Liver transplantation: Issues for the next 20 years

Authors


  • Conflict of interest
    No conflict of interest has been declared by the authors.

Professor Elwyn Elias, The Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. Email: elwyn.elias@uhb.nhs.uk

Abstract

The growing numbers of potential transplant recipients on waiting lists is increasingly disproportionate to the supply of cadaveric donor organs. The hope for the next 20 years is that supply will satisfy demand. This requires both a reduction in indications for the procedure and an increase in the transplants performed. A multi-pronged approach is needed to increase cadaveric organ donation, generating enthusiasm for donation among both the general public and hospital staff. Accurate assessment of marginal grafts with stringent criteria known to predict graft function will diminish wastage of organs. Methods of rehabilitating marginal grafts during extracorporeal perfusion will increase organ availability. Supply of non-heart beating donors can be greatly expanded and protocols developed with ethical consent to optimize their initial function despite warm ischemia. Splitting livers that fulfill selection criteria, thus providing for two recipients, should be universally applied with acceptable incentives to those units who do not directly benefit. A proportion of recipients, though not those transplanted for autoimmune disease, will be spared the side-effects of immunosuppression thanks to immune tolerance. Protocols for close monitoring of those patients for rejection during treatment withdrawal must be carefully observed. In addition to gene therapy, it is highly likely that hepatocyte transplantation will replace orthotopic grafting in patients without cirrhosis, especially for inherited metabolic diseases. It is much more difficult to envisage that heterologous stem cell transplantation or xenotransplantation will have clinical impact in the next 20 years, although research in those areas has obvious long-term potential.

Introduction

Certainly, great strides have been made over the last two decades. This exemplary lifesaving procedure has been through various phases of evolution since the first documented success in 1967.1 Initial outcomes were modest,2–4 but the introduction of cyclosporine in the 1980s coincided with improvements in graft and patient survival which prompted increased activity in liver transplantation across the globe in parallel with other organ transplantation.5 Although the essence of the surgical technique per se has not changed dramatically, refinements and innovations to the craft had been tried and tested to optimize the outcome. Concurrent advances in our understanding of the overall transplant process, including ischemia-reperfusion injury, organ preservation techniques,6–8 and immunological mechanisms of rejection,9 together with new immunosuppressant agents10 and advances in perioperative care have combined to engender the relative success of the story thus far. The relatively low immunogenicity of the liver compared with other organs has also contributed to the success.11

Many lives were saved by liver transplantation and a significant improvement in quality of life measures has been achieved.12 Clinical and translational research have been key factors in the development. Future advances are likely to be focused around increasing the pool of available donor organs so as to maximize the availability of the procedure and, in parallel, maximizing the benefit derived by all recipients. Various issues, several common to organ transplantation in general and others specific to liver transplantation, will need to be addressed if they are not to impose their limitations on further expansion.

Liver transplantation: current status

In recent years, the intermediate and long-term outcome attained following cadaveric liver transplantation yields 1-year and 5-year survival figures reaching 90% and 75%, respectively. This success has inspired current management guidelines to recommend that every patient with end-stage liver disease (ESLD) should be referred for liver transplant assessment.13 As a consequence, there is an ever growing number of potential transplant recipients on waiting lists, which are increasingly disproportionate to the supply of cadaveric donor organs. This widening gap has become a major concern among the transplant community. Against this background, regardless of the various organ allocation policies adopted by different transplant programs aimed at benefiting patients, waiting list mortality remains a major issue. Rationing of resources and selection of the ideal candidate to receive an organ is a difficult task faced by transplant teams worldwide. The hope for the next 20 years is that the current indications for liver transplant will be significantly diminished by alternative approaches to treatment, and that, for the remainder, supply will satisfy demand (Table 1).

Table 1.  Indications for liver transplantation may be replaced by other treatment modalities in the future
IndicationPotential therapeutic approach
Metabolic disorders 
 Alpha-1 antitrypsin deficiencyHepatocyte transplantation
 Wilson's diseaseGene therapy
 Primary hyperoxaluria type –I 
 Crigler-Najjar syndrome 
 Tyrosinaemia 
 Porphyrias 
Fulminant hepatitis 
 Toxin or drug inducedHepatocyte transplantation
 Extracorporeal liver support
 Artificial liver
 Bio-artificial liver (hepatocytes based)
Alcoholic liver diseaseAntidote in the booze
Viral hepatitis 
 HBV and HCVVaccination
 Anti-viral therapy
Hepatic fibrosisFibrolytic treatment
Auto-immune disease 
 Auto-immune hepatitisImmunogenetics
 Primary biliary cirrhosis 
 Primary sclerosing cholangitis 

