Artigo Acesso aberto Revisado por pares

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

2002; Lippincott Williams & Wilkins; Volume: 35; Linguagem: Inglês

10.1097/00005176-200208002-00014

ISSN

1536-4801

Autores

Étienne Sokal, G. J. Cleghorn, Olivier Goulet, Themis Reverbel da Silveira, S. V. McDiarmid, Peter F. Whitington,

Tópico(s)

Congenital Anomalies and Fetal Surgery

Resumo

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 introduced when a patient is being considered for liver transplantation. The critically ill child, in the intensive care unit or on life support, still suffers a significant survival disadvantage compared with all other children. In one study using the UNOS database, the relative risk of death was 2.4 times higher for children on life support compared with nonhospitalized children. This knowledge underscores the critical importance of early referral to transplant centers for children with chronic liver disease. Previous abdominal surgery has also been associated with an increased risk of bowel perforation after transplantation, which in turn is associated with an increased morbidity and mortality secondary to infection. This is of particular concern in children who have had previous surgical treatment for biliary atresia. An important extrahepatic complication affecting mortality after liver transplantation in children is renal failure. Dialysis before transplantation has been associated with a 47% increase in mortality and in children requiring dialysis after transplantation; the mortality rate in one study was 85%. Donor factors affect outcome in pediatric as well as adult transplantation. Livers from very young donors, particularly neonatal donors, have a poorer outcome, although liver grafts from other pediatric age donors have a superior outcome. Pediatric patient and allograft survival is, however, significantly worse if children receive adult organs compared with those from pediatric donors. In the early posttransplantation period, the most important factors affecting outcome are primary nonfunction of the allograft, hepatic artery thrombosis, infection, and retransplantation. Interestingly, allograft rejection, although a cause of morbidity after liver transplantation, is now seldom a cause of mortality or graft loss, although the immunosuppression necessary to maintain the graft can contribute to both. Primary nonfunction is unusual in pediatric liver transplantation, occurring in less than 5% of patients. It is rarely reported in living donor grafts. It most commonly occurs in very young donors younger than 2 months of age. Hepatic artery thrombosis is the most important surgical complication in pediatric liver transplantation. Not only is it still the most important cause of graft loss, it is a direct contributor to both mortality and morbidity after pediatric liver transplantation, and because of its associated complications, a common indication for eventual retransplantation. The need for retransplantation itself carries a risk for both patient and graft loss. In most large pediatric series, retransplantation occurs in approximately 10% to 20% of patients. Patient survival of 82% has been reported with elective retransplantation compared with 46% in emergent re-transplantation. The most common cause for retransplantation remains hepatic artery thrombosis followed by primary nonfunction and initial poor function. In recent large series, chronic rejection accounts for about 2% of retransplantations. In a large single-center U.S. study, pediatric recipients of a single liver graft had actuarial patient survivals of 85% at 1 year compared with 71% for recipients of two grafts. Technical Aspects of Liver Transplantation in Children Transplantation in small children remains technically daunting, with many special challenges. Early experience involved mainly older children, who were similar to adults from a technical point of view. However, it has become apparent that the major focus of pediatric liver transplantation needs to be the transplantation of children younger than 2 years of age. Reduced-Size Donor Livers The increasing organ donor shortage prompted the development of reduced, living-related, and split liver transplantation. Reduced size OLT was popularized in the early 1980s by Henri Bismuth of Paris (2), Jean Bernard Otte in Brussels (4), Russell Strong in Brisbane, and Christopher Broelsch (3) in Chicago. The success of partial grafts in reducing pediatric patient mortality waiting was first illustrated by de Ville de Goyet in a study of 314 liver grafts transplanted between 1984 and 1991 (9). Before the introduction of reduced size transplantation, the overall pediatric mortality while waiting was 14% but 25% in the highest risk group of children younger than 1 year of age. By 1991, with the successful implementation of partial liver grafting, the overall mortality rate of pediatric patients waiting was 5%, and for children younger than 1 year of age, the mortality had fallen to 8.3%. Living related transplantation (LRT) is a natural extension of reduced liver transplantation. The use of a portion of the liver from a living donor was attempted by Raia in 1988 and first successfully carried out by Strong in 1989 (5). The driving forces behind the development of LRT, with its attendant ethical dilemmas, was the increasingly unacceptable mortality in pediatric patients waiting for cadaveric donor organs and the absence of a cadaveric donor pool in Japan. Broelsch et al. (6) published the first results from the University of Chicago in 1990,which demonstrated the success of living donor transplantation for the recipient, as well as safety for the donor, but also described the meticulous process of a two-staged consent, and other aspects of donor protection, which were mandated in the protocol (7). Tanaka et al (8), in