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.
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.
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.
Laparoscopic and Robotic Surgery
Minimally invasive surgery is gradually progressing. This has been because of developments in infrastructure, including screen and three-dimensional technology, instruments, and surgical expertise. Living donor surgery to resect the left lateral segment and left and right lobes for transplantation is being performed laparoscopically and over the next few years will become the standard approach in large-volume centers. The liver is retrieved after resection through a small incision in the lower abdomen. The laparoscopic approach has been extended to the use of robotic-assisted surgery to perform right lobe retrieval in leading centers, and studies are underway to compare open and minimally invasive techniques, patient safety, and transplant outcome. The advent of robotic surgery will open up minimally invasive surgery to a wider group of surgeons, and the improved access and visualization will facilitate microvascular surgery. The future could be long-distance laparoscopic or robotic surgery, including living donor liver retrieval and implantation performed by surgeons on-site assisted by colleagues at a distant center of excellence, potentially removing the risks of learning curves and reducing technical failure rates.
Anatomical Models in Surgical Training
Textbooks are already being transformed into virtual three-dimensional models on the internet. Surgical trainees can observe, change, create, and analyze anatomical models in detail. Learning three-dimensional structures and practicing three-dimensional movements is invaluable for surgical development using laparoscopic and robotic techniques, potentially shortening or removing the learning curve for trainees. Dynamic visualizations enable learners to acquire advanced spatial awareness and ability. Imaging allied to three-dimensional technology will personalize each patient’s operation, allowing the surgeon to rehearse and perfect surgical techniques before the surgery. This will revolutionize the teaching of surgery.
Selection of Patients and Timing of Transplant
The timing of transplantation is driven by life expectancy. As transplantation becomes safer, treatment for quality-of-life issues such as growth potential, attendance at school, or general well-being becomes more important. Timing of transplantation in children will change as our understanding of physical and mental health in the context of liver disease improves. Over the longer term, some indications, particularly for metabolic diseases, could disappear as gene therapy or manipulation becomes effective. It is likely that biliary atresia will continue as an important indication for transplantation; however, the potential for using cells from these diseased livers to repopulate the transplanted graft is likely to be exploited to try to avoid the need for long-term IS. Over time, medical treatment for portal hypertension and fibrosis may alter the natural history of these apparently irreversible liver diseases.
Repopulating Livers After Transplantation
Researchers have looked at the repopulation of donor livers by the recipients’ own cells after liver transplantation, presumably by circulating pluripotential progenitor cells. It is well recognized that endothelial cells are replaced in the graft within 3 months in the majority of transplant recipients. One study identified recipient bile duct epithelial cells in 5 out of 16 and hepatocytes in 1 out of 5 liver transplant recipients, respectively. The potential of using recipient cells to repopulate or repair livers has become increasingly attractive. From simple ideas of infusing recipient cells or stem cells to the transplanted liver to the decellularization of organs and repopulating them with recipient stem cells, all have been shown to be possible in the mouse heart. The idea of using an animal or human liver and being able to decellularize and repopulate it with recipient stem cells and create viable grafts may become possible. The next step from that would be the creation of artificial liver scaffolds, which would be repopulated with patient’s own stem cells or organoids (small, self-organized three-dimensional tissue cultures derived from stem cells used to replicate some of the functions of an organ), and these techniques are being investigated in the laboratory.
The use of three-dimensional printing is becoming commonplace in many areas of life, including medicine. The ability to “print” cells to create tissue is, at present, limited by the problems of providing an effective blood supply to provide oxygen and nutrients as the structure gains depth and complexity. Printing layers of cells, such as the creation of tubular structures, and rudimentary hollow organs such as the bladder are possible, and the potential is there to develop more sophisticated structures. Clinicians are developing techniques to grow small livers in the recipient (using a left lateral segment for example) and manipulating the environment by modulating portal hypertension and portal venous inflow to avoid small-for-size syndrome. Laboratory research is exploring the potential of growing livers in animals before use in humans, but this may be limited by ethical and immunological considerations. However, competing technologies that heal or repair diseased livers will hopefully mean that liver transplantation in the distant future is only required for traumatic liver injury.
Currently, we rely on monitoring liver function tests and interpreting abnormality allied to liver biopsy and histopathology and other specialist blood tests for such things as viral infection, including cytomegalovirus (CMV) and Epstein-Barr virus (EBV). The development of “omics,” including proteomics, genomics, and metabonomics, is being used to transform the potential for monitoring novel biomarkers that may identify rejection, infection, and vascular disturbance earlier and with a greater degree of certainty than with current technology. The use of peripheral blood samples to study gene expression, free DNA, microRNAs, proteins, and autoantibodies among many other molecules is being evaluated and refined to try to help in the management of transplant recipients. Metabolomics allows the identification of more subtle and distinctive patterns of metabolic disturbance and may help greater understanding and early recognition of the complexities of early and late graft function. Clinical trials with in silico organs-on-chips technology can use stem cells and microchips as models of human cells, organs, or physiological systems. In this way, clinical trials would be faster and more accurate. These chip and cell combinations reproduce functional units of the body and are likely to be valuable research vehicles for the future and could be used to predict donor–recipient interactions and drug effects before transplantation.