Recent resurgence of non-heart beating organ donation (NHBD) has been embraced by the liver transplant community as one way of ameliorating the shortage of organs. NHBD liver transplantation was originally described in the 1960s but became obsolete in subsequent years because of poor results and the introduction of brain stem death criteria; these facilitated cadaveric donation and was associated with better outcomes. More recently, experience of successful renal transplantation with NHBD grafts, following procurement under ‘controlled’ conditions defined at the Maastricht Consensus Conference, has led the liver transplant community to return to this organ source.14–16 Despite the higher risk of primary non-function and delayed graft function associated with these grafts, acceptable long-term outcomes are achieved.17–19

Understanding of the lobar structure of hepatic anatomy and simulation of the liver to a ‘paired organ’ has led to the concept of living donor liver transplantation (LDLT) and split/reduced liver transplantation. The mortality risk it carries on the living donor has been minimized by careful planning, hepatic volumetry assessments, and improved postoperative management.20 LDLT is extremely popular in Asia–Pacific countries where ethical and religious barriers exist to cadaveric donation. Elsewhere, the lessons learned from LDLT were used to pioneer split liver transplantation, in which a single donor liver is divided between two recipients.21 While the ‘classic’ split technique benefits an adult and a child, recent advances on ‘left/right’ split through the middle hepatic vein yields two hemi-livers that can be transplanted to two adult recipients.22,23

Despite these measures, the problem of organ shortage currently faced by the transplant community continues to grow. Though the total number of liver transplants performed worldwide is increasing every year, growth of supply continues to be outpaced by demand, fuelled by an expansion in indications. Contraindications to transplantation which were regarded as ‘absolute’, such as HIV infection, are no longer considered such and have become ‘relative’ contraindications thanks to better anti-viral and other treatments becoming available with the forward march of Medicine. Congenital and metabolic diseases have added to the list of indications for transplant.24 The incidence of non-alcoholic fatty liver disease (NAFLD) and its associated ESLD is on the rise globally, putting more pressure on transplant systems than ever before.25 If liver transplantation is to approach a level where it can be provided for all recipients in whom it is deemed their optimal treatment, it is necessary to identify the constraints in the present system, and unresolved issues that are obstacles to progress.

Challenges and unresolved issues

Barriers for organ donation and implications

Lack of infrastructure and facilities, in particular the shortage of intensive care (ICU) beds, stands out as one of the major constraints upon donation from the available cadaveric donor pool.26 Organ donation is often not achieved when the demand for ICU beds is high; maintaining a brain-stem dead (BSD) patient on life support for many hours until organ donation takes place consumes vital resources and may be abandoned in favor of another critically ill patient.27 The motivation for organ donation is also reduced where awareness of its benefits is lacking among attending clinical staff. A survey done by UK Transplant revealed that in as many as 33% of patients in whom BSD criteria were never tested, it was the most likely diagnosis.28 There appears to have been loss of a significant number of potential donors because of the fact that no approach had been made to the family, or failure to achieve organ donation even if these prerequisites were fulfilled. The ethics of maintaining patients on life support for the sole purpose of organ donation is debated.29,30 High rates of refusal for donation remain a barrier. In some parts of the world, especially Asia and the Far East, BSD is not legislated or accepted by the general public because of cultural and social beliefs which place massive restraint on cadaveric transplantation. ‘Transplant tourism’ has become the by-product of this growing problem of organ shortage, though less so in the field of liver transplantation in comparison with other organs.31,32

Marginal grafts

Our inability to predict which donor organs will fail because of primary non-function, and poor correlation between the apparent quality of a potential liver graft and its function following transplantation remains a mystery.33 Criteria for organ donation vary between centers and regions. Although organ yield has been increased by ‘extended criteria’, the reproducibility of these results remains in doubt.34 Moreover, accurate assessment of the marginal grafts that would accurately predict primary non-function or initial poor function is not possible using a single objective criterion in isolation. A recent histopathological study of liver grafts which had been discarded on clinical and biochemical grounds revealed nearly 35% of these grafts were probably suitable for transplantation.35 Assessment of the suitability of liver grafts for transplantation during the harvesting procedure is subjective, and varies according to the experience of the procurement surgeon.36

Competing patient groups

Against the backdrop of organ shortage, competition on the waiting lists has been increased by the entry of patients requiring transplantation of combined organs (kidney-liver transplantation), multi-visceral transplantation, and late re-transplantation of the liver. Having a common waiting list for all these groups leads to prolonged waiting times, morbidity, and mortality.

