Q J Med 1999; 92: 547-550
© 1999 Association of Physicians
Editorial |
Liver transplantation
Liver unit, Queen Elizabeth Hospital, Birmingham
Liver transplantation has come of age: the procedure is no longer considered experimental, indications and contra-indications are relatively clearly defined and agreed, and survival rates, at least in the short- and medium-term, are now acceptable, with most centres reporting five-year survival rates in excess of 70%. Coming of age is associated with maturity and (without wishing to overstretch a weak analogy) maturity is associated with new problems and challenges. In this editorial, some of the challenges and opportunities will be outlined.
The gap between the number of donors and the number of potential recipients is increasing. Thus, in the UK, between 1993 and 1997, the number of new registrations for liver transplantation rose from 569 to 698;1 the number of donors (this figure includes all offers of donation and includes those which are unsuitable for any reason, such as co-existing infection or malignancy) rose from 727 to 868; however, the number of donors is now falling, with a 9% reduction in cadaveric solid organ donors between 1998 and 1999. In the first five months of 1999, compared with 1998, there was a 19% increase in patients on the national liver transplant waiting list, and a 2% increase in the number of liver/lobe transplants from cadaveric donors. Statistics are more worrying in the US,2 where the numbers of new registrations rose from 2997 to 9637 between 1993 and 1997; the number of donated livers increased from 3763 to 4579. In the UK, the mortality of patients on the waiting list is about 18%.
The number of potential recipients is increasing for several reasons: there is wider knowledge of the benefits of liver transplantation, so more patients are being referred for consideration. Furthermore, indications for transplantation are changing: thus, in Europe in 1983, PBC accounted for 57% of transplants for end-stage cirrhosis and now accounts for only 20%; conversely, the main growth areas for cirrhosis are viral hepatitis (mainly HCV), increasing from 34% to 48%, and alcohol-induced cirrhosis, from 8% to 32%.3 As anaesthetic and surgical techniques improve, complications such as portal vein thrombosis are no longer contra-indications to transplantation. Paradoxically, complications of liver disease, such as the hepatopulmonary syndrome and hepatic osteopenia, are now indications rather than, as previously, contra-indications for liver replacement. At both ends of life, the age span of potential recipients is increasing, with successful transplantation being undertaken in babies in the first few weeks of life and adults over 75-years-old. At the same time, despite widespread efforts at raising awareness and increasing public participation, donor rates are falling. In part, this reduction in donation rates is due to the welcome reduction in deaths on the road, but still there remains a large cohort of potential donors who, for a variety of reasons, are not used. Donation rates vary widely between countries within Europe.4 Reasons for this variation have not been clearly defined. In part, this is due to resources: the increasing pressure on scarce ITU beds means that it is increasingly difficult to maintain potential recipients until the brain-death criteria can be met. Spain, which has an intensive and well-resourced programme of co-ordination for donation, has the highest rate of organ donation in Europe.
At present, there are three systems for obtaining consent for organ donation: informed consent, required consent and presumed consent. Informed consent is a voluntary system of organ donation where relatives are asked for permission for organ donation at the time that brain-death is established. Organs will not be used in the face of family opposition even if the donor had previously indicated a willingness to donate. For required consent, clinicians responsible for the care of the potential donor are required to ensure that the family are asked about organ donation. In presumed consent, permission for organ donation is presumed unless the patient has specifically indicated a wish not to donate. There remains continuing controversy about the advantages of moving from a system of informed consent (as exists in the UK) to presumed consent. There remains uncertainty whether such a move would result in increased donation. Experience from continental Europe has cast doubt on the benefit.
The effect of the increasing discrepancy between the numbers of donors and the number of recipients means that the waiting time for patients will increase. As a consequence, there will be a significant mortality on the waiting list. Furthermore, as the patient's illness progresses, the morbidity and mortality of transplantation becomes greater.
