Liver transplantation

The enormous progress that has been made in liver transplantation over the past two decades has culminated in survival approaching 90% at 12 months. The success of the procedure combined with the widening spectrum of disease processes deemed amenable to liver transplantation has meant that there are too few donors for those awaiting transplantation. This has extrapolated to many patients having such advanced disease by the time a suitable donor liver is available, that they are almost non-transplantable. The immediate options facing the transplant community are to decrease the number of patients listed or to increase the number of living donor transplants. Alternatives to liver transplantation such as hepatocyte transplantation, gene therapy, xeno-transplantation and the bioartificial liver are being sought but, at best, are some way from clinical application. It is anticipated that a number of liver diseases that are indications for liver transplantation at this time will have progression arrested or will be cured by medical therapy in the future.

Keywords: alternatives, distant future, immediate future, liver transplantation, present status

The current status of liver transplantation is the product of rapid development during the past two decades, built on the pioneering efforts of Starzl and Calne over the previous 15 years. These pioneers established the basic technical requirements to successfully perform the procedure but were thwarted by many barriers, not the least of which was rejection. The introduction of cyclosporine was a major step in the reduction of rejection as a cause of graft loss and there followed a proliferation of liver transplantation in the mid 1980s. This, together with the development of the University of Wisconsin preservation solution, witnessed a dramatic change - from an emergency, stressful procedure with an unpredictable outcome, to a semi-elective, reasonably controlled operation, with a high likelihood of success.

Along the way, many other advancements and innovations evolved: better pre and post transplant management; improved anaesthesia; innovative surgical strategies; early detection and treatment of infective complications; further progress in immunosuppression. Improved results emanated from these advancements, so that the turn of the century has seen survival approaching 90% at one year - a far cry from that achieved 10 years ago.

It might be expected that a future vision for transplantation would be an optimistic glowing prediction of improved results by reduction or elimination of factors that cause graft failure or patient demise; the prolongation of graft storage time and the development of organ banks; the non-necessity for immunosuppression; the ability to prevent recurrent disease in the graft etc. These parameters may well be attained in future years as many workers strive to accomplish improvements in their areas of interest and expertise. Hopefully, these efforts will continue and come to fruition. Logic and scientific projections flounder because of yet to be made discoveries which will undoubtedly change the face of transplantation - who knows what the human genome project or genetic engineering will achieve?

The vision of where liver transplantation will be at some undefined time in the future is burdened by the knowledge that for the present and foreseeable years ahead, transplantation is shrouded with difficulty. The paucity of cadaveric donor organs relative to the number of patients awaiting transplantation is disturbing. The many strategies that have been introduced to improve organ donation have only been marginally successful and it is envisaged that the plateau has probably been reached. Therefore, the immediate future is bleak - too few donors for those awaiting transplantation. In the longer term, alternatives to liver transplantation will be sought: hepatocyte transplantation; liver directed gene therapy; tissue-engineered organs; extra corporeal liver support; xenotransplantation and ultimately, medical therapies to control and prevent progression of liver disease so that transplantation will become an infrequent event.

The many advances that have been made in liver transplantation over the past two decades have not been sequential step by step processes but have been intertwined, one with the other, to reach the present position. It is not possible in this review to cover these in any comprehensive manner but significant contributions and salient features of the current status are highlighted.

Initially, liver transplantation was performed for primary hepatic malignancy and for end-stage chronic liver disease. Over time, the improvement in results was accompanied by a widening of the spectrum of disease processes deemed amenable to liver replacement and included chronic liver disease from alcohol and viral hepatitis, fulminant hepatic failure from a variety of causes and inborn metabolic defects without parenchymal disease. Many of these have stood the test of time. Some, such as chronic hepatitis B, were associated with poor results due to recurrent, rapidly progressive disease and were abandoned as an indication by many units, only to be reintroduced with the development of nucleoside analogues with therapeutic potency. The early enthusiasm for transplantation for large, non-resectable primary malignancy was dampened by the high recurrence rate. On the other hand, the small hepatocellular carcinoma (HCC) in the setting of cirrhosis is probably best treated by transplantation rather than resection. With time, the indications and contraindications for transplantation for malignancy have been better defined. Table 1 outlines the broad categories and more common indications, keeping in mind that liver transplantation has been performed for some 60 distinct liver diseases.