Organ allocation criteria—MELD and beyond

Model for end stage liver disease (MELD) has been adopted by transplant groups as an objective and evidence-based system for transplant listing,37 but not all patients requiring a liver transplant are served by MELD criteria.38 Transplantation of a patient on the basis of ‘sickest first’, e.g. one with acute liver failure, is shown to increase the mortality risk by 0.8% and reduce the expected outcome for each and every other patient on the waiting list by eight quality-adjusted days.39 In the next two decades we must look for a system beyond MELD, which can more justly reflect the competing needs of patients on the waiting list.

Organ sharing

Organ sharing between patients and institutions is another aspect where improvements may relieve the burden on waiting lists to a certain extent. For example, currently many centers without a pediatric transplant program do not participate in liver splitting as it does not serve their own cohort of patients. Ideally, a good quality organ which can benefit two recipients should always be considered for splitting. Surveys suggest that the majority of patients align themselves with the ‘utilitarian’ concept when it comes to the question of receiving a split liver, rather than ‘self preservation’.40,41 Many patients awaiting transplantation expressed support for prioritization of children over adults and a willingness to receive a split liver, even if the benefits were thus reduced in comparison with transplantation of an intact liver.41 Conflicting interests among transplant teams therefore need to be addressed to promote split liver transplant activity as a method of combating organ shortage.

Future of liver transplantation

Aiming for increased organ donation

Maximum utilization of the presently available potential donor pool is the first and foremost priority of the liver transplant community. The ‘Spanish model’ is by far the most successful, and lessons learned from the Spanish are being incorporated elsewhere. In the United Kingdom, an Organ Donation Task Force recently made a series of recommendations to increase donation, and optimistically aimed to increase by 50% the number of transplants performed in the medium term. Organ donor registries will not be sufficient to expand organ donation rates while awareness among the general public remains low. The alternative ‘opt out’ system or ‘presumed consent’ has been suggested as a solution, but is widely debated;42,43 rigid implementation of such an ‘opt out’ system, where objections from family members do not preclude organ donation, appears unsound in the current ethical climate. Therefore, the future challenge lies in creating more awareness among the general public of the benefits of organ transplantation and encouraging ‘opting in’ to the donor registers. Further, donor registers need to be centralized and continuously updated.

Increasing organ utility

Measures need to be taken to utilize every single transplantable organ procured. Procurements are often carried out at hospitals distant from the transplant center, in many cases by a team different from that implanting the graft. Disparity of opinion and a communication gap between these two teams can contribute to organ wastage. Universally accepted criteria for objective assessment of organ quality, accessible to every member involved in decision making will minimize this issue. In the United Kingdom, a National Organ Retrieval Imaging System (NORIS) was pioneered,44 giving online access to the images of organs uploaded at the time of procurement (Fig. 1). Development of other similar systems should lead to better decision making and thus prevent organ wastage in future.

Figure 1.

National Organ Retrieval Imaging System (NORIS) providing on-line access to the retrieval images.44 (a) The color and (b) sharp edges of the harvested liver graft suggests minimal steatosis, while additional information like size of the hepatic artery (c) and relevant vascular anatomy (d) may prove vital information when implanting center is located geographically distant to the harvesting/splitting centers. (http://www.noris.org.uk)

Biomechanical impedance and transient elastography (Fibroscan) have been shown to predict steatosis/fibrosis with reasonable accuracy in patients with chronic liver disease, and use of these tools may be extended in assessment of the donor liver.45–47 With increasing prevalence of NAFLD in the donor population, more surrogate markers of organ quality are needed.48,49 Livers that are obviously fatty and in which a third or more of hepatocytes contain fat are traditionally been frowned upon by transplant surgeons for whom it is a harbinger of poor initial graft function. Potential exists to significantly increase the number of donations by application of techniques that measure graft quality in ways which correlate strongly with subsequent graft function with a high positive predictive value.

