Liver and Intestinal Transplantation in Children: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

LIVER TRANSPLANTATION History and Results The first attempt to transplant a liver in a human was reported in 1963 (1). This 3-year-old child with biliary atresia died during the procedure because of extensive blood loss. Four years later, the first truly successful liver transplantation was accomplished, on a 1½-year-old with hepatocellular carcinoma, with survival exceeding 1 year after surgery. After early attempts at transplantation in the early 1970s, the advent of cyclosporine immunosuppression and advances in surgical techniques led to the development of many clinical programs of liver transplantation being started in the United States and Europe in the early 1980s. For more than 15 years now, orthotopic liver transplantation (OLT) has been a recognized option in the therapeutic approach to children with end-stage liver disease. Approximately 600 liver transplantations are performed annually in the United States, 350 in Western Europe, and in excess of 300 in the Asian-Pacific region. The expected need for pediatric liver transplantation is estimated to be between 2 to 3 per million inhabitants per year. In populous countries such as India and China, this would suggest that there could be in excess of 2,000 to 3,000 candidates per year who would benefit from liver transplantation. The procedure is not only life-saving but also improves the quality of life in children with non–life-threatening conditions. The overall long-term survival after OLT is 71% for the 2,500 children registered in the European Liver Transplant Registry (ELTR) since 1984, with continuous improvement in survival observed between the 1980s and the 1990s. For example, the 5-year graft survival in Brussels, Belgium increased from 73.6% for 209 children grafted between 1984 and 1990, to 85% for 206 engrafted between 1991and 1996. Similar results were reported from the University of California at Los Angeles, with 75% survival at 5 years for 256 children transplanted between 1984 and 1992 compared with 85% for 184 children transplanted between 1993 and 1997. Biliary atresia accounts for approximately half of the cases of pediatric OLT in Western countries. In countries in which consanguinity is frequent, metabolic diseases, such as familial cholestasis, may also be prominent indications. Fulminant hepatic failure and autoimmune liver disorders are other major indications. Forty to sixty percent of the pediatric liver transplants are performed in children younger than 2 years of age, but the proportion of young children is increasing with the success of the procedure. The previously reported poorer survival in young patients is no longer observed in recent series; however, significantly poorer survival is observed in infants with acute liver failure (about 50% survival), and children with hepatic tumors (about 30% survival). I: SUMMARY OF THE PROBLEM Posttransplantation Survival Is Not the True Indicator of Success; 7% to 15% of Registered Patients Will Die While Waiting Parents and families are more concerned about patient survival and quality of life issues from the time of referral rather than from the time of transplantation. Mortality is highest in the less than 1-year-old group, according to the UNOS registry. Another 10% of infants are removed from the list before transplantation, many of whom had become too ill to undergo transplantation. Survival curves should therefore take into account the pretransplantation and waiting list mortality. Pretransplantation mortality is highest in patients awaiting cadaveric donor organs, whereas it is reduced significantly in children receiving living-related transplant (LRT) donor organs. In the United States and other countries, children with end-stage liver disease may not have access to the procedure because of health insurance issues. In developing regions of the world, there may be little or no access to liver transplantation because of the lack of suitable programs and because of financial burden. The actual number of children dying of liver disease is unknown in countries in which not only the cost of providing liver transplantation is prohibitive but the priority to provide the service is necessarily low, because of other overwhelming health problems affecting the general population. The precise cost of liver transplantation is widely variable, ranging from $80,000 to $150,000. Pretransplantation and Peritransplantation Mortality Malnutrition is one of the most important risk factors in the peritransplantation period for children. Malnutrition increases mortality both before and after transplantation. Malnourished children after transplantation have a higher incidence of infection, more surgical complications, more days in the intensive care unit, and longer ventilator dependence. The recognition of this problem and aggressive attempts to correct it have resulted in significant improvements in patient survival and a reduction in patient morbidity both before and after transplantation. Patients with end-stage liver disease have increased energy requirements, and the provision of adequate calories is essential. The routine supplementation with an appropriate infant formula and vitamins and other micronutrients should be a patient is being for liver transplantation. The ill in the intensive care or on life a significant survival compared with other children. In one the UNOS the risk of was higher for children on life compared with children. This the of early referral to transplant for children with liver disease. has also been with an increased risk of after transplantation, which in is with an increased morbidity and mortality to This is of in children who have had surgical for biliary important affecting mortality after liver transplantation in children is before transplantation has been with a in mortality and in children after the mortality in one was factors in pediatric as as transplantation. from young have a poorer liver from other pediatric have a patient and survival however, significantly children compared with from pediatric In the early the most important factors affecting are of the hepatic infection, and a of morbidity after liver transplantation, is a of mortality or graft the immunosuppression to the graft to is in pediatric liver transplantation, in less than of is reported in donor most in young younger than 2 of is the most important surgical in pediatric liver transplantation. Not only is it the most important of graft it is a to both mortality and morbidity after pediatric