Current Results and Evolving Indications for Liver Transplantation in Children

The successful establishment of paediatric liver transplantation in the early 1990s has meant a dramatic increase in the number of children undergoing liver transplantation worldwide. The difficulty in obtaining size-matched organs and the donor shortage have led to the development of innovative surgical techniques, such as split-liver grafts and living-related liver transplantation. These techniques not only directly benefited children dying of liver disease who were on the waiting list, but also expanded the range of indications to include children with metabolic disease requiring liver replacement for severe extrahepatic disease and children with unresectable hepatic tumours. Simultaneously, there have been significant developments in medical therapy that have not only altered the natural history and outcome of certain metabolic liver diseases but have also influenced the timing and selection for transplantation. Data about long-term survival and outcome after transplantation, which include potential recurrence of disease, have taught us many important lessons about selection of appropriate patients. This review will concentrate on how current results have altered indications and selection for liver transplantation. CURRENT RESULTS OF LIVER TRANSPLANTATION Current results from international centres worldwide indicate that 1-year survival for paediatric liver transplantation maybe as high as 90%(1-3) with 5- to 8-year survival rate ranging from 60% to 80% (4-8)(Table 1). There is no evidence that these survival figures have changed significantly during the past 3 years(4), although patients receiving elective living-related liver transplantation are reported to have higher 1-year survival rates (78% for cadaveric grafts and 94% for living-related grafts)(9).TABLE 1: Current results of liver transplantationInnovative Surgical Techniques The traditional form of operation, orthotopic liver transplantation, in which the whole diseased liver is removed and replaced with a whole donor organ is now a rare occurrence in paediatric liver transplantation because of the difficulty in obtaining size-matched organs for young children. The scarcity of size-matched donor organs in the 1980s meant a high waiting list mortality rate, particularly in young, sick children(10), leading to the view that liver transplantation was contraindicated in infants less than 1 year old who weighed less than 10 kg. The first surgical innovation, reduction hepatectomy, in which the left lateral segments of a larger liver are cut down to fit a child(11,12), had a dramatic effect on waiting list deaths, which declined from 15% to 5% (3,9,13,14). It also extended the range of liver transplantation to very small infants less than 1 year old (2). Although graft and patient survival rates were slightly less in reduction hepatectomies than with whole liver grafts, this may be because the reduced grafts were first performed in younger, sicker children (12,15). A more recent series of 314 transplants found no difference in outcome or long-term survival between the two operative techniques (14). The increasing problem of donor shortages has led to the development of split-liver transplantation, in which a single donor liver graft is offered to two recipients (16). Although initially 1-year graft survival rates for split-liver grafts were between 30% and 50%, more recent results suggest that in situ liver splitting with cooperation between transplant centres may improve graft and patient survival(17). Of particular relevance for paediatric liver transplantation is the development of living-related liver transplantation. This was the only form of transplantation permissible in Japan where the most experience has been gained (18,19). There are many ethical problems related to this procedure, which has a significant donor morbidity and potential mortality (20). The main benefit, however, is that transplantation of children with chronic liver disease may be planned before there is significant hepatic or nutritional deterioration. Recent results have shown that there is a 90% 1-year survival rate in elective cases (9) but the survival rate in emergency cases is only 57% (18), which is comparable with results obtained using cadaveric donors for children with similar disease severity (7,21). The choice of living-related transplantation in the management of children with fulminant hepatic failure is controversial. Not only is graft survival less likely(18), but parents may not be able to make clear decisions concerning donation, thus creating emotional pressure for themselves and the surgical team. Auxiliary liver transplantation is a potentially attractive technique in which part of the donor liver is inserted beside or in continuity with the native liver, which is retained in case of graft failure or for future gene therapy. In those metabolic liver diseases in which there is a functionally normal liver but transplantation is indicated for severe extra hepatic disease (e.g., Crigler-Najjar type I), auxiliary liver transplantation has proved successful in reducing the levels of unconjugated bilirubin and has improved quality of life (22). Auxiliary liver transplantation is also an option in patients with fulminant or subfulminant hepatic failure in which it is hoped that the original liver may regenerate sufficiently to recover normal function. In a recent study, 5 of 9 patients who received auxiliary liver transplantation for fulminant hepatitis showed rapid regeneration of their native livers. The auxiliary graft was removed in three and was left to atrophy in one. Cirrhosis developed in the native liver of one patient, who died of infectious complications after surgery (23). Factors Influencing Survival Age at Transplantation Historically, age at transplantation has been a significant risk factor influencing