Liver transplantation in the new millenium

Liver transplantation in the new millenium



1. Improved liver allocation

The number of patients waiting for a liver is growing continuously. Therefore, the gap between the number of donor organs and the number of patients on the waiting list is always widening.
Several systems of organ allocation exist in different organ transplant organisations.
Allocation of a liver graft is often very complicated.
The basis of any liver graft allocation system should be equal access for every sick patient to this scarce resource.
A new model examining the survival of the patient with chronic liver disease after 1, 3 and 12 months has been developed in the United States. The MELD system (Model for End-stage Liver Disease), is based on 4 objective parameters, which have been integrated into a simple formula. These parameters are : degree of jaundice (bilirubinemia), blood coagulation (INR), renal function (creatinine level) and etiology of the liver disease (cholestatic and alcoholic disease versus all other diseases).
The chosen parameters correlate well with the survival of the liver disease patient. The formula has the merit that it avoids subjectivity and variability of the values between different laboratories and medical teams and that it resembles discriminating parameters.
The United States Network of Organ Sharing (UNOS) unanimously accepted this system in February 2002. Comparison between the waiting lists of the first few months of 2001 and 2002 showed a 15% reduction in the rate of mortality on the waiting list.
Several European organ allocation organisations are currently looking at implementation of this liver allocation system.


2. Improved utilisation of the donor pool

Until now, most of the organs used in liver transplantation originated from brain-dead heart-beating donors. This donor pool has stabilised over the last years. One possible way of expanding the number of available organs lies in the use of the non-heart beating organ donors.
Due to the efforts of Dutch and Spanish transplant communities, it has been shown that not only kidneys but also livers originating from such donors can be used successfully for transplantation. A non-heart beating donor is a donor in which the heart function has already ceased for a time period (defined as more than 10 minutes) after which brain function is irreversibly damaged.
More complex resuscitation methods, such as the introduction of cardiopulmonary bypass in such patients has enabled even more organs to be recovered.

At the beginning of the eighties, the concept of using one liver for two patients was developed. « Split liver transplantation » had a very faltering start because of the negative impact of the technical complexity on patient and graft survival.
Since the end of the second millennium and the beginning of the third millennium, there has been a revival of split liver transplantation.
Due to the continuous interaction between liver transplantation surgery and resectional surgery (this means removal of a part of the liver for the treatment of a liver tumor) the technique of split liver transplantation has fully come to maturity.
Initial attempts were mostly devoted to the use of the large right liver lobe for an adult and the smaller left liver lobe for a child or an infant.
Restriction of this technique to a child and an adult is however insufficient. 90% of patients on the waiting list are adults and the indications for adult liver transplantation are ever increasing due to the major role of liver transplantation in the treatments of post-viral C cirrhosis and liver cancer. The organ pool can be extended greatly by the « splitting of a liver » for two adults. This more sophisticated technique has been promoted by the liver transplant groups of Los Angeles (UCLA) and Paris (Paul Brousse Hospital). Increasing experience with the technique has identified various risk factors. They are the status of sickness of the recipient, the length of hospitalisation of the donor and the fat content of the liver allograft.
From the larger Japanese experience in living related liver transplantation, it has now become clear that split liver transplantation for two adults can only be successful if enough liver mass is given to both adult recipients. The relationship between the weight of each liver part and the body weight of the recipient should be more than one percent.

World-wide experience with more than 80.000 liver transplants since 1968 has almost ruled out any contraindication to this procedure. The only formal exceptions remain active infection (sepsis – infection of the blood) and extra-hepatic tumor spread of hepatobiliary cancers. Technical progress has eliminated one of the last contraindications namely the diffuse thrombosis (occlusion) of the venous vessels of liver and intestines. Implantation of the vena cava of the recipient into the portal vein (the main vein bringing the blood to the liver) of the graft makes successful transplantation possible in such situations.

