Liver Transplantation in Children

Approximately 600 liver transplantations are performed annually in the United States as lifesaving therapy for children with advanced liver disease. Innovations in surgical technique, improved postoperative care, and better immunosuppressive regimens have resulted in dramatic gains in posttransplant survival during the past decade. Current data demonstrate expected 2-year patient survival at 80% to 90% (1–3). Clearly, liver transplantation is effective and appropriate treatment for children with end-stage liver disease when measured in potential for survival after transplant, particularly when compared with the survival statistics of children with many common liver diseases who do not undergo transplantation. Although short-term survival statistics are good, long-term data are scarce and actuarials do not allow accurate prediction of long-term prognosis. However, long-term survival after liver transplant is possible. The longest living hepatic allograft recipient was 9 years old when the transplant was performed 39 years ago (in 1963). Thus, mounting evidence suggests that liver transplantation is not just a short-term treatment but is a long-term solution for many otherwise untreatable pediatric liver diseases. AREAS OF EMPHASIS Access to Transplantation Despite impressive advances in the field of transplantation, there is much room for improvement. Many children still die of liver disease. Approximately 900 American children progress to end-stage liver disease each year, yet only 600 pediatric liver transplantations are performed. Thus, 300 children are denied access to therapy because of the shortage of organ donors, a lack of insurance or other means of payment, a lack of access to transplant centers, and the failure of many physicians and families to acknowledge the need for transplantation. Therefore, the prognosis of children with progressive liver disease is affected unfavorably by failure to undergo transplantation. Improved access is imperative for achieving acceptable results in the care of children with liver disease. Technical Aspects of Liver Transplantation in Very Small Children Transplantation in small children remains technically daunting with many special challenges. Early experience comprised mainly older children, who were similar to adults from a technical point of view. However, a major focus of pediatric liver transplantation should be transplantation in children younger than 2 years of age because most children with end-stage liver disease, about 60% to 80%, are younger than 2 years. Technical advances have led to the gradual inclusion of young patients and a decrease in the median age at transplant to younger than 18 months in most major pediatric centers. Yet disproportionate numbers of young children still die awaiting transplantation, 10% of infants according to 1999 United Network for Organ Sharing statistics (UNOS 2000 Annual Report). Another 10% of infants were removed from the list before transplantation, many of whom probably became “too sick to transplant.” Furthermore, graft loss is high, due to technical difficulties such as arterial thrombosis, so retransplantation is needed more often. Even though liver transplantation is technically feasible in newborns, the survival rate of recipients 0 to 3 months old is significantly less than for older recipients. Further technical improvements must be achieved to serve the population of very young children with liver failure for whom there is no alternative effective treatment. Immunology, Immunosuppression, and Transplant Virology Children are distinctly different from adults in their immune responses and susceptibility to viral infections. Young children have relatively immature immune systems that cannot protect them from common viruses. Thus, common childhood infections caused by rotavirus, respiratory syncytial virus, and adenovirus may be serious or even life threatening in the young liver allograft recipient. Paradoxically, young children have an increased rate of allograft rejection, which may be more resistant to therapy than that of adults. This may result in graft loss and the need for excess immunosuppression, which in turn results in increased rates of opportunistic viral infections. Herpes virus infections, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) in particular can cause considerable morbidity and mortality in young immunosuppressed patients. Effective therapy for CMV has been available for some time, but resistant strains have emerged. No effective antiviral therapy for EBV has been developed. Young children are often naïve to this infection, and primary EBV infections in immunosuppressed infants leads to relatively high rates of posttransplant lymphoproliferative disease (PTLD). Protection from and treatment of EBV infections are important to address. The accessibility, delivery, and bioavailability of immunosuppressive agents remain problems in young children. Proper testing of new drugs in pediatric populations is difficult to achieve, and the relatively small population to be served makes testing a low priority for pharmaceutical companies. As a result, some drugs are not yet approved for pediatric use. Other drugs are not available in dosage forms suitable for children or have poor bioavailability. The pharmaceutical