NHBD organs—further potential

The recent increase in the NHBD transplant activity has contributed to increase the number of transplants with outcomes comparable with those being achieved with cadaveric organs. Issues surrounding the initial warm-ischemia associated complications need to be addressed.50 Identifications of biomarkers that specifically reflect viability of harvested NHBD livers need to be identified.51 Pharmacological manipulation or pretreatment with serine protease inhibitors has been shown to minimize the damage caused by warm ischemia in experimental models.52,53 Addition of anti-thrombolytic drugs (Streptokinase) to the perfusion solutions has also been shown in both animal studies and renal transplantation, to improve the microcirculation54–57 but there is little evidence for its value in liver transplantation. Pharmacological manipulation of the donor prior to cardiac death within an ethically acceptable framework may result in better outcomes. In situ perfusion was thought to be beneficial in terms of minimizing warm ischemia, but the results of renal transplantation in units practicing this technique suggest otherwise.58

Machine perfusion of organs and organ ‘reconditioning’

Extracorporeal machine perfusion of liver grafts is another significant recent development with potential benefits for the future. Various techniques of extracorporeal machine perfusion have been investigated in animal studies during the past two decades, including pulsatile and dual perfusion, normothermic or sub-normothermic perfusion.59–62 The key benefits are a reduction in preservation injury and improved ability to withstand prolonged ischemia with preserved hepatocellular function.63,64 Similar techniques have been used with success in clinical transplantation involving other organs, with promising results.65–69 Experimental studies on liver have shown that extracorporeal perfusion has the ability to ‘recondition’ the marginal liver grafts that have undergone warm ischemic injury during NHBD procurement, and in those with steatosis.64,70–73 Selectively applied, these organ preservation and salvage techniques carry promise of a significant supply of grafts rehabilitated in vitro.

Split liver activity

An increase in split liver transplantation activity is expected. The classical split technique is well established in centers running concurrent adult and pediatric transplant programs. To maximize its potential, full cooperation is required from centers not presently involved, and development of incentives for sharing grafts that are suitable for splitting.74–76 Technical innovations in liver splitting22 and better understanding and management of the ‘small for size syndrome’ should lead to a further increase in both split liver transplant and living-related transplant activity.77–80 In future we may also witness an increased transplant activity with ‘dual grafts’, which were pioneered to ensure maximum donor and recipient safety. Essentially this involves living-related transplantation, where implantation of left lateral segments donated by two donors into a single recipient. A further step ahead in this novel concept is the incorporation of a right posterior segment containing segments VI and VII with a left lateral segment.81,82

Novel biomarkers

Diagnostic markers of early graft dysfunction and primary non-function need to be developed, which by providing an early diagnosis open up the possibilities for organ rescue. Early and selective increase in interleukin-8 [IL-8] and C5a has been shown to be associated with rejection, well before the rise of transaminases.83 Metabolomic studies may provide organ-specific metabolic markers associated with primary non-function and rejection.84

Immune tolerance

It is well known that many recipients have survived with normal liver function following liver transplantation despite having defaulted from taking any immunosuppressive drugs for many years. With improved understanding of the mechanisms underlying this acceptance of the graft, it is hoped that, in 20 years' time, most recipients will live without the need of major immunosuppressive therapy. The advantages are obvious with reduction of the risk for immunosuppression-related side-effects including lymphoproliferative disorders and elimination of opportunistic infections and the metabolic syndrome which is strongly related to corticosteroid use and calcineurin inhibitors and among the commonest cause of late death.

Historically, the story of liver transplantation has been one characterized by a progressive tendency to reduce the immunosuppressive load on the patient. Fear of allograft rejection dominated the early thinking of pioneers in the field; patients were prophylactically administered grams of methylprednisolone at induction and in the post-hepatectomy phase of the transplant operation. The result was that many of those who managed to survive the surgical procedure later succumbed to fatal opportunistic infections by organisms such as Aspergillus fumigatus and Pneumocystis carinii not seen in the immunocompetent population. Blunderbuss destruction of lymphocytes, regardless of their ability to reject or induce tolerance of the liver, permitted later recovery of random clones of lymphocytes, some of whom had the potential to produce acute cellular rejection of the graft, thus putting those who survived the transplant operation at risk of acute cellular rejection during the second post-transplant year and beyond. Gradually it was realized that the liver was favored by a lesser tendency to rejection compared with other organs and this encouraged new policies with reduced dosages of immunosuppressive agents.

The work of Bishop and McCaughan85–87 supported the rationale of withholding massive dosages of lympholytic treatments at the time of transplantation. Tolerance of the graft became seen as an active state of finely balanced immunity, not one in which all immune elements able to recognize the graft as foreign had been eliminated. By exposing the graft to an intact immune system, the seeds were sown for later actively controlled immune balance. A restrained approach to immunosuppression in the early post-transplant period enables the entire lymphocyte population to encounter the graft. Passenger leukocytes migrate to lymphoid tissues and induce apoptosis of alloreactive naïve T cells. Antigen-specific activation and subsequent deletion of naïve and effector cells within the liver itself purge the repertoire of alloreactive T cells. Should there be aggressive acute rejection, a bolus of high-dose steroids has the ability to selectively delete the replicating activated clones, including those responsible for mediating the rejection, and thus favor a new balance of immune tolerance.