Chronic liver disease	Primary biliary cirrhosis Primary sclerosing cholangitis Biliary atresia HBV or HCV cirrhosis Alcoholic cirrhosis Autoimmune chronic active hepatitis Haemochromatosis Budd-Chiari
Malignancy	Small HCC in cirrhosis Non-resectable, chemosensitive hepatoblastoma Epithelioid haemangioendothelioma Neuroendocrine metastases (rarely)
Inborn errors of metabolism	Primary oxalosis Crigler-Najjar Type I Urea cycle defects Familial amyloid polyneuropathy
Fulminant liver failure	Viral hepatitis Drugs - halothane, paracetamol Toxins Unknown

The introduction of the University of Wisconsin (UW) solution in the late 1980s was a major advance.¹ It allowed a longer cold ischaemia time which extrapolated to the ability to procure the donor organ from distances greater than could previously be achieved. It reduced the urgency of the recipient hepatectomy and engraftment and permitted the development of a number of innovative surgical strategies. The improved preservation with UW solution may have had an added benefit of reduction in rejection through a decrease in cell damage with less up-regulation of major histocompatibility complexes, but this is purely speculative.

Although the liver occupies a rather privileged position with regard to rejection when compared with other transplanted organs, the pioneers were plagued until the introduction of cyclosporine in the early 1980s. While other developments occurred around the same time, it was this single event that was most influential in the improved results and the consequent proliferation of liver transplantation throughout the world. A new immunosuppressive drug FK506 (tacrolimus) underwent clinical trials in liver transplantation in the early 1990s and was found to be a powerful agent which reduced acute and refractory rejection in humans and reduced the need for polyclonal or monoclonal antibodies.^2,3 Baseline immunosuppression with a triple regimen of steroids, azathiaprine and either cyclosporine or FK506 is used in early therapy with reduction to double or single therapy within 3-6 months, with cyclosporine or FK506 being the basic component of the therapy. It is rare, nowadays, to encounter loss of graft or patient from acute rejection and chronic rejection is infrequent, when compared with heart or kidney transplants.

The pioneers established the basic technical requirements in performing a whole liver transplant (Figure 1). The development of veno-venous bypass during the anhepatic phase was a major advancement that stabilised the haemodynamics of the patient following caval and portal vein clamping. This reduced blood loss and transfusion requirements, eased pressure on surgical teams to rapidly perform difficult vascular anastomoses and encouraged trainees to undertake the procedure during the learning curve. Although used routinely for a number of years, veno-venous bypass is now used selectively by most units, based on the individual physiological parameters encountered during the operation. Over recent years, the piggy-back technique has come to the fore - retaining the recipients inferior vena cava to which the donor supra hepatic cava is anastomosed end to side. This may further reduce the need for bypass, as caval clamping can be removed after one anastomosis.

Absence or thrombosis of the portal vein in the recipient or aberrant hepatic arteries in the donor were previous contraindications to liver transplantation. The use of iliac vein and iliac artery grafts obtained from the donor have overcome these problems and they are now standard procedures.