3. Medical and surgical complications in liver transplantation

Many technical problems of liver transplantation have been solved due to international exchanges of experience and due to the introduction of endoscopic and interventional radiological techniques. For instance, narrowing or even complete obstruction of the portal vein can be resolved without a reoperation. Dissolution of the thrombus (thrombolysis) and application of stents in the portal vein can resolve this dramatic post-transplant complication.
Another major threat to the success of liver transplantation was the occlusion of the hepatic artery (which brings oxygenated blood to the graft). Microsurgical techniques and the development of fine surgical sutures have virtually eliminated this graft- threatening complication. All these technical progresses are of utmost importance in a time where the gap between obtained allografts and waiting patients is ever increasing.

Better knowledge of the epidemiology of bacterial, viral and fungal infections in transplant patients has substantially reduced their rates of morbidity and mortality. Improved surgical techniques, more effective antibiotics and most of all individualized (tailored) immunosuppression regimens have been fundamental ways to reduce infectious problems in liver transplant patients.


4. Living related liver transplantation

Since the first living related liver transplantation in 1989 by R. Strong in Australia, more than 2500 such procedures have been done in the eastern and western hemispheres.
The concept of living related liver transplantation originated from the east. For religious reasons, post-mortem organ donation is almost non-existent in these countries. Despite introduction of a law in Japan authorizing organ harvesting in brain dead patients, to date , only a couple of such organ procurements have been done.
The surgical schools of Kyoto, Tokyo, Shin Shu, Hong-Kong, Taiwan and Sydney have in particular fostered the living related technique. Initially, the procedure was designed for the transplantation of children ; the small left lobe of an adult liver being implanted into a child.
More confidence with liver procurement in healthy persons led to the development of the procurement of the right liver or the right lobe of an adult, to be implanted into another adult patient. The first such procedures were done in 1993 by Makuuchi in Tokyo (left liver) and in 1994 by Yamaoka and Tanaka in Kyoto (right liver).
The development of living related liver transplantation especially between adults has been extremely rapid because of the increasing demand for transplantation. This transplantation technique became officially recognised in a landmark paper presented by the American Society of Transplantation.
Registries in the US and Europe were created in order to document carefully all adverse events (morbidity) and mortality of healthy liver donors.
The mortality of this intervention is 0.2% (six donor deaths reported worldwide).
Living related liver transplantation between adults and children but more especially between adults and adults has some major advantages. It represents the ultimate expansion of the donor pool and it allows liver transplantation to be performed electively. In contrast, however, there are ethical concerns and potential medical risks for the healthy donor.
It is important, therefore, to clarify the relationship, whether genetic or emotional, between donor and recipient. All these principles have, however, been recently overruled by the so-called good Samaritan - donor !
In order to be successful the surgical technique should be perfect, and the liver mass given to the patient should be sufficient in order to guarantee a metabolic life sustaining function of the graft. The graft volume / recipient body weight ratio must be equal or more than 0.8 – 1 %.
Another advantage of the method results in the fact that it will become possible to immunologically manipulate the graft. This may open the way to achieve graft tolerance, which means acceptance of the graft without the need to take immunosuppressive drugs.
Technical progress and advances in perioperative care of living related liver allografts has made it possible to obtain almost equal results as these obtained in cadaveric liver transplantation. These techniques have also allowed physicians and surgeons to get a more comprehensive view of the physiopathology of liver regeneration.
Liver regeneration is the basis for every liver resection and liver transplantation. This regeneration process has always intrigued humanity. The original description is found in the Prometheus legend of Greek mythology in which his liver was eaten every morning by the vulture of Zeus…every morning because of the overnight regeneration of the organ.

Careful follow-up in the recipient of the liver graft procured from a healthy person and of the residual liver mass in the liver donor has improved insights into the complex process of liver regeneration.
It is well documented that liver regeneration essentially takes place during the first three weeks ; this regeneration, which is equal in donor and recipient, is better if the donor is aged less than 50.
It has also been established that the (bilirubin and lactate) clearing function of the liver is proportional to the transplanted hepatic mass, to the state of jaundice of the recipient, and to the intraoperative blood loss.