liver transplantation, and because of complications, a for The need for a risk for both patient and graft loss. In most pediatric in approximately 10% to of survival of has been reported with compared with in The most for hepatic and In recent accounts for about of In a pediatric of a liver graft had patient of 85% at 1 year compared with 71% for of of Liver in in children with many who were to from a of it has become that the major of pediatric liver transplantation to be the transplantation of children younger than 2 years of The increasing donor the development of and liver transplantation. OLT was in the early 1980s of in in and in The success of in pediatric patient mortality waiting was first in a of liver transplanted between 1984 and the of reduced transplantation, the overall pediatric mortality waiting was but in the highest risk of children younger than 1 year of with the successful of liver the overall mortality of pediatric patients waiting was and for children younger than 1 year of age, the mortality had to transplantation (LRT) is a of reduced liver transplantation. The of a of the liver from a donor was in and first in The the development of with was the mortality in pediatric patients waiting for cadaveric donor and the of a cadaveric donor in the first results from the University of in the success of donor transplantation for the as as for the but also the of a and other of donor which were in the in the and the in pediatric donor transplantation in the observed that living-related donor transplantation is in survival is and that donor and in donor that blood is not an with pretransplantation and for to an to cadaveric liver transplantation a suitable cadaveric donor is survival as as has been reported for from which are at with cadaveric Approximately have been performed with only one reported donor for an overall donor mortality of there may be donor The reported donor morbidity from to In 1990, the first of donor liver in which the was and with the or being transplanted to a child and the being for an This is in a number of transplant programs and has waiting list mortality in of programs to approximately in the of this is with an increased risk of biliary complications, with the child at approximately and the at In other the risk of biliary is After Liver In to providing long-term pediatric liver transplantation to provide a that development and from the and of and The problem of liver transplantation in the 1980s was affecting the of children. The during that for acute for and for and may graft The advent of has the incidence of being reported in than of children from pediatric has also and more are the of after pediatric liver transplantation. was in and in a led to significant reduction in the incidence of overall and compared with approximately 50% of transplant as for pediatric liver transplantation. and not to be significantly between cyclosporine and but not have or the most of pediatric patient after liver transplantation, not as a of hepatic biliary or which 1 to 3 after has become less because of morbidity has been reduced since has been for the or be in blood and is as a of and as a of of are and Posttransplantation more have been to and of increased of immunosuppression are with the of was for in The from cyclosporine to cyclosporine and to was with a to incidence of in is also with an increased incidence of ranging between and with a higher risk in patients with higher blood and of For example, reported a incidence of in transplanted children younger than than 5 years of of whom This to a incidence of in children younger than 5 years of in of cyclosporine but in of children. is with most pediatric liver transplant are before OLT and may be the graft or during the procedure. patients reported in after and after This to after transplantation and during immunosuppression is the most for the higher incidence of in children as compared with may the or and are not and should be in of or or in a pediatric transplant clinical general and than half of the patients increased may be the first of or also be of after liver transplantation or of and increasing as who have transplants are also to and more with in may after transplantation. children should be and before transplantation. should and Mortality or graft 1 year or more after pediatric liver transplantation is Approximately 10% of children The most important of graft that is most to or surgical such as biliary and important of morbidity in the is an of end-stage liver disease in OLT is performed for of in the is as observed in patients have been with the graft or transplant procedure 1990, 15% of pediatric transplant were at and liver graft of donor for peritransplantation has become For children who have been no is children with with in Los Angeles, liver failure of and died of liver and one the only one also may children who have the only in this is but to this is observed after 1 year in to 15% of should be that after transplantation and autoimmune In transplant patients also may autoimmune in disease in to of the patients in and may or years after Patients have a of and autoimmune or Patients to increasing of or cyclosporine but to and is observed after liver transplantation, in on the of the children. is of to and to that after OLT was for at at and for transplantation. Four years after was for at and the since not a number of of immunosuppression are also and both are in patients with are not a of patients with of after transplantation to and is to that of to have reduced compared with whereas were to have and compared with who have transplants should a and with cyclosporine or is not a for however, is not to of the infant to OF and of the major issues transplantation has been that of to and the of the donor are important more to be to in to increasing and need to be The recent of to the of a pediatric donor from younger than years to less than in has reduced the number of pediatric from 7% to of the donor This was from that pediatric of liver had a significantly patient and graft survival compared with pediatric receiving from in and need to be may be a to the problem of however, have the this in this important to be transplantation is a procedure that has the to correct metabolic liver or liver failure of human attempts have been in the most successful being reported in a child with attempts were in and liver of the significant problems is that only a of transplanted and may be to an adequate transplanted of the of transplantation is essential. be transplanted after being with for a or in the has been the disease for this which has