The relative lack of donor organs has resulted in the need for rationing of donated livers. There remains uncertainty as to how allocation of this scarce resource can be achieved equitably and fairly. Clearly, there needs to be transparency in how the rules are developed, agreed and applied. There is need to balance the requirements for equity (all potential recipients will have an equal access to a scarce resource) and utility (the limited resources are used most effectively). A recent grouping of all the designated Liver Transplant Units in the UK and Ireland proposed a system of allocating donor livers: there were three main principles: donated organs were a national resource; transplantation should be offered to recipients who were estimated to have a 5-year post-transplant survival of greater than 50%, with a quality of life that is acceptable to the patient; utility is more important than equity.5 These principles will need wider debate before they can be accepted and put into practice. There are many implications should these principles be accepted and implemented: that the donated organ is a national rather than local resource means that the harvesting centre may not use that liver for a patient listed in that centre; furthermore, it follows that the criteria for listing a patient should be similar in all centres. No centre would take on experimental procedures (such as transplantation for patients with HIV or with extrahepatic hepatocellular cancer) without the prior agreement of the other centres. These principles also circumvent any concerns about certain subgroups where the role of transplantation is uncertain or controversial, for example, the mentally handicapped, the elderly or those with alcohol-associated liver damage: the main criterion is whether the length and quality of survival meet the agreed criteria. It must be emphasized that application of these principles is appropriate only because of the shortage of donor livers. There are also possible drawbacks were these principles adopted: there is the potential that adoption of guidelines could stifle development of new techniques or treatments and evaluation of new indications; it is recognized that the criteria to predict post-transplant survival are relatively poorly defined at present.
Clinicians need to be aware of the public's views regarding donor allocation: clinicians are accountable for their actions. When public confidence is eroded, however unjustifiably, donation rates fall. Nonetheless, surveys of the public, both in the US6,7 and in the UK,8 clearly indicate that the public priorities differ from those of the gastroenterologists, who refer patients, and transplant clinicians, who allocate livers. The public seem to take a far more judgemental view: giving very low priority to those with alcoholic liver disease, those with antisocial behaviour and those with self-induced liver damage. For a clinician to follow the public view in these cases would be clearly unethical. How best this dilemma can be solved is uncertain.
In the light of the increasing shortage of donated organs, transplant surgeons are looking at new techniques to make better use of those organs that are offered.
The marginal liver is one where there is uncertainty whether there will be early graft function. At the current time about 10% of livers offered in the UK for transplantation are not considered because the clinicians feel there is a high-risk of primary non-function. Mirza9 has shown that there is very little agreement amongst transplant surgeons as to what constitutes a marginal liver. This suggests that some potentially viable organs are not used. Further work is required to identify those organs which are unlikely to function. Matching of donors and recipients is also important: a relatively well recipient can tolerate a poorly-functioning graft for the first few days, whereas a high-risk patient (such as one with very advanced liver disease and renal failure) is unlikely to tolerate a marginal liver. The greater understanding of the mechanism of reperfusion injury will also allow new interventions to counteract the effects of ischaemic/reperfusion injury and so increase further the donor pool.
Further understanding of the vascular and biliary anatomy of the liver has allowed techniques of splitting livers whereby a large, adult liver can be divided so that either a small recipient can receive part of the liver or two recipients can benefit: usually an adult is given the larger right lobe and a paediatric recipient the smaller left lobe. Split livers and reduced livers are increasingly being used in paediatric transplantation with good effect.10 Currently, several centres are evaluating split livers for adults. Livers may be split either in vivo or in vitro. Considerable resources are required for a programme to undertake splitting livers: it needs expertise and skill to divide a liver successfully, and two transplant teams are needed to complete the recipient operations.
Use of living related donation has been advocated for some years. There are many advantages to this procedure: the transplant procedure can be done electively when the patient is relatively well. Furthermore, there is a relatively short cold ischaemia time, so the probability of non-function is much less. In the early years of living related transplantation, this procedure was limited to patients with acute liver failure, where there is a very short window between the recognition of non-recovery and the development of complications precluding a successful outcome after transplantation. As experience has grown, this technique has been expanded into paediatric recipients with chronic liver disease and more recently into adult recipients.