As a result of failed porto-enterostomy and progressive cirrhosis from biliary atresia, infants and small children constitute the bulk of paediatric recipients who require liver transplantation. The relative scarcity of paediatric donors meant that there was considerable mortality while these infants waited for a suitable size whole liver graft. Bismuth and Houssin (1984) first reported a reduced-size liver transplant in a child, where a small size donor liver was reduced to a hemiliver, prior to engraftment in an orthotopic position (Figure 2).⁴ Arguments prevailed about re-arrangement rather than expansion of the paediatric donor pool. The innovations by Strong et al (1988) and Ringe et al (1988), allowed the bridging of size discrepancies between adult donors and infant recipients and eliminated the need to rely on larger-sized paediatric donors (Figure 3).^5,6 Further reduction of the left lateral segment to a monosegmental graft followed when it was too large to be accommodated in a small infants abdomen.⁷

The success of the segmental graft technique was the forerunner of other reduced-size liver transplant procedures. Instead of discarding the right hemiliver when performing a reduced-size liver transplant, it was used in an adult recipient.

First performed by Pichlmayr et al (1989), split-liver transplantation allowed an adult and a paediatric recipient to be transplanted from a single adult donor (Figure 4).⁸ Hampered by less than optimal results due to poor donor selection and technical complications, the procedure went into abeyance but resurfaced with the increasing pressures on transplant programmes to find suitable grafts for the ever expanding recipient population. With increasing experience, better understanding of anatomical requirements and improved donor selection, split-liver transplantation has produced results equivalent to those of whole liver grafts in adults and reduced-size grafts in children. ⁹

Figure 4: Split liver transplantation into an adult and paediatric recipient. (IVC; inferior vena cava; LHV; left hepatic vein; LHD:left hepatic duct; LPV:left portal vein. LHA: left hepatic artery; CBD: common bile duct; HA:hepatic artery; PV:portal vein)

The natural extension of these techniques was the use of a living donor to provide the graft. The first successful living related liver transplant was performed by Strong et al in 1989¹⁰ Since that time, more than 1500 living donor liver transplants (LDLT) have been performed, the most significant numbers being carried out in Japan, where brain death has only recently been legally recognised. The increasing discrepancy between the number of cadaveric organs donated and the number of patients awaiting transplantation has been a trigger for extension of living donor transplantation to adult recipients.

Post-transplant survival has gradually improved over the past 20 years. The European Liver Transplant Registry has reported a near 25% improvement at one and 5 years (76% and 66%, respectively) from 1988-1997, when compared with 1968-1987 (52% and 41%, respectively) with patients transplanted in 1997 achieving a survival of 83% at one year.¹¹ The actuarial survival curves from our own series of near 700 liver transplants in Brisbane are shown in Figure 5. In the last period 1995-2000, the survival at one and five years was 87% and 84%, respectively.

Figure 5: Actuarial survival curves for the three periods 1985-1989, 1990-1994, 1995-2000, for all patients transplanted by the Queensland Liver Transplant Service, Brisbane

The shortfall in donor organs means a delay in transplantation for many patients with consequent deterioration of liver function and overall physical status. The lessons learned about transplantation prior to becoming too advanced in the course of end-stage disease are still applicable but have dissipated with the lack of suitable donors. The advanced stage of disease extrapolates to a high postoperative mortality and it is difficult to foresee survival after liver transplantation being substantially better than the present results.

Having maximised the use of cadaveric liver grafts with expansion of the donor pool by using older donors, so called marginal donors, split-liver transplantation and the domino procedure, the transplant community faces two immediate options: (1) an increase in the number of living donor liver transplants (LDLT) (2) a reduction in patients assigned to receive a liver graft.

The realisation and acceptance that donor numbers are unlikely to increase and that alternatives to liver transplantation will not be available until some time in the future means that there are few options available. It is natural for transplant surgeons to use whatever methods are available to save the lives of their patients and many innovations have emanated to achieve this goal. The use of living donors introduced a whole new perspective in liver transplantation. The success of the procedure in paediatric recipients has been a salvation in the past decade and together with split-liver grafts has, overall, covered their needs. The problem is mainly with adult recipients and the instinct is to extrapolate the LDLT experience to this group.

