hepatologic care is greater.19 Finally, it should be remembered that allocation of a donated liver to the highest priority suitable recipient is no guarantee that the recipient will receive the organ.20 Like any system, it can be manipulated and, given the life-saving nature of transplantation, it is scarcely surprising that both legal and illegal methods have been adopted to artificially raise the MELD score and distort allocation. These cases will no doubt continue to occur but there remain other deeper concerns.21 In the US, as in other large countries, the distribution of both donors and recipients vary and rarely are parallel, so if geographic equity is to be achieved, organs may need to be transported long distances, which will prolong ischemic times, increase cost, and may lead to worse outcomes (although improvement in preservation techniques may mitigate some of these concerns). There is, inevitably, strong evidence of geographic inequality.22, 23 The distribution of transplant centers has developed largely because of the enthusiasm and dedication of surgeons rather than in a planned manner. The degree of competition between units is associated not only with numbers on the waiting list but differences in outcomes, costs, and risk appetite.24 In this edition of Hepatology, Northup et al. from Charlottesville, VA,25 analyzed the Scientific Registry of Transplant Recipients (SRTR) data to examine the impact of exemption and show that those who had HCC MELD exceptions have superior outcomes with respect to time on the waiting list, risk of death on the waiting list, and transplant rates. While we would argue that time on the waiting list is less important (and indeed, time waiting may be an excellent opportunity to improve the outcome after transplantation by improving nutrition, for example), the risk of death and access to transplantation are clearly cause for concern. Therapeutic modalities for treatment of HCC are improving: options of resection, ablation, chemoembolization, and chemotherapy are becoming more effective and supplement the role of transplantation, so the management of patients with HCC has several effective options, treatment algorithms need frequent revision, and extrapolation of conclusions derived on past performance cannot be simply transferred to future management. Liver transplantation for HCC is under constant reevaluation and currently under proposals for policy changes so that we are transplanting those who are in greatest need of livers while those who could be safely managed without transplant are not given immediate priority. Where then does all this leave allocation and distribution? The need for a transparent, national, objective, and evidence-based approach to organ allocation is undeniable, but should patients, clinicians, and the public accept that no system will deliver perfection? Differences in geography, in patient characteristics, and in patients' and surgeons' appetite for risk will ensure that no system will deliver a perfect solution. Rather than spend too many resources on striving for a perfect allocation system, perhaps we should accept and welcome a system that allows some room for innovation and remains dynamic; of course, we should continue to examine variations and learn from them, but we should consider diverting some of the resources used to develop and implement a perfect allocation scheme into increasing the number of donors and livers used for transplant and, in the longer term, finding treatments and interventions that will render liver transplantation a treatment of historic interest. James Neuberger, D.M., FRCP1David Mulligan, M.D.2 1Liver Unit, Queen Elizabeth Hospital Birmingham, UK 2Section of Transplantation and Immunology Department of Surgery, Yale-New Haven Hospital Transplantation Center, Yale School of Medicine New Haven, CT, USA