The safety of the liver procurement in the donor is of course proportional to the resected volume. The morbidity (complication rate) is estimated between 30 to 60% and the mortality is 0.2%.
The technical progresses, made in the procurement of the liver in a living donor have also had a profound impact on the knowledge of classical liver surgery as applied to the treatment of hepatobiliary cancers.
The cross fertilization between all techniques gathered in liver transplantation and in classical liver resection surgery, will boost the development of these two fields of hepatology and surgery. This is of utmost importance as humanity is overwhelmed with the worldwide explosion of hepatitis C virus infections; these are responsible not only for the enormous increase in the number of cirrhotic liver patients but also in the number of liver cancers. One should not forget that it is not HIV infection but hepatitis C virus infection is the most frequent infection worldwide.

Domino or sequential liver transplantation
Some patients have a metabolic disease that is localised only in the liver. They need a liver transplant in order to stabilise or to definitively cure their disease. Some of these diseases, such as familial amyloid polyneuropathy (FAP), in which an abnormal albumin is accumulated in the body, are non cirrhogenic, this means that these patients do not develop a liver disease. It is best to transplant such patients early or even pre-emptively (before destruction of the body occurs by the different metabolic deposits).
The liver of these patients can theoretically then be implanted in another patient in need of liver transplantation. Actually, almost 100 such domino liver transplantations, registered in the FAP world registry, have been done worldwide, mostly for hepatic cancer. The available cadaveric or living related liver allograft is implanted in the patient with the metabolic disease ; his liver will in turn be implanted in another recipient.
Progress in living related liver transplantation and split liver transplantation has enabled the transplantation of two patients with metabolic disease liver leading to the concept of « one for three » livers. This concept has been promoted by the groups of Coimbra (Prof. L. Furtado) and Paris (Prof. H. Bismuth).
Other non cirrhogenic metabolic diseases such as oxalosis (accumulation of oxalate in the body) may also apply to this concept.


5. Indications for liver transplantation

Since its inception in 1963, by Thomas Starzl, the indications for liver transplantation have now become very standardized and very clear.

Liver cancer has become an important cause of death ; indeed liver cancer is the second most frequent cancer in humans.
Despite progresses made in liver resection surgery, even in cirrhotics, tumor recurrence remains very high (60 % at three years). This is explained by the fact that sick (cirrhotic) liver tissue remains behind, which will remain « irritated » by the continuous carcinogenic effect, especially that of B and C viruses.
Worldwide experience has allowed better selection of those patients that can be cured by a total hepatectomy and liver replacement.
The Milan group (Prof. V. Mazzaferro) showed that the presence of less than 3 tumors in a cirrhotic liver, all of them with a diameter of less than 3 cm or the presence of one single tumor less than 5 cm in diameter, are the best guarantees for successful liver transplantation.
Recently, it has also been shown that the degree of tumor differentiation is also important. The Miami experience (Prof. A. Tzakis) showed that very large tumors (even more than 5 cm) can also be transplanted successfully on the condition that tumor differentiation is good and vascular invasion is absent.
Due to the fact that many patients are surviving for long periods after liver transplantation (20 to 30 years), physicians have obtained more insight into the recurrence of some diseases in the liver graft. It is now established that patients transplanted for autoimmune liver diseases should continue with steroid treatment. The role of different new immunosuppressants may play a role in the incidence and the rapidity of disease recurrence in the allograft.

Acute and chronic liver diseases due to hepatitis B viral infection remain excellent indications for transplantation. Newer antiviral drugs such as viral nucleoside analogues allow successful transplantation even in the presence of highly infectious viruses.
Many concerns of the transplant physicians relate to allograft reinfection by the hepatitis C virus. Immunogenetic background (recipient defence) and the type of virus play an important role in the importance of recurrent disease. Interferon and Ribavirine are important weapons in protecting the newly implanted liver from aggressive reinfection. Much progress remains however to be made in the future.