industry, the Food and Drug Administration, and pediatric transplant centers should join efforts to improve access to and testing of all potentially useful immunosuppressive agents. Outcomes Research Relatively little is known of the long-term outcome for pediatric liver transplantation recipients. Such areas as life expectancy, developmental outcome, expected school and work performance, earning potential, ability to have families, and long-term need for medical care and its costs require investigation. Carefully conducted outcomes research is necessary to provide accurate information to families, to form the basis of cost–benefit analyses, and to provide a benchmark for future therapies. RESEARCH GOALS Investigation of Methods to Increase the Supply of Organs Suitable for Transplantation in Infants and Children A major problem in transplantation involves the shortage of human donors. The number of cadaver organ donors has not increased in parallel with the number of patients on transplant waiting lists. Indeed, the liver organ supply has been stagnant at between 4,500 and 5,000 per year, whereas the number of patients on waiting lists for livers was almost 15,000 during 1999 (UNOS 2000 Annual Report). People of all ages die waiting for donor organs, but the impact on young children with end-stage liver disease is perhaps the greatest. This is because of an overall lack of suitable cadaver donors; the relatively rapid progression of liver disease; and the severe impact of liver disease on nutrition, growth, and development in this age group. The advent of reduced-size, split-liver, and living-donor liver transplantation has improved this situation. However, recently the number of adult candidates has increased rapidly, putting immense pressure on the cadaver organ system. A new organ distribution system, the PELD/MELD system, has been developed and validated. The impact of this system on availability for pediatric recipients must be carefully monitored, especially for older children and adolescents. The principal problem is an overall deficient number of donors—the system is not now an “allocation system” but rather a system for rationing. Despite the successes in pediatric liver transplantation, a critical imbalance remains between the number of children in need of transplants and the availability of donors. The increased use of split-liver transplants promises to ease this imbalance; however, currently about 15% of infants in need of liver transplantation die while waiting for a donor. Research focused on decreasing the deficit of organs available to children will have a huge impact on the survival of children with liver disease. Surgical Approaches to Improve Outcome of Liver Transplantation in Newborns and Small Children The need for transplantation is greatest in young children. More than 80% of children in whom end-stage liver disease develops are younger than 2 years old. During the past decade, transplant surgery has adapted to this need, and the median age at transplantation in most large pediatric centers is just older than 1 year. Graft loss and the need for retransplantation are relatively high in this young population. Hepatic arterial thrombosis remains a major problem in young infants who undergo liver transplantation. The younger than 3-month-old population has inordinately high mortality after transplantation. These problems are unique to the small child who undergoes transplantation and must be addressed by careful study. The Immature Immune System, Effect on Transplantation, and Interaction With Pharmacologic Immunosuppression The immunology of pediatric transplantation is uniquely complicated and not well understood. The immature immune system of the infant should promote allograft tolerance, but experience does not bear this out; instead, it predisposes young transplant recipients to severe opportunistic infections. Secondary malnutrition, so common in pediatric allograft recipients, further complicates the scenario. Immunopharmaceuticals developed for adult use are either not approved or are not properly designed for use in children. Posttransplant malignancy affects pediatric allograft recipients at an inordinate rate. The field of pediatric transplant immunology requires further investigation to resolve these dilemmas. Outcomes Research—Assessment of Quality and Quantity of Life Issues and Financing Pediatric Liver Transplantation The long-term outcome for pediatric liver transplant recipients deserves careful investigation. Studies to date have been limited in scope or have had significant design flaws, such as assessment tools that have not been validated or too few subjects to permit proper stratification. Yet important insight has been gained in regard to growth, cognitive and intellectual abilities, and long-term side effects of immunosuppressive drugs. Outcome analysis is a new and emerging field of study in transplantation medicine. Although quality of life is difficult to assess in children and infants, validated tools are now emerging for tracking quality of life after solid-organ transplantation in children. These, and anticipated better instruments, must be used to study the rehabilitative stage of liver transplantation to determine what factors play a role in long-term outcome. RESEARCH STRATEGIES Investigating Methods to