is also of that is to the which have the for hepatic Liver about the surgical for donor liver in rather than and or in the is that the of in has a to or other and donor significantly increasing the of donor to be for patient and graft survival of for the and for the this be more with of between patient or graft to be to the number of Biliary in and both of have led to a reduction in the overall waiting list the to of biliary improvement of the surgical and a of the factors to and and to Posttransplantation and and need to be and of be to and are also of has become a routine at many transplant of or of to for appropriate for reduction of to of the of this approach is for recognition of of have become to in This is in cases of the need to of such as be and clinical as a and For the patient with or at the time of liver transplantation, no is should be in children from early of in of the cases of for such as or should be for in patients with disease to Posttransplantation The development of an to autoimmune in the in at of children who have The to with and of in cases of has been after that to and a significant proportion of the children 2 for this and appropriate of are not in are in the early of the of long-term in children have been a major The is on early however, most have not been The incidence of after has been reported between and cyclosporine successful has been in more than of children. also to be less in more recent that as with has been to however, may to a risk of For is more with to rather than with with success of to is the other major there have not been in pediatric liver is to or to or as of the of or to The of and may to be in cases of such as the and or have not been in pediatric liver transplant of however, clinical in pediatric patients are in to health care may development of liver transplantation programs in developing countries, it should be that access to the procedure may the with children and families for the procedure with and programs should be on to in a and and transplant provide to the of and the for patient care and to provide the with to The and patients as of the transplantation which be of at the time in which referral and the of and the of in as in should the reduction in of the pediatric donor and the increased on families to donor UNOS that pediatric of pediatric liver had a significantly patient and graft survival compared with pediatric receiving from should be to other such as Pretransplantation and Peritransplantation Mortality should be to the pretransplantation and of intensive and or and early with and referral to transplant the of and in Liver has been estimated that suitable were for not only would on the pediatric waiting list become but children could be transplanted more after are in to programs in which the techniques of liver transplantation be and are essential. The development of appropriate for who may not have in the techniques should become a priority of surgical This transplant and of surgical and could be to of appropriate to this to would be the to This is to programs only or children. the on graft and patient survival and of the of transplantation are as as the of such on mortality on the waiting could be that children are transplanted is are less the overall cost of transplantation in the pediatric may the of in children should on donor and the of graft The and development of and for of pediatric transplantation is to the in pediatric results lack adequate of patients to provide such as the in Liver in which a that be to and the of liver transplantation, should be in Europe, and is a of donor organs, because are and the need for donor has become more to of and the of the of on and in provide a to transplanted have to liver before transplantation an to of this approach in should be before attempts are in with metabolic liver of pediatric patients have not been in early of In the of which may have and at children be in early of The be to pediatric patients in in the early of important has been that the of are in children as compared with in young who the highest proportion of children receiving liver and to of in children need to be on a of are important and have not been that long-term of on and be and improvements in the surgical and and in the and development of children liver transplantation to be in many The factors may be and is to the of factors and of in children of with liver disease and on liver transplantation. The of the between the child and the donor need to be and of and the of early to need to be into and the development of more or should to reduction of the of disease. TRANSPLANTATION History and Results transplantation was first to be in in and in in the early The and resulted in morbidity and mortality. the a for patients with which many and children to with a quality of life long-term is with such as liver and that to therapeutic In the cyclosporine had a on long-term survival in patients transplantation but not provide immunosuppression for recent advances have a option for the of end-stage failure with liver transplantation, and the development of in the early 1990s. The recent results that may be an clinical of for the of and of patient and and quality of life after transplantation. more than have been performed the world, in the United States, and the United The Transplant Registry reported on the results of transplantations in patients programs Approximately of were children or The major for in the children were and disease The immunosuppression for cyclosporine for and other or no immunosuppression for from patient survival was for for and for was failure or with of was in of and was in a of in SUMMARY OF THE Survival is from the Registry and from programs that during the but not survival is with the of with survival after that had performed at transplants had graft and patient survival compared with programs that had performed than pediatric and were reported the University of which patient survival of and at 1 year Results from in children transplantation immunosuppression and transplants the patient and graft survival at and 5 years of and for and and for children transplants immunosuppression in since and to 5 survival were and for and 30% and for is to an overall in survival between and transplantation. In clinical of is at the time of transplantation, as the and survival of 30% and in patients who had not transplantation and the number of on the waiting the graft has a higher incidence of and more immunosuppression to This that liver may the risk of not provide improvement in patient or graft survival in pediatric or After the of