In Asia, where cadaveric organ donation is uncommon or rare, living donor programmes are well established and have excellent results. The standard use of a left sided graft in paediatric or small adult recipients has the limitation of insufficient volume for the metabolic needs of most adult recipients. Therefore, adult to adult LDLT requires the use of the right hemiliver, which comprises 60-65% of liver volume. The removal of a major portion of the donor liver has commensurate greater complexity and potential for short- and long-term sequelae for the donor. Nevertheless, there has developed a general thrust towards this method and it is being used with increasing frequency in Asia and the United States. To date, the results achieved in centres where carefully controlled programmes have been established would indicate that this is a feasible proposition.^12,13 However, caution is needed. Living donor liver transplantation has been accompanied by donor deaths and some significant donor complications and these are likely to increase with unbridled acceptance and performance of adult to adult LDLT.¹⁴

The cadaveric donor liver has become a scarce resource with a significant deficiency in the availability to meet the needs of patients awaiting transplantation. Despite the ever increasing waiting lists, there appears to be a reluctance to address the issue of rationalisation. In the same way that funding issues have forced rationing of healthcare, donor organ shortage must lead to rationing of transplantation. Justice demands that there should be optimal use of a scarce resource - for maximal social and patient benefit. It is essential that the process of assessment and assignment to a waiting list addresses the spectrum of individual and collective benefit, bearing in mind that it is the general public who donate cadaveric organs and their priorities differ from those of the medical profession. It is encumbent on the transplant community to come to terms with the problem of insufficient donors for the ever-expanding number of recipients. Difficult decisions have to be made on who should and should not be placed on the transplant waiting list. Patients who will experience only short-term palliation or recurrent disease in the graft, with little prospect of survival beyond a limited, finite period, cannot be accepted as candidates in an era of severe organ shortage. Such activity compromises patients whose end-stage liver disease will be cured by transplantation and they are further disadvantaged by awaiting list inflation - listing and transplantation before end-stage disease is reached and the procedure is necessary.¹⁵

There will be much debate on these issues in the future. The transplant community must not abrogate its responsibilities but be able to defend its activities from any scrutiny or judgement.

Manipulation that exploits the activity of natural products derived from the immune system will probably replace the present nonspecific immunosuppressive drugs. By manipulation of three cell-surface molecules - B7 on the antigen - presenting cell, CD28 on the T cell and CTLA4 on the surface of the activated T cell, a state of antigen-specific unresponsiveness occurs and this system is already under clinical trial.¹⁶

Using a powerful lymphocyte-depleting antibody, Calne (2000) reported great success with half-dose cyclosporine monotherapy maintenance in recipients of cadaveric renal allografts. He called this prope (almost) tolerance but as the cyclosporine had not been ceased, it is not known if these patients are fully tolerant.¹⁷ Clinical experience in liver transplant recipients has shown that either due to noncompliance with taking immunosuppressive drugs or the necessity to withdraw such treatment because of severe side effects, a proportion of patients survive without graft rejection.

At present, there is no reliable way of determining when immunosuppression withdrawal will be successful. The liver is known to have an important function in the induction of tolerance but the question is whether tolerance can be induced safely and reliably and whether it can be maintained.¹⁸ The recent demonstration that haemopoietic chimerism can induce tolerance in humans, opens the way for the achievement of transplantation tolerance and if this can be obtained without potent toxicity, a new era in patient management will ensue.¹⁹

The realisation that there are too few donors for those awaiting transplantation and that this discrepancy is likely to continue makes the immediate and more distant future somewhat bleak. Alternatives to liver transplantation will be sought.