survival. Originally, liver transplantation was contraindicated in infants less than 1 year old because of the greater technical problems in this age group and the difficulty in finding suitable donors for elective transplantation (10-12,24). Early studies indicated higher morbidity and mortality rates in infants less than 1 year old: -64% 1-year survival rate compared with 75% in older children (25). Postoperative complications, particularly vascular complications, and the necessity for retransplantation were more common in this group (33% compared with 17% in older children)(26). However, more recent experience has documented a significant improvement in survival in these young infants that is associated with developments in surgical technique (3,9,15,19,27) and medical management (2). Because the incidence of rejection may be less in young infants, there may be an immunologic advantage in early transplantation (28). Many centres now report that there is no difference in outcome between age groups (2,14,19,27), but others continue to report lower survival rates in younger children (7,29). Nutritional Status Before Transplant Protein energy malnutrition is inevitable in 60% of children with end-stage liver failure. Morbidity and mortality after transplantation have both been related to the degree of pretransplant malnutrition, and thus nutritional status is an important risk factor for survival after liver transplantation. Chin et al. (30) evaluated 26 children for more than 12 months after transplantation and noted a significant difference in the 2-year actuarial survival for children with standard deviation scores (SDS) for weight less than -1 (57%) compared with the survival rate in those more than -1 (95%) (30). Similar data were generated using height SDS, in which children who were less stunted at the time of transplantation had a significantly better outcome(31), highlighting the necessity for intensive preoperative nutritional support (32). Severity of Liver Disease Results in many different studies indicate that short-term survival is better in children transplanted electively, compared with those transplanted for acute liver failure or fulminant hepatitis (4,7,21). In particular, those children who received more medical intervention before transplantation had poorer survival rates(4). Rodeck et al. (21) have recently established a number of risk factors for children awaiting liver transplantation, which included bilirubin >340 µmol/l, albumin <33 g/l, and SDS for weight less than -2.2. Patients with one or more of these risk factors were considered to require urgent liver transplantation. There was a statistically significant difference in survival at 1 year (57% vs. 90.5%) and 4 years (49% vs. 90.5%) when elective and urgent groups were compared after liver transplantation (p = 0.0001), indicating that children with significantly decompensated liver disease or poor nutritional status had a higher mortality rate after transplant (16). Recurrent Disease After Transplant With increasing experience with liver transplantation, data are now available on the incidence of recurrent disease after transplant and the effect on long-term outcome. Recurrence of hepatitis B virus (HBV) infection after liver transplantation is almost 100% in those patients who are HBV-DNA-positive or HBe antigen-positive at the time of transplantation(33). Recurrent HBV disease is always associated with histologic abnormalities, that include chronic hepatitis or cirrhosis (79%) and submassive necrosis (9%), whereas fibrosing cholestatic hepatitis, which is a uniformly fatal form of fulminant hepatic failure, has been described in as many as 25% of patients with recurrent HBV infection (34,35). Preliminary results from trials in adults with the nucleoside analogue lamivudine, which effectively reduces HBV-DNA, may alter the future recurrence rate for chronic hepatitis B after transplant(36,37). Recurrence of HBV infection after fulminant hepatitis is less common and has a more benign outcome(28). Chronic hepatitis C is a rare indication for liver transplantation in childhood, in that most children with hepatitis C after transplant will have been infected at surgery (38,39). Nevertheless, in adults, recurrence of hepatitis C after liver transplant is almost universal; but histologic hepatitis develops in only 50% to 80% of patients and may be difficult to distinguish from rejection(40). It is possible that rejection may be more common in this group of patients (41), but there is no difference in long-term patient or graft survival (42). There has been limited success in treating posttransplant adults with hepatitis C with interferon, although preliminary studies with ribavirin are more encouraging (44). There have been no similar studies in children, yet. Several studies have indicated that biliary complications are more common in patients in whom transplants were performed for primary sclerosing cholangitis than for other indications (45,46), whereas the classical fibro-obliterative lesions have been reported to recur in 14% of patients transplanted for primary sclerosing cholangitis(47). It is also clear that autoimmune hepatitis may recur, both immunologically and histologically (48,49), after transplant. Giant-cell hepatitis with autoimmune haemolytic anaemia is a rare disease that responds poorly to immunosuppression and may also recur after transplant(50). The poor outcome related to transplantation for malignant hepatic tumours is related to the rate of recurrence of these tumors(51), and thus it is essential to ensure that there are no extrahepatic metastases at the time of surgery. Rigorous selection of patients has improved survival rates in children transplanted for hepatoblastoma (51), but the outcome with hepatocellular carcinoma (52) and haemangioendothelioma(53) remains bleak. Previous Surgery and Vascular Anomalies Children who have undergone