There remain considerable moral and ethical considerations. The procedure to the donor is not without risk, and indeed two deaths have been recorded. Other complications occur in about 13–20%.11 Unlike standard surgical procedures, the donor operation is not done for the physical benefit of the patient.
In rare situations, such as familial amyloidotic polyneuropathy, there is a metabolic defect within the liver which is otherwise structurally and functionally normal. In this situation, it may be justifiable for the explanted liver to be grafted into another patient who would otherwise die. Initial experience has shown that, at least in the short term, this procedure is safe for the recipient, although experience remains short-term.
Hepatocyte transplantation is being investigated in an increasing number of areas. These include metabolic liver disease where the liver is structurally normal but has a metabolic defect such as seen in the Crigler-Najjar syndrome. However, recipients of allogeneic hepatocytes will require long-term immunosuppression. An alternative approach is to use gene therapy to modify autologous hepatocytes.
The shortage of human donor livers has also encouraged the use of animals as donors of transplanted organs. To date, eight whole-organ liver transplants have been carried out using livers from baboon, pig and chimpanzee.12 Only one recipient has survived more than 72 h. In the immediate term, there remain problems associated with rejection. Hyperacute rejection is a response trigger by donor antigen and endothelial cells, mediated by the host xenoreactive preformed naturally-occurring antibodies. This leads to activation of the classical and alternative pathways of complement, damaging graft endothelial cells and so resulting in extensive intravascular thrombosis and haemorrhage. This immune response is directed primarily against the gal(1,3)-
-gal epitope. Several approaches have been adopted to overcome this problem, including inhibition of complement activation using cobra venom or soluble complement receptors, depletion or blockade of the preformed anti-gal antibodies, and genetic manipulation of donor animals to reduce expression of the gal--gal epitope on the endothelial cells. The development of strain of pigs transgenic for human decay accelerating factor, which regulates human complement activation, has been a start.
Even when these problems are overcome (and it is only a matter of time before such a success is achieved), there will remain further problems. These include acute rejection and chronic rejection as well as the uncertainty of the effect of the xenograft producing animal proteins rather than human proteins. At the present time, the risks of introducing animal viruses into humans has precluded further experimentation. Whilst theoretically this approach is attractive, and if successful will abolish the consequences of shortages of human livers, in the opinion of the author at least, it is many years before such an approach will be available for routine patients.
After transplantation, quality of life is excellent for most recipients but it cannot be considered to be normal. Although some patients do become tolerant of their graft, the majority require lifelong immunosuppression. In addition to the specific problems related to individual immunosuppressive drugs, the effect of immunosuppression on increased susceptibility to infection and the increased risk of malignancy adds an increasing toll to the outcome. One of the more severe complications of the calcineurin inhibitors (tacrolimus and cyclosporin) is that of renal failure. Even at the lower therapeutic doses currently used, 80% of survivors have impaired renal function, while 4% may develop renal failure, with half of these requiring renal transplantation.13 Other complications, such as malignancy, are increasing as more patients achieve long-term survival.
Most centres use double or triple therapy based on either tacrolimus or cyclosporin along with azathioprine and coritcosteroids, although many centres are withdrawing corticosteroids after the first few post-operative months. The introduction of new agents has given the transplant clinician a much wider armamentarium of potential drugs for use in patients. Of these, mycophenolate mofetil, a potent selective and reversible non-competitive inhibitor of inosine monophosphate dehydrogenase, is being used increasingly. Other drugs which will shortly be reaching the market place include deoxyspurguallin, brequinar, myzoribin, and leflonamide. Clinical trials will be required to find the optimal combination of therapeutic agents. In practice, however, the logistics of mounting worthwhile clinical trials are great; the success of most patients means that a large number of patients need to be enrolled; the end-points ideally will be patient and graft survival and surrogate end-points, such as prevention of acute rejection, may not be appropriate.
