Future of Liver Transplantation in Children

Introduction

Liver transplantation was a dream only a century or so ago. The idea of replacing a diseased organ with a new one was a matter of science fiction. However, innovations in surgery, the development of intensive care and anesthesia, progress in the understanding of how the immune system works, and the introduction of effective immunosuppressive medication have led to the advent of clinical programs of solid organ transplantation beginning with the kidney in the 1950s and the liver starting in 1947 when Dr. Vittorio Staudacher, an Italian surgeon, published a technique for liver transplantation performed in dogs. Subsequently, Thomas Starzl attempted the first human liver transplant in 1963 and performed the first successful procedure in 1967 ; however, early results were poor owing to the lack of effective immunosuppressive drugs, with a 1-year survival of less than 30%. Transformation of the outcome of organ transplantation came with the introduction by Sir Roy Calne of cyclosporine, an effective immunosuppressant introduced into clinical practice in 1981, and immediately resulted in a 1-year survival rate of 70%. By 1983, liver transplantation was established as the treatment for end-stage liver disease. To date, improvements have occurred in all aspects of liver transplantation, and these will be briefly reviewed in conjunction with ideas about future developments.

Organ Donation

Liver transplantation continues to rely on human donation, either deceased heart-beating brain death or after circulatory death (DCD) and by living donation. The full potential of cadaveric donation has been realized in a very small number of countries worldwide. National programs of organ donation and retrieval such as that established in Spain have delivered high rates of cadaveric donation and organ use. Currently, the world of liver transplantation is polarized, with cadaveric donation being practiced predominantly in the West and living donation in the East. Challenges for the future are to develop effective cadaveric and living donation throughout the world. Shared practice and expertise have been shown to be effective in increasing cadaveric organ donation in countries that have not had a culture of donation. Living donation has been shown to be a highly effective way of transplanting young children and adults with suitable donors and will continue to make an important contribution for the next 20 years. Adult living donation remains restricted in the West at present because of a lack of suitable donors and the risk entailed with right lobe donation.

Organ Preservation and the Advent of Machine Perfusion

The introduction of the University of Wisconsin solution for cold preservation of the liver allowed for storage times of up to 20 hours. This allowed livers to be transported over longer distances and for more complex cases to be transplanted. In addition, it made possible the surgical reduction of the liver (including split) and thus established effective pediatric liver programs that could offer liver transplantation to children of all sizes. More recently, a new paradigm shift has occurred with the introduction of machine perfusion. Ex vivo perfusion of the liver can be at body temperature (normothermic) or at colder temperatures (hypothermic), and these techniques offer different ways of maintaining or improving liver function by potentially reducing ischemia/reperfusion injury and allowing time to assess potential function before use. Data are being accrued currently through prospective randomized studies to understand the effectiveness of this technology and to develop the next generation of perfusion machines. It appears that oxygenated hypothermic perfusion of livers replenishes energy levels in mitochondria and reduces the severity of ischemia reperfusion injury. Normothermic blood-based perfusion of the isolated liver allows the ischemia-reperfusion injury to occur on the machine with subsequent assessment of liver function and graft viability. The avoidance of cold preservation would allow for the use of fatty livers as a matter of routine. The use of in situ normothermic regional perfusion has the potential to resuscitate organs before surgical retrieval at DCD donation and also allows the assessment of liver function before transplantation. The early results of these techniques have been promising, with low rates of graft failure and ischemic cholangiopathy. The combination of hypothermic followed by normothermic perfusion may be synergistic with a significant reduction in the ischemia-reperfusion injury, which would protect more marginal grafts, thereby increasing the donor pool. This technology will be developed further to try to optimize liver function, making liver transplant safer with better long-term graft survival. Other groups are experimenting with supercooling of livers at − 4° C to try and preserve livers for longer periods but still maintain function. At present, techniques are being developed in animal models, but in the long term, preservation of organs may evolve to the point that they can be stored for long periods and used at the optimal time for the individual patient with selection by blood group, size, and tissue matching. Although attempts are continuing to develop xenograft liver transplantation, the immunological and physiological barriers remain significant in the short term, and in the longer term the use of pigs as potential organ donors may prove unacceptable to future societies. The potential for xenotransplantation using pig organs is most likely to succeed with the heart and kidney, but the liver is likely to offer more physiological obstacles.

Surgical Techniques

Over the last 50 years, surgeons have developed techniques that simplify transplant surgery, enabling all surgeons to be able to perform the majority of cases. The early experience of liver and caval replacement using venovenous bypass have been simplified and replaced piggyback or cavo-caval implantation techniques. Technical innovation has been driven by the need to transplant small children. Size-matched whole livers suitable for small children are uncommon; before 1988, children under 10 kg were excluded from liver transplantation because of the technical and medical challenges involved in their care. Techniques to reduce whole livers from adult donors to partial grafts radically increased the potential donor pool for children. Initially, livers were reduced to a left lateral segment (segments II and III) or left lobe graft (segments I to IV or II to IV). Subsequently, split-liver transplantation (the division of a liver to provide two grafts) was developed to offset the potential loss of livers in the adult pool and living donor liver transplantation initially to reduce waiting list mortality in children and subsequently in adults. More recently, the use of monosegment grafts (either segment II or III) has enabled transplantation of even the smallest child with an appropriately sized graft. Further refinement to these techniques can be expected to ensure that early graft function is assured with a low incidence of technical complications.

Auxiliary liver transplantation has been developed in the setting of acute liver failure to allow for recovery of the native liver with subsequent withdrawal of immunosuppression (IS) (see Fig. 47.1 ). This has been very successful in children using left lateral segment grafts, with short-term survival comparable with liver replacement and better long-term survival because of the high rate of IS withdrawal and avoidance of long-term drug complications.

Surgery is becoming more refined, with the emphasis on fewer technical complications and particularly the need for retransplantation. The use of microsurgery to minimize arterial and biliary complications will be the standard of care. In the future, monosegment liver transplantation will become routine in all pediatric centers. In the longer term, for a surgeon, it would be marvelous to develop invisible wound healing without scars and normal abdominal wall reconstitution. On a similar futuristic note, it would be great if we could three-dimensionally print or design livers of the correct size and weight with vessels and bile ducts that allow for liver transplantation without technical complications.