6. Viral and bacterial infections

Adequate antiviral therapy has almost eliminated graft and patient loss due to some viral diseases such as cytomegalovirus infection and herpes simplex viral infection. Prophylactic treatments can both prevent and cure these infections.
Great concern has been raised in relation to the development of multiresistant bacterial infections. Better and adapted antibacterial chemotherapy will be necessary to overcome this problem.


7. Immunosuppressive strategies

The introduction of cyclosporine (Sandimmun-Neoral)Ò at the beginning of the eighties made the development of solid organ transplantation possible on a large scale.
Since then, more drugs, each having a specific action and a specific profile, have been introduced into clinical practice. The introduction of another calcineurin inhibitor, tacrolimus (PrografÒ) during the nineties was another breakthrough in transplantation. Several controlled studies showed that tacrolimus is a very safe and excellent immunosuppressive drug. The main benefit of this medication was that immunosuppression with steroids became unnecessary.
This medication also significantly reduced the number of corticosteroid resistant rejections.
Nowadays, 3 month and 12 month patient and graft survival rates of over 90% can be reached.
Unfortunately, the two main immunosuppressive agents, cyclosporine and tacrolimus, are both nephrotoxic. Long survival times, more than 2 and even 3 decades have therefore led to the development of renal insufficiency.
Some newer drugs such as mycophenolate mofetil (CellceptÒ) and rapamycine (SirolimusÒ) have been introduced into clinical practice. These medications are powerful immunosuppressants which do not have nephrotoxic side-effects.
These drugs are already used not only to replace cyclosporine and tacrolimus in existing patients but more recently have also been used from the beginning of liver transplantation.
Calcineurin inhibitor-free immunosuppressive schemes will be necessary in the future in order to avoid the need for renal transplantation in successful liver transplant patients.


8. Quality of life

Due to the enormous progresses that have been made in operative as well as perioperative care of liver transplanted patients, results of graft and patient survival are now excellent. The main interest of the transplant physicians will shift in the future to the quality of life of the patient. Steroids and calcineurin inhibitors are as already mentioned, are responsible for many physiological and psychological problems.
Individual titration of these different drugs for specific patients will be the most important development in the future evolution of transplantation.
Global care of a transplant patient should achieve an excellent quality of life encompassing social, familial and professional reintegration. Multiple, detailed, studies have already been done in this context.
The best quality of life after solid organ transplantation is obtained after a liver transplant. The quality of life is lowest, as may be expected, in hepatitis C viral infected patients due to the fact that recurrent allograft disease is very frequent and causes psychological distress to the recipient.
Successful transplantation leads to an euphoric condition during the first half of the first post-transplant year; the second post-transplant year is more stressful. During this period, the patient starts to raise questions about his future, his donor and the longevity of the new liver.
Liver transplant patients should be managed carefully by the transplant team including a psychological support team.


9. Conclusion

Since the introduction in 1963 by Thomas Starzl of the « impossible operation », major progresses have been made in the field of liver transplantation.
These progresses have been made possible due to the development of operative techniques, perioperative care, powerful immunosuppressants and adequate anti-infectious chemotherapeutics.
Surviving for more than ten years following a liver transplant has become routine.
Due to this enormous success, more and more patients are becoming candidates for a liver transplant. Unfortunately, the gap between available organs and number of patients on the waiting list is ever increasing. This gap has led to the development of innovative techniques such as liver splitting and living related liver transplantation.
Liver transplantation becomes, more than ever, not only a surgical and medical project but what is even more important, a social and ethical discussion point.
Transplant physicians and surgeons must be vigilant in order to allow correct development of the latest developments added to the « book of liver transplantation ».
Availability of living related liver transplantation may not be responsible for a decreased interest of the medical community and the « greater public » in to the problem of (cadaveric) organ donation.

One should not forget that the most generous gift that one can make in life is to make available ones organs for patients who would otherwise die.