Kyoto, adopted the technique and established the largest experience in pediatric living donor transplantation in the world. They observed that living-related donor transplantation is feasible even in emergency situations, although survival is somewhat less, and that judicious donor selection and expertise in operative technique can protect donor safety. They showed that ABO blood group mismatching is not an absolute contraindication if combined with pretransplantation and posttransplantation plasmapheresis for high isohemagglutinin titers. LRT appears to afford an acceptable alternative to cadaveric liver transplantation when a suitable cadaveric donor is unavailable. Recipient survival as high as 90% has been reported for LRT from individual units, which are at least comparable with cadaveric grafts. Approximately 1,200 LRTs have been performed worldwide, with only one reported donor death, for an overall donor mortality rate of 0.08%. However, there may be unreported donor deaths. The reported donor morbidity varies from 3% to 17%. Split Livers In 1990, Broelsch's group (6) described the first series of 30 donor liver splitting procedures in which the allograft was divided and shared by two recipients, with the left lateral segment or left lobe being transplanted to a child and the remainder being used for an adult recipient. This technique is used in a number of transplant programs and has helped reduce waiting list mortality in some of these programs to approximately 5%. However in some centers, the use of this technique is associated with an increased risk of biliary complications, with the child recipient at approximately 25% and the adult recipient at 33%. In other Centers, the risk of biliary complications is considerably lower. Medical Complications After Liver Transplantation In addition to providing long-term survival, pediatric liver transplantation aims to provide a normal life, that is, normal development and growth, cure from the original disease, and absence of transplantation- and immunosuppression-related complications. The main problem of liver transplantation in the 1980s was allograft rejection, affecting the majority of children. The rejection rates during that decade reached 59% for acute rejection, 14% for steroid resistant rejection, and 8% for chronic rejection. Steroid-resistant rejection, and particularly chronic ductopenic rejection, may affect graft survival. The advent of newer immunosuppressive agents has dramatically decreased the incidence of chronic rejection, being reported in fewer than 5% of children from several large pediatric series. Steroid-resistant rejection has also decreased. Cyclosporine, and more recently tacrolimus, are the mainstays of primary immunosuppressive therapy after pediatric liver transplantation. Tacrolimus was introduced in 1994, and in a randomized-controlled trial, tacrolimus therapy led to significant reduction in the incidence of overall rejection, steroid-resistant, and chronic rejection compared with cyclosporine. Thus, approximately 50% of transplant centers now use tacrolimus as their primary immunosuppressive therapy for pediatric liver transplantation. Nephrotoxicity and neuro toxicity appear not to be significantly different between cyclosporine and tacrolimus, but tacrolimus does not have any associated hirsutism or gingival hypertrophy. Infectious complications remain the most direct cause of pediatric patient death after liver transplantation, not infrequently as a result of hepatic artery thrombosis, biliary leak, or bowel perforation. Cytomegalovirus (CMV) disease, which occurs within 1 to 3 months after transplant, has become less frequent because of effective prophylactic antiviral therapy regimens. CMV-related morbidity has been reduced since ganciclovir has been made available for its treatment: the main manifestations include unexplained fever, hepatitis, pneumonia, or gastrointestinal symptoms. CMV antigen can be reliably detected in blood and is helpful as a marker of infection and as a parameter of efficacy of treatment. CMV-DNA tests are new and under evaluation. Epstein-Barr Virus–Associated Posttransplantation Lymphoproliferative Diseases New, more potent immunosuppressive agents have been introduced to prevent and treat allograft rejection. However, use of increased amounts of immunosuppression are associated with the occurrence of Epstein-Barr virus (EBV)–associated posttransplantation lymphoproliferative diseases (PTLD) (10). OKT3 was used for rescue therapy in steroid-resistant allograft rejection. The escalation from cyclosporine to cyclosporine + OKT3 and then to tacrolimus rescue treatment was associated with a 40% to 60% incidence of PTLD in some Centers. Tacrolimus itself is also associated with an increased incidence of PTLD, ranging between 5% and 20%, with a higher risk in patients with higher blood levels and doses of tacrolimus. For example, Cox et al. reported a 22% incidence of primary EBV infection in 105 transplanted children younger than than 5 years old; 39% of them developed PTLD, 45% of whom died. This corresponds to a 3.8% incidence of PTLD in children younger than 5 years of age. PTLD occurred in 3% of cyclosporine treated patients, but in 19% of tacrolimus-treated children. PTLD is clearly associated with primary EBV infection; most pediatric liver transplant recipients are EBV naive before OLT and may be infected by the graft itself or transfusions received during the procedure. Of 66 PTLD patients reported in various series, 56 (85%) occurred after primary EBV infection and 10 after reactivation. This relationship to primary EBV infection after transplantation and during immunosuppression is the most commonly accepted explanation for the higher incidence of PTLD in children as compared with adults. PTLD may involve the adenotonsillar tissue, lymph nodes, or any solid