The development of encapsulation symptoms may allow the transplantation of cells that are separated from the immune system by a selectively permeable membrane.²⁰ Whereas transplant rejection effector mechanisms are excluded, the membrane allows oxygen and nutrients, together with biotherapeutic substances to exchange between cells and blood. Encapsulated cell technology could, theoretically, permit the transplantation of human cells and tissues without the need for immunosuppression and likewise allow the use of cells from animal species. The majority of the research and human clinical trials have been directed towards the treatment of diabetes with encapsulated islet allografts. A recent study has shown that cryopreserved animal hepatocytes retain their regenerative capacity in vivo and therefore the ability to replace liver function. ²¹ This could translate into the capacity for a single donor liver to treat a large number of patients. It has been estimated that some 10-30% hepatocyte replacement would be required to achieve function in specific somatic defects and somewhat more to treat fulminant hepatic failure. ²²

There are many problems to overcome, not the least being the acquisition of sufficient human hepatocytes, preservation and storage and expansion of cells by growth factors or other means.²³ Because of the potential for complications of cell infusion, the maximum hepatocyte mass to be transplanted in human trials, to date, has been 5% of liver cell mass. The most likely application in the future would be treatment of metabolic liver disease in children.

Gene therapy is possible by either an ex vivo or in vivo technique. Ex vivo gene transfer uses the patients harvested hepatocytes which are transduced with a therapeutic gene and transplanted back into the patients liver. It is regarded as somewhat impractical. In contradistinction, in vivo transfer uses a vector that transduces non-dividing cells and has the advantage of normalising physiologic function without the need for proliferative capacity. ²⁴ Gene targeting and site-specific repair can correct a defective gene and it is envisaged that there will be considerable clinical application of this technology in the future with a reduction in the need for liver transplantation for diseases such as alpha-1-anti-trypsin deficiency, Wilsons Disease, Crigler-Najjar Syndrome Type 1, disorders of the urea cycle, etc.

Is xenotransplantation going to be the great salvation? Animal sources may be viewed as a limitless supply of donor organs that would overcome the present major shortage of human organs. Pigs are perceived as the preferable species because the organs are of similar size to the human, are in plentiful supply, can be bred in a sterile environment and transgenic technology, by introducing human genes that code for complement regulatory proteins, allows pig organs to be protected from complement-mediated hyper acute rejection.²⁵

There is the prospect that the immunological barrier can be overcome but there is a great concern regarding transmission of disease. Porcine endogenous retroviruses (PERVs) are a permanent part of the genome in mammalian species and although they do not replicate or cause disease, transplantation to an immunocompromised host might result in viral recombination or activation. It has been reported that PERVs released from cultured pig endothelial cells can infect human cell lines in vitro.²⁶

With these misgivings, xenotransplantation is not just around the corner and it is envisaged that it will not have clinical application for a very long time.

A bioartificial liver is an extracorporeal assist device in the treatment of acute or chronic liver disease. Despite considerable progress over recent years, the efficacy in the experimental arena has not translocated to the clinical setting of acute liver failure. There have been reports of reduction in intracranial pressure, improvement in encephalopathy and some cases of successful bridging to liver transplantation. ^27,28 There is a long way to go before the device will have widespread application in the treatment of acute liver failure and even further before it has a place in managing chronic liver disease.

History has shown that many incurable or untreatable diseases are now ameliorated by previously unknown therapies. It is anticipated that a number of disease processes that are indications for liver transplantation at this time will have progression arrested or will be cured by medical therapy.

Lamivudine has changed the management of patients with hepatitis B in that patients previously considered not to be candidates for liver transplantation are now undergoing the procedure. The question of whether early treatment with Lamivudine for chronic hepatitis B can prevent the progression to end-stage disease and its sequelae is unanswered but inhibition of viral replication with the drug, resulted in significant improvement in liver function in patients with decompensated hepatitis B virus (HBV) induced cirrhosis.²⁹ Other nucleoside analogues under development may have therapeutic potency. The hope that vaccination programmes will eliminate the scourge of HBV over the next few generations is tempered by the evidence that they are effective in protecting against perinatal transmission of the wild type HBV but have accelerated the accumulation of mutations.³⁰ Humoral and cellular responses may be induced by DNA-based immunisation with the potential to eradicate the virus.³¹