during the first after transplantation, clinical of disease have been the major after transplantation. immunosuppression graft may that become factors in patient and graft for of the and of the graft for or are of which are than and and a it is important to other of that may such as or other and be after The the Transplant Registry with of has been in of and in for a of in In the of major complications, of an from time ranging from days in the to days in the The longer time to after a more from the surgical procedure compared with and the of in patients that the and long-term graft is on the of and performed in have that transplantation the of and After of the is for the most there is between and in the in have of the graft the In a it was that and after transplantation and that were the first to should be as early as after transplantation, or an to factors and and for or extensive of the was the first for transplantation. After extensive of the most and on the and of and of disease in the a number of children 10% to not after In children or with extensive or to may not the of is less than the of transplantation also be in children with disorders or disease. disorders extensive disease and In extensive is than the for long-term is transplantation is an is a in of clinical of and In the to of patients become on or transplantation has been performed in with for failure are recognized as for disease and are disorders with of of whereas is with and The in both is with have successful OF is to in survival between and transplantation. In clinical of is at the time of transplantation and to the of morbidity and mortality. This is the and survival of patients who have not transplantation being 30% and and the number of on the waiting the graft not only has the highest incidence of but also more In the most results have been with graft was less and less in as that liver The which the liver is of donor was but such as or of to as the of or and the of the of in is into the in are important in the of for for in In transplantation should be it has been that the approach such as of the or of a may be to transplantation. with factors such as human may the need for transplantation in the of in pediatric and patients are in in the United States and in in only a number of patients with are candidates for The of complications, liver is the major for on and the lack of also may be for and for The number of candidates for is to because of the of patients in programs and because is In a it was estimated that 2 per year per million inhabitants be candidates for a that both and children who were on long-term at the time of the is that not of patients as or liver transplantation. to of and in because is patient be for survival and quality of be that may or long-term and of life after transplantation in patients was performed transplant with reported significant improvement in the quality of life and This is in children need to be has with extensive metabolic or liver or should be as an or with Liver Patients with failure and end-stage liver disease are candidates for For patients with less liver it is to the of liver to the of that during an transplantation procedure. patients with hepatic or are for Patients with failure and significant liver disease to be as candidates for extensive the to of metabolic disorders or disease with and with risk of in of patients with may be because of to or patients may also be for for to are to to other organs. of the for morbidity and mortality after and the donor the patient have the to an benefit from the procedure. or or and may be to for and of Liver are for of referral for transplantation. for or transplantation to be there is an of In have reported a in clinical between children for from with and care In a recent of for transplantation was in children with 50% in with and with the survival of children with failure for transplantation were in patients age, for with a waiting time of the patients who not undergo transplantation, The factors with younger than 1 surgical hepatic or 3 and from to may take to the waiting time for has been in survival at 1 year is only is that patients for transplantation are more and have This may the patient and graft survival in compared with reported from could to be compared with the intensive of that the patient with liver Liver disease in patients is to the disease or of may an on the The factors to liver disease disease or that and and have been to liver disease to of the of or or of or of of to of to hepatic appropriate and of which and the pediatric which provide appropriate as as and which to and reduced liver since pediatric patients of waiting for transplantation, and therapeutic should be for of failure in and need to that as early as the patient with that patients should be early to in to and at in transplantation of from the and was reported for the first time in of This procedure but is not transplants are in such as a the region. In pediatric transplantation is for with is from that and not graft survival after The that long-term survival was with the of a number of donor in the led to that may a in the and of The of with donor during the period has to graft the long-term or need for immunosuppression are not is being as a is of significant is with the of because it is with to be as The of the long-term to in This is in clinical for patients with the long-term survival of in The recent of to the at to graft survival after improvements in on early of patients with failure an improvements of immunosuppression or in and of appropriate is is to long-term The are to of of the to infants with to and liver are of at pediatric and liver of of between pediatric and who take care of and the pediatric is of Liver for of of liver in need to the of the liver to the of to the and of of the Transplant Registry and are to the registry. This is the of performed at and of and transplant are that be of of of acute to the in for and Will need to a of to and and for of and of for and of to and in both and that may and more than such as of and and human the between and for example, that and the and of need to and for of of in this is a and of patients which is not is to have for of in for other organs. of of are need to the therapeutic of in is it to be from that for other to the of to may to long-term to immunosuppression with to transplant in the of and development of that the between the to the graft of of graft time and of appropriate to and development of children after of and to and for and of and and disease of for the of should be of in to and of children and families after