Ultimately the goal of the transplant clinician must be the development of tolerance so that immunosuppression can be withdrawn. Several studies have shown that perhaps 1 : 5 patients can have immunosuppression safely withdrawn.14 The problem faced by the clinician is being able to identify those patients in whom immunosuppression is no longer required. Attempts to withdraw immunosuppression may lead to rejection, and later acute rejection may be followed by chronic rejection and graft loss in perhaps 50%.
Another major problem facing transplant clinicians is prevention and treatment of recurrent disease. Autoimmune diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis may recur in the graft. The last is readily treated by introduction of increased steroid dosage. The first two may occur in the graft and may lead, in a small proportion of cases, to graft failure. The failure to find an aetiology and a specific treatment for these two cholestatic diseases means that progression of graft damage is slow but inevitable.
Hepatitis C almost invariably recurs in the graft, but the pattern of graft damage may be variable. At the moment, strategies to prevent graft infection and to mitigate the effect of such infection have been unsuccessful. In contrast, strategies for prevention of graft infection by hepatitis B virus are more successful. The increasing use of lamivudine has resulted in a much lower rate of graft infection and graft failure. Nonetheless, the development of mutant viruses still poses a problem.
In conclusion, therefore, coming of age has not been painless. The original challenges of liver transplantation have largely been overcome. Current problems relate primarily to the shortage of donor organs but the medical complications following transplantation still present challenges for the clinician and researcher. It is essential that the drive to improve the outcome after transplantation does not divert attention from the need to develop strategies to improve the management of patients with acute and chronic liver disease so that transplantation is no longer indicated.
References
1. United Kingdom Transplant Support Service Authority, Bristol, 1999.
2. United Network for Organ Sharing. OPTN/SR 1998 Annual Report. Department of Health and Human Services, 1999.
4. International Transplant Coordinators Society. Annual Report 1997.
5. Neuberger J, James OFW. Allocation of scarce donor livers. Lancet 1999; in press.
6. Oregon Health Services Commission. Prioritization of Health services: a report to the Governor and legislature. Portland OR, Oregon Health Services Commission, 1992.
7. Ubel PA, Loewenstein G. The efficacy and equity of retransplantation: an experimental survey of public attitudes. Health Policy 1995; 34:145–51.[Web of Science][Medline]
8.
Neuberger JM, Adams DH, McMaster P, Maidment A, Speed M. Assessing priorities for allocation of donor grafts; survey of public and clinicians. Br Med J 1998; 317:172–5.
9. Mirza D, Gunson B, Da Silva R, Mayer AD, Buckels JAC, McMaster P. Policies in Europe on marginal quality donor livers. Lancet 1994; 344:1480.[Medline]
10. Sindhi R, Rosendale J, Mundy D, Taranto S, Baliga P, Reuben A, Rajagopalan PR, Hebra A, Tagge E, Otherson HB. Impact of segmental grafts on pediatric liver transplantation—a review of the United Network for Organ Sharing Scientific Registry Data (1990–1996). J Pediatr Surg 1999; 34:107–10.[Web of Science][Medline]
11. Grewel HP, Thistlethwaite JR, Loss GE, Fisher JS, Cronin DC, Siegel CT, Newell K, Bruce DS, Woodle ES, Brady L, Kelly S, Boone P, Oswald K, Millis JM. Complications in 100 living donors. Ann Surg 1998; 228:214–19.[Web of Science][Medline]
12. Lambrigts D, Sachs DH, Cooper DK. Discordant organ xenotransplantation in primates: world experience and current status. Transplantation 1998; 66:547–61.[Web of Science][Medline]
13. Fisher NC, Nightingale PC, Gunson BK, Lipkin G, Neuberger J. Chronic renal failure following liver transplantation. Transplantation 1998; 66:59–66.[Web of Science][Medline]
14. Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B, Williams R. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 1998; 27:926–33.[Web of Science][Medline]
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