The continued efforts to find ways of treating hepatitis C will eventually be rewarded. Combination therapy would appear to be showing some promise and the possibility of the discovery of a suitable vaccine, although remote, is not beyond belief.³² Although the cohort of affected patients is considerable and will be a burden on medical resources for a long time, the ability to test blood donors for hepatitis C should markedly decrease this source of infection and with public health measures such as needle-exchange programmes, may well see a marked decline of the disease in future generations.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are cholestatic liver diseases in adults and have been common indications for liver transplantation. Primary biliary cirrhosis is thought to be an auto-immune disease and PSC an immune-mediated process but attempts at treatment by suppression of the immune system have been unhelpful. What has become evident is that PBC is less commonly an indication for transplantation with the advent of effective therapy in a proportion of patients. In particular, ursodeoxycholic acid has shown a significant prolongation of transplant-free survival after 4 years treatment³³ with slowing of clinical progression of the disease.^33,34 Ursodeoxycholic acid had no effect on transplant-free survival in PSC but the median follow-up period has been limited, compared with PBC, and endoscopic treatment of a dominant stricture may add to the improvement in PSC patients.³⁵ The Mayo group have shown no adverse outcome in patients who had transplantation after previous endoscopic intervention or biliary surgery and have recommended that if an extra hepatic stricture is deemed to be the major cause of obstruction, surgery should be considered as this may prolong transplant-free survival and may even avoid it in a proportion of cases.³⁶ These findings confirm the personal experience of the author. It is anticipated that the antigens responsible for the autoantibody attack on the biliary epithelium in PBC and the mechanism of immune-mediated effect in PSC will be elucidated and appropriate therapy instigated to switch off the attack.

Hepatic fibrosis and cirrhosis are the result of ongoing chronic injury to the liver and are similar without regard to the under-lying cause of injury. It is now known that stellate cells are the source of the extracellular matrix in fibrosis and it is the activation of these cells in liver injury that leads to the laying down of collagen and scar formation. This is the final common pathway of healing, irrespective of the aetiology of the injury. Although it is hoped that the primary condition causing the injury can be treated, if this is not feasible or until such time as it is possible, attempts will be made to limit fibrosis and its consequences on hepatic function. The proposed mechanisms of action of antifibrotic agents being studied are: cytoprotective/anti-oxidant; anti-inflammatory/immunomodulatory; modulators of collagen synthesis and degradation; inhibitors of stellate cell activation.³⁷ To prevent or even reverse fibrosis will have enormous ramifications in the future management of liver disease and greatly reduce the need for liver transplantation.

It has been exhilarating to be part of the tremendous progress in liver transplantation over the past two decades. It should be a pleasant task to predict a bright future but alas, this would be a delusion. At a time when many of the early obstacles have been overcome and the expectation that the remaining barriers can be hurdled, transplant programmes are facing the challenges of 15 years ago, attempting to rescue patients with such advanced disease that they are almost nontransplantable. The lessons learned about transplanting, before patients becoming too advanced in the course of end-stage disease, are still applicable but have dissipated somewhat with the shortfall of cadaveric donor organs. Waiting list mortality of around 15% for adult recipients is forcing programmes to choose adult to adult LDLT using the right hemiliver. The risk-benefit analysis of this procedure, as yet, has not been ascertained. A concerted effort at rationalization of who should or should not be assigned to transplantation will need to be made. To place patients on a waiting list knowing they will not survive to receive a liver is to abrogate clinical responsibility.

The prospect of genetic therapy correcting inherited disorders is exciting and, hopefully, will remove the need for transplantation of many metabolic diseases. Equally, the potential for medical therapy to cure or arrest progression of many liver diseases should lead to the abatement of end-stage liver disease and negate the need for liver transplantation which will, in due course, pass into medical history as an era of medical ingenuity that overcame otherwise untreatable disease.

Correspondence: Professor R.W. Strong, Department of Surgery, Princess Alexandra Hospital, Ipswich Road, Brisbane Qld 4102, Australia

CLINICAL REVIEW

Liver transplantation: current status and future prospects