Increase the Supply of Organs Carefully designed and executed studies are necessary to determine whether split-liver transplantation produces acceptable graft and patient survival in young recipients without major complications. Based on these data, changes in organ allocation policies may have a major impact on the overall survival of children with liver failure. If a portion of every liver from an adult cadaver donor were available for use in pediatric liver recipients, there would be no shortage of grafts for pediatric recipients. Split-liver transplantation, the use of the right hepatic lobe for one patient (usually an adult) and the left-lateral segment for another (the child), is technically feasible. Results comparable to whole and reduced-size transplantation have been reported using an in vivo splitting technique wherein the left lateral segment is removed from the cadaver donor in an operation identical to the living-donor operation. Despite the obvious benefits, the split-liver operation is performed in a minority of United States transplantation centers. Refinement of several aspects of the surgical procedure would serve to increase its use and acceptance and as a result would improve the care of children who require transplantation (4,5). Studies comparing in vivo and ex vivo splitting are needed urgently. In vivo splitting seems to have some advantage with regard to quality of the left-sided graft that is typically used for transplants in a child. However, the technique has major practical disadvantages in regard to organ procurement because it requires a technically sophisticated liver procurement surgeon, prolongs the procurement process, and delays the removal of other organs (6). As a result, procurement teams are frequently opposed to this technique, which would benefit only the child awaiting liver transplantation and not adults awaiting other organs. Only clear demonstration of the superiority of the in vivo or ex vivo split technique could lead to recommendations requiring that it be performed whenever possible. If ex vivo splitting were shown equally effective, this procedure could be adapted more quickly because it would not prolong harvesting and would be performed by the surgeon at the transplant center. A paradigm for organ sharing must be developed (7,8). Currently, split-liver transplantation is performed only in centers with adult and pediatric programs and appropriate recipient candidates. Because adult-only transplant programs have little incentive to provide part of a split liver for a pediatric recipient at another center, to rectify the situation and make more organs available to children will require careful research in several areas. Assessment of donor organ suitability for splitting will be necessary to define situations in which splitting should take place. Objective parameters must be established to ensure that organs are split when donor need is present and adequate surgical expertise is available (9–12). Careful cost–benefit analysis must be completed to determine whether the value of splitting in terms of human life can be justified. For instance, there may be an extra economic burden to the adult recipient of the right lobe who would have received a whole liver if not for the split. Finally, the bioethics of organ splitting has not been addressed. Is it ethical to require an adult recipient to give up part of the graft if it increases the risk or the cost of transplantation? Xenotransplantation, the development of suitable animal sources for organs to be used in human transplantation, is of potential importance to pediatric transplantation (13–15). Although primates have been used in attempts at xenogenic liver transplantation, for economic and ethical reasons, the use of pigs is a better alternative. Early attempts at “humanizing” porcine livers through transgenic technology have partially decreased the human immune system's recognition of important antigenic determinants of immediate xenograft rejection (16). Much additional molecular genetic work is necessary to produce a pig or other farm animal source of organs that human recipients can tolerate for extended periods (17). In particular, the xenografted liver must produce many circulating proteins that are active in humans. Furthermore, recent about pig that could be of risk to human recipients should lead to new research of particularly the risk of on immunosuppressed patients studies this is probably not a significant problem Surgical Approaches to Improve Outcome of Liver Transplantation of the hepatic is a major cause of graft loss and recipient after transplantation in small children to of grafts in children who less than are affected by this which results in the need for retransplantation in most patients and graft in many of the patients. thrombosis may result from surgical technique, medical or a of the the of the and the problem would grafts and Careful analysis of the use of surgical technique compared with technique in the arterial is use of the recipient hepatic to the graft the to large arterial to the to No has more effective in thrombosis Such a study would require and careful No studies have the on the rate of thrombosis of pressure at of more or of other during the critical after transplantation. 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