organ, including liver, kidney, lungs, and brain. Gastroenterologic manifestations are not uncommon, and PTLD should be suspected in case of any unexplained appetite or weight loss, diarrhea, or gastrointestinal bleeding in a pediatric transplant recipient. Other clinical symptoms include fever, impaired general condition, irritability, and encephalopathy. More than half of the PTLD patients develop hypergammaglobulinemia; increased gammaglobulin levels may be the first indication of PTLD. Monoclonal IgG or IgM bands also can be detected by protein immunoelectrophoresis. Virologic markers of EBV after liver transplantation include transient or delayed appearance of specific anti-EBV immunoglobulin M (IgM), and increasing EBV-DNA load as monitored by quantitative polymerase chain reaction (PCR). Children who have received transplants are also susceptible to opportunistic infections and more severe infection with common childhood infections. Adenovirus, in particular, may cause fulminant hepatitis after transplantation. If possible, children should be immunized against poliovirus (killed vaccine), measles, varicella, hepatitis B virus (HBV), hepatitis A virus (HAV), and streptococcal pneumoniae before transplantation. Yearly influenza vaccination should protect against infection. Long-term Morbidity and Mortality Patient or graft loss 1 year or more after pediatric liver transplantation is relatively uncommon. Approximately 10% of children require retransplantation. The most important cause of graft loss remains chronic rejection, including that precipitated by noncompliance (11,12). Death is most often attributable to sepsis or PTLD. Late surgical complications such as biliary strictures, infections, and PTLD remain important causes of morbidity in the late posttransplantation period. Hepatitis C (HCV) is an uncommon cause of end-stage liver disease in childhood. However, if OLT is performed for HCV, recurrence of HCV in the allograft is uniform, as observed in adults. Other patients have been primarily infected with HCV by the graft or transplant procedure itself. Before 1990, 15% of pediatric transplant recipients were infected by HCV at some centers and developed chronic liver graft dysfunction. Since introduction of donor screening for HCV, peritransplantation infection has become exceptional. For those children who have been infected, no therapy is currently efficient. Of 12 children with chronic HCV treated with interferon alpha in Los Angeles, four developed rapidly progressing liver failure requiring retransplantation. Three of them relapsed and died of liver failure, and one cleared HCV. Amongst the remaining patients, only one cleared HCV. Hepatitis B virus also may infect children who have received transplants: the only proposed treatment in this circumstance is lamivudine, but resistance to this drug is observed after 1 year in up to 15% of treated patients. HBc antibody positive donors, even if hepatitis B surface antigen (HbsAg) negative, should be excluded. Other diseases that recur after transplantation include hepatoblastoma and autoimmune hepatitis. In addition, transplant patients also may develop de novo posttransplantation immune hepatitis (PTIH), resembling classical autoimmune hepatitis in nontransplant patients. Such disease occurred in 2% to 3% of the patients in Brussels and may appear months or years after OLT. Patients have a history of steroid dependency, high serum gammaglobulin levels, and autoimmune markers including antinuclear antibody (ANA), smooth muscle antigen (SMA), or liver–kidney mocrosome (LKM) antibodies. Patients respond poorly to increasing dosage of tacrolimus or cyclosporine but respond well to steroids and azathioprine. Catch-up growth is observed after liver transplantation, depending in part on the steroid treatment of the children. It is of importance to wean steroid doses and switch to alternate-day therapy. A British group showed that height 6 months after OLT was influenced by Z score for height at OLT, bilirubin level, prednisolone dose at 6 months, and indication for transplantation. Four years after OLT, height was still influenced by Z score for height at OLT, and by the cumulative prednisone dose since OLT. Although not life-threatening, a number of cosmetic effects of immunosuppression are also evident. Hypertrichosis and gingival hyperplasia both are seen in patients treated with cyclosporine. These cosmetic side effects are not a feature of patients treated with tacrolimus. Quality of Life Children after transplantation generally return to normal life, education, and physical activity. Academic achievement is similar to that of their healthy peers. Girls tend to have reduced scholastic cognitive competence compared with their healthy peers, whereas adolescent boys were shown to have lower global self-worth and lower perceived physical competence compared with their healthy peers. Children who have received transplants becoming adults should ideally achieve a normal social, professional, and family life, although these aspects remain insufficiently studied. Immunosuppression with cyclosporine or tacrolimus is not a contraindication for pregnancy; however, breast feeding is not advised, to avoid postnatal exposure of the infant to immunosuppressive agents. II. MAJOR ISSUES IN NEED OF INVESTIGATION OR IMPLEMENTATION Organ Donation and Recipient Selection One of the major issues regarding organ transplantation has been that of strategies to increase organ donation and the size of the donor pool (14). Although these are very important issues, more attention needs to be drawn to reducing demand in addition to increasing supply. Appropriate recipient selection and listing criteria need to be standardized. The recent decision of Eurotransplant to modify the definition of a pediatric donor from younger than 16 years to less than 40 kg in