previous surgery, usually for biliary atresia, have an increased risk of postoperative complications, including gastrointestinal perforation (54). Although this may have a significant effect on morbidity, it is not a significant factor in survival and is not a contraindication for liver transplantation(55). Biliary atresia, which is a common indication for liver transplantation may be associated with situs inversus and vascular anomalies. Although early results suggest that there was a high rate of primary nonfunction with this condition, recent improvements in diagnostic radiology and surgical technique have resulted in successful liver transplantation(56). Postoperative Complications The spectrum of postoperative complications after liver transplantation remains unchanged, but management strategy has advanced. The most common complications include sepsis (60-70%) (57), mainly bacterial sepsis, related to central catheter insertion, and acute rejection, which varies from 20% in infants (28) to 70% in older children (4). Cytomegalovirus (CMV) infection is almost inevitable in children who are cytomegalovirus-negative before transplant who have a cytomegalovirus-positive donor (52). Treatment with gancyclovir is necessary for those with systemic disease and is highly effective. Surgical complications include biliary complications (in 20%), which include biliary leaks and ischaemic strictures (5,58). Radiologic biliary dilatation and insertion of stents has now replaced surgical biliary reconstruction as first-line treatment for biliary strictures and is an important therapeutic advance. The incidence of hepatic artery thrombosis after paediatric liver transplantation varies from 26% in whole grafts to 4% in reduced grafts (59), because of the larger size of the donor arteries in reduced grafts. Hepatic artery thrombosis may also be prevented by the use of antiplatelet agents(aspirin and dipyridamole) and by maintaining the haemoglobin at less than 10 g/dl (60). Graft and patient survival rates are less after retransplantation(61), but the incidence of retransplantation has decreased with increased surgical experience (62). In a recent study of 200 consecutive liver transplants, retransplantation was indicated most frequently for primary nonfunction and vascular complications in the first 100 patients, whereas the main indication in the second group was for chronic rejection. Retransplantation was more likely in patients who underwent transplant for fulminant hepatitis (62). Quality of Life and Long-Term Outcome Long-term studies in children and adolescents have shown that successful liver transplantation promotes nutritional rehabilitation(63). This is particularly striking in infants, who may achieve dramatic nutritional rehabilitation with improvement in weight, midarm fat and midarm circumference within 12 to 18 months of transplantation(2,30,63). Catching up in linear growth is more difficult to achieve and may be related to glucocorticoid administration (64), preoperative stunting(65), and postoperative complications(66). Although many children achieve normal feeding patterns and growth, approximately 20% of children have persistent behavioural feeding problems requiring long-term tube feeding and a consequent reduction in quality of life (66). In many studies, normal, if delayed, pubertal development and growth spurt have been clearly documented (63). Successful pregnancies have been reported (67), which is vital to long-term quality of life. In several studies, investigators have evaluated the psychosocial development of children before and after liver transplantation. Early studies indicate that outcome was less favourable in those children who had an early onset of liver disease and who were older at the time of transplant(68,69). These children had significant motor delay and subsequent educational difficulties and never achieved a fully normal life. In subsequent studies, results have indicated that if children undergo transplant early, before significant growth or developmental retardation, normal psychosocial development may be expected (70). This is particularly true in infants less than 1 year old who undergo transplant before significant psychomotor retardation. In a prospective study of 25 infants observed for 4 years after transplant, it was clear that developmental scores for social interaction and language deteriorated at 1 year after transplant but recovered within 2 to 3 years after transplant. There was no significant deterioration in intellectual performance throughout the observation period, implying that even young infants may be expected to have normal psychosocial development after transplant(71). The Long-Term Effects of Immunosuppression: Considerable short term data are available that demonstrate the side effects of all commonly used immunosuppressive drugs. Steroids cause stunting, hypertension, and obesity, whereas gingival hyperplasia, and hirsutism are well established side effects of cyclosporin A (72,73). Hypertension, neurotoxicity, and nephrotoxicity are caused by cyclosporin A and the newer immunosuppressive drug tacrolimus (74). In contrast to adults, children rarely require dialysis or renal transplantation for chronic renal failure after transplant(75). Almost 65% of children will be Epstein-Barr negative before transplant, and in most, a primary infection will develop within 18 months after transplant (57). The significance of this infection is related to the potential development of posttransplant lymphoproliferative disease, which occurs in immunosuppressed patients in whom there is Epstein-Barr-associated B-cell lymphoproliferation, which ranges from benign hyperplasia (infectious mononucleosis) to malignant lymphoma. Most patients respond to reduction or discontinuation of immunosuppression. The overall incidence of posttransplant lymphoproliferative disease in liver transplant patients is 