The introduction of calcineurin inhibitors (CNIs) transformed the outcome of all organ transplantation. Cyclosporin and subsequently tacrolimus have proved highly effective immunosuppressive agents such that acute rejection is no longer seen as a significant problem for the majority of patients after liver transplantation. At present, there are no new immunosuppressive agents in development to replace CNIs. New agents that have been introduced into clinical practice supplement CNI IS often for renal sparing. Other agents are used for treating the occasional case of steroid-resistant rejection. Induction therapies have not proved effective in lowering the overall level of IS or inducing tolerance. Given the effectiveness of current therapy, there is little mainstream commercial drive to develop new drugs. Innovation is likely to come with novel ways of inducing graft-specific tolerance, perhaps through regulatory T-cell therapy and sophisticated tests to identify degrees of IS or tolerance with top-up treatments. At present, researchers are trying to develop biomarkers that identify operational tolerance with the intention of weaning IS to withdrawal. Although up to 40% of children can be weaned from IS, currently reliable biomarkers have yet to be identified, and weaning carries risks of late rejection and graft loss. Maintenance of optimal renal function is probably the most important factor associated with long-term patient survival, but even this remains a research objective at the present time. In the future, biological markers of IS will be available to help minimize the consequences of IS. The ability to produce graft-specific tolerance using novel technologies, thereby avoiding the need for long-term IS, has to be the holy grail for transplantation.
Long-Term Survival and a Natural Life Span
The improved survival seen over the past 50 years in pediatric liver transplantation will continue; however, the challenge has turned to the prospect of achieving a normal life span. This in turn means trying to optimize mental, social, and physical development and improving well-being. The timing of transplantation to achieve this will need to be reevaluated. The most important factor will be the minimization or avoidance of IS as described previously. The provision of transition medicine and care of young adults will improve survival during adolescence and beyond. The use of social networks to provide support to individuals at times of vulnerability and help with appropriate risk-taking and development is only just beginning. The use of mobile phones and the “internet of things” will refine communication, influencing and monitoring recipients, and this will transform follow-up and long-term care. With this new era, we will need a new vocabulary replacing patient, disease, and transplant with prevention, maintenance, and repair. The use of novel technologies using biomarkers or nanotechnology to monitor health and early detection of injury will allow for organ repair and the avoidance of transplantation. Nanotechnology may prove to be a key step in developing health maintenance by sensing, controlling, or effecting change within the microenvironment of the body. A simple example is a nanosensor of green spheres composed of fat and l -arginine molecules that give off magnetic resonance imaging–detectable and light signals when cells are alive.
Other technologies will be targeted at interfering with the “aging” process. Cellular receptors appear to work less efficiently or not at all with increasing age. The ability to improve function by removing and repairing damaged proteins could, for example, improve the ability to metabolize sugars, fats, and alcohol. Managing the comorbidities of modern life with high cholesterol levels, insulin-resistant diabetes, and hypertension will continue to be important and challenging in the transplant population.
The use of extracorporeal artificial and bioartificial devices has not yet shown a survival benefit in the treatment of acute liver failure. With each iteration of the technology, the possibility of liver “dialysis” to support patients with liver failure gets closer to being a reality. The combination of hepatocytes in bioartificial reactors linked to hemodiafiltration should become more effective and enable survival of patients with decompensated liver disease until transplantation can be performed.
Equality of Access to Health Care
The inequalities of health care are evident in liver transplantation, with marked variations in transplant rates around the world. Currently, the majority of the world’s population does not have access to this lifesaving surgery. Even in countries with liver transplantation, access may be restricted by organ shortage and ability to pay. If liver dialysis technology becomes practicable, the shortfall in organs will increase further. Living donation offers a partial solution but is never likely to fulfill demand. Even growing left lateral segment grafts will not suffice. Once transplanted, the continuing need to fund medical follow-up and particularly drug costs is significant and beyond the ability of many to pay. Can transplantation be performed inexpensively with universal access using “artificial” repopulated liver grafts without the need for long-term IS?
Disease prevention remains the area most likely to reduce the long-term health burden worldwide, particularly for liver disease. Hepatitis B vaccination has already had an impact, which, over the next 30 years, will reduce the incidence of liver disease and hepatocellular carcinoma. The potential eradication of hepatitis C will also have a significant impact on liver disease and cancer. The development of novel vaccines has the potential to modify many “modern” diseases that drive liver disease, including EBV and CMV, in transplantation. Will vaccination against pathogenic strains of gut flora help prevent fatty liver disease, or the risk of liver cancer?
The Long Term
Over the next 50 years, the advances in medicine and basic sciences will reduce the burden of liver disease. The ability to vaccinate against many diseases has the power to transform health worldwide at an affordable price. Being able to monitor for injury and fibrosis will allow for maintenance work to prevent disease progression. The development of the “omics” will allow individuals to understand their risk to health through interactions of genetics and environment. Liver transplantation will eventually disappear and be consigned to an early era of medicine. However, the dream for a surgeon of this era would be to 3D print a liver of the right size with blood vessels and a bile duct ideal for implantation, with guaranteed function and no need for IS and for the graft to be ready at the beginning of a workday.