The holy grail of rejection-free transplantation without need of any immunosuppression can be seen as a further step-wise progression along this continuum. The requirement is for graft recognition by an immune system that has intact its ability for surveillance of damaging antigenic epitopes, yet accepts the graft per se. A permanent and stable immunosuppression-free state is currently achievable in a proportion of liver recipients transplanted for non-immune mediated liver diseases. Maintenance of perfectly normal graft function in the total absence of maintenance immunosuppression is known as clinical operational tolerance (COT). Worldwide experience demonstrates that COT can be achieved in one-quarter of selected individuals following liver transplantation, irrespective of the immunological background of donor and recipient, patient age, indication, study endpoint, length of the weaning period and of pre/post-weaning follow up, presence or not of chimerism.88 COT is much more difficult to achieve after renal transplantation. Only one case of COT has been reported after lung transplantation and no cases have been described after other types of solid organ transplantation.89

Withdrawal of immunosuppression under close scrutiny for evidence of acute rejection is likely to become the norm in long-term survivors who experience side-effects from immunosuppression following liver transplantation for non-immune mediated liver diseases. Future strategies that have potential to promote tolerance of hepatic grafts include T-cell costimulation blockade, mixed chimerism induction, T-cell depletion, and tolerance induction through regulatory T-cells.90

Hepatocyte transplantation

Fisher, and Strom reviewed 78 human clinical hepatocyte transplant experiences performed for acute liver failure, chronic liver failure, and metabolic disorders.91 Generally speaking the resultant benefit has been relatively short-lasting, suggesting a progressive loss of transplanted cells. The brevity of transplanted hepatocyte survival is not a major problem when the indication has been fulminant hepatic failure. Although recipients suffering from acute fatty liver of pregnancy92 or Amanita phalloides poisoning93 recovered fully, without controlled trails it is not possible to say whether the transplanted cells had a significant impact on survival. When performed for chronic indications such as Crigler-Najjar syndrome type I,94 urea cycle defects,95,96 Refsum's syndrome,97 or inherited Factor VII deficiency,98 the metabolic benefit was transitory and patients later required orthotopic liver replacement. The next 20 years should see a major advance in our ability to sustain donor hepatocyte lineages within host liver so that the genetic defect is permanently overcome.

Stem cell transplantation and gene therapy

Fewer than one in 20 000 hepatocytes divide each day.99 Regardless of whether production of new hepatocytes occurs directly as a result of adult stem cell plasticity or requires fusion of adult stem cells with endogenous hepatocytes, the number of hepatocytes produced is very low in the vast majority of situations. Thus, for the foreseeable future, stem cell infusions are unlikely to impact clinically other than for autologous applications.100 Similarly, gene therapy has theoretical promise but also major obstacles to overcome.101

Xenotransplantation

Xenotransplantation has only a remote possibility of making a significant breakthrough in the next 20 years despite a century of effort.102. Discovery in humans of anti-alpha-Gal antibody, which leads to hyper-acute rejection of discordant organs, can be considered a step toward successful xenotransplantation.103 Genetic engineering and induction of tolerance are among approaches aimed at breaking the barriers.104,105

20 years or more?

Maybe in 20 years' time liver transplantation will have had its day in the way that gastric surgery for peptic ulcers has become passé. End-stage viral liver disease (ESLD) may be a thing of the past as immunization against hepatitis B and (hopefully) hepatitis C consigns chronic viral disease to the history books. Genetic diseases such as Wilson's disease, alpha-1 antitrypsin deficiency, and hemochromatosis will be diagnosed at post-natal screening and corrected by gene therapy. Autoimmune disease will be suppressed by manipulation of immunogenetics. Alcoholic beverages will contain antidotes that prevent hepatotoxicity. Antifibrotic agents will inhibit hepatic fibrosis and cause cirrhosis to disappear. Rare cases of fulminant hepatitis resulting from idiosyncratic reactions to novel agents will be recoverable by repopulating the liver with compatible donor cells drawn from a banked repository and without recourse to hepatectomy. We can all hope and dream!

Ancillary