10% but may increase with the use of more toxic immunosuppressive drugs (76). ADVANCES IN MEDICAL THERAPY Recent advances in medical therapy have changed paediatric practice and have altered certain indications for liver transplantation. Inherited Metabolic Liver Disease The management of tyrosinaemia type I has changed dramatically the of which the of toxic and rapid improvement Before the of liver transplantation was indicated for acute or chronic liver failure, the development of hepatocellular or Current indications for liver transplantation now include only those children who have not to or in whom there is a high degree of of hepatic Because not the development of hepatocellular carcinoma in for hepatic in children with is essential but Recent data suggest that there may be a in the levels associated with the of hepatic on or hepatic may be in of liver of are rare that are associated with in the of to primary with and has been in children with and in of liver and of liver is a rare cause of fulminant hepatitis in which within the first to of life and and extrahepatic Although liver transplantation has been performed in this group of their small severity of disease, and the difficulty in obtaining suitable donor organs in has to a high mortality rate The recent use of and in with such as has reduced mortality and morbidity and has liver transplantation in The main of hepatic disease in patients with is hypertension, in that hepatic is a Liver transplantation is only in those children who have hepatic albumin severe malnutrition, or to medical treatment of these children with to improve has proved an important therapeutic strategy and may have reduced complications, including sepsis Although results in several trials have indicated that reduces and the and nutritional status of patients with it is that the use of this drug will liver transplantation before the development of significant liver disease Children with severe disease will require and liver early liver transplantation is indicated in children with disease before the development of significant It is to the of liver support in the management of children undergoing transplant for acute liver failure. Nevertheless, data are available on use as to transplantation in adults, although long-term outcome has not been not LIVER TRANSPLANTATION surgical and medical techniques have for liver transplantation have surgical experience has improved results in children with previous surgery, vascular and and has extended liver transplantation to the Long-term however, has certain that now be considered for liver transplantation. infection is a clear contraindication for liver transplantation, because immunosuppression may well to fatal and is a for children with fulminant hepatitis in whom there is an increased incidence of postoperative Disease Liver transplantation is contraindicated in children who have severe or central disease that is not by liver transplantation or to pretransplant Many children with liver disease will have associated such as or and or It is important when these children to the during liver transplantation and to for surgery before transplant if although transplantation is not indicated in those children with A of children with end-stage liver disease have which is if liver transplantation is performed early In children with or and may be Disease These rare are associated with or of that may many organs in the The include acute liver failure with and which is not by liver It may be difficult to these children from those with other of liver failure there is a history of development or It is possible that an increased of in the in the of a normal of may indicate whereas of an in may suggest It is to the of in these children by a and with appropriate support before for liver is a rare to a of the hepatic It of and in the and leading to renal failure and systemic Successful management of this liver transplantation before the development of renal failure or severe systemic although in because of in most patients require a liver and transplant Successful of the have been documented although this the success rate may not be as high in young infants with severe systemic In in two infants who had acute renal failure to in the first year of life received liver and transplantation. successful grafts, the because of problems related to systemic and children with severe systemic with reduced may not be suitable for liver transplantation. Recurrent Disease the risk of recurrence of hepatitis B and C and autoimmune disease, transplantation is not not only because these diseases may develop after transplant, many years of quality life but also because therapy is Liver transplantation to be successful and treatment for acute and chronic liver failure, and many important lessons have been The development of innovative operative techniques has reduced the waiting list mortality rate and has extended transplantation to younger and sicker children and to those with functionally normal who may from auxiliary liver transplantation. The incidence and range of postoperative complications have improved with increased medical and surgical on long-term outcome for liver transplantation is it is clear that many children will from early elective liver transplantation before the development of significant growth or psychosocial retardation. Early transplantation is also indicated in children with cirrhosis and or with the period, medical therapy has altered the natural patient and timing of transplantation in children with tyrosinaemia type primary and It is now clear that children with significant disease, such as or severe systemic are no suitable for liver transplantation. The successful development of liver transplantation has quality life to many children and their There are many lessons to and there are future such as the problems of donor scarcity and the for but less toxic immunosuppressive