body weight has reduced the number of pediatric donors by 40%, from 7% to 4% of the donor pool. This decision was made despite data from UNOS, spanning 6 years, showing that pediatric recipients of pediatric-age liver donors had a significantly improved patient and graft survival compared with pediatric recipients receiving livers from adult age donors. These discrepancies in organ allocation and recipient selection need to be addressed formally. Xenografting Xenografting may be a future strategy to alleviate the problem of organ shortage; however, concerns over animal viral transmission have tempered the enthusiasm over this approach. Further work in this potentially important area needs to be continued. Hepatocyte Transplantation Hepatocyte transplantation is a new procedure that has the potential to correct metabolic liver diseases or fulminant liver failure by intraportal infusion of isolated human hepatocytes. Several attempts have been made in humans, the most successful being reported in a child with Crigler Najjar syndrome. Other attempts were made in urea cycle disorders, alpha-1-antitrypsin deficiency, and fulminant liver failure. One of the significant problems is that only a fraction of transplanted cells will effectively engraft, and repeated infusions may be necessary to achieve an adequate transplanted mass. Further investigation of the role of hepatocyte transplantation is essential. Gene Therapy Cells can be transplanted after being transfected with cDNA for either a defective or absent protein in the original liver. Familial hypercholesterolemia has been the candidate disease for this approach, which has achieved limited success. Gene transfer therapy is also possible by use of vectors that target hepatocytes. Risk is currently related to the viral vectors, which have the potential for causing hepatic injury. Split Liver Donor Techniques Much debate exists about the optimal surgical technique for performing donor liver splitting procedure; in situ splits rather than back-table splits and long artery segment or short artery segment in the child. There is some concern that the technique of in situ splitting has a potential to alienate or disadvantage other organ donation teams and donor hospitals by significantly increasing the organ harvesting time. With careful choice of donor livers to be used for splitting, experienced larger centers now report patient and graft survival of 80% for the right lobe and 93% for the left lobe (15–18). Determining how this technique can be more fully applied, with sharing of split segments between institutions without sacrificing patient or graft survival, needs to be explored to expand the number of allografts available. Biliary Complications in Split and LRLT Procedures Although both of these technique have led to a reduction in the overall waiting list mortality, the 20% to 25% rate of biliary strictures requires further improvement of the surgical techniques, and a better understanding of the factors contributing to segment II and III bile duct anastomosis fragility and sensitivity to ischemia. Posttransplantation Lymphoproliferative Disease Prophylaxis and Treatment Specific and efficient antiviral agents directed against EBV need to be developed, and efficacy of currently available drugs must be evaluated. Efforts to develop and test anti EBV vaccines are also required (13). Currently, serial monitoring of EBV-DNA by quantitative PCR has become a routine test at many transplant centers. Early detection of rising or high loads of EBV DNA appears to allow for appropriate timing for reduction of immune suppression to avoid emergence of PTLD. More controlled data regarding the outcome of this approach is needed. Education must aim for better recognition of preliminary symptoms of PTLD. More recently, anti-CD20 monoclonal antibodies have become available to potentially control B cell proliferation in these patients. This treatment is possibly useful in cases of concomitant rejection, preventing the need to reduce immune suppression. Enhancement of cellular immunity against EBV response, such as specific anti-EBV CD8 cell populations, must be studied and its clinical utility as a treatment strategy evaluated. Hepatitis C and B For the patient with active HBV or HCV infection at the time of liver transplantation, no effective treatment post-OLT is available. New treatments should be tested in children from their early stage of development, in view of the progressive cases of posttransplantation hepatitis C. Similarly for hepatitis B, new antivirals, such as entecavir or adefovir, should be made available for trials in patients with ongoing disease resistant to lamivudine. De Novo Posttransplantation Immune Hepatitis (PTIH) The development of an immune hepatitis, similar to autoimmune hepatitis in the nontransplant child, occurs in at least 5% of children who have received transplants. The response to treatment with azathioprine and corticosteroids mandates consideration of PTIH in cases of apparent unresponsive rejection. Growth Although catch-up growth has been demonstrated after OLT, studies show that final height remains 0.5 to 1.0 SD below normal, and a significant proportion of the children remain below 2 SD. Reasons for this stunting and appropriate measures of prevention are still not understood. New Perspectives in Immunosuppressive Therapy—Steroid Withdrawal Steroids are uniformly used in the early stages of posttransplantation immunosuppressive regimens. However, the growth inhibiting effects of long-term steroid use in children have always been a major concern. The current emphasis is on early steroid withdrawal; however, most reports have not been randomized trials. The incidence of allograft rejection after steroid withdrawal has been reported between 11% and 22% under cyclosporine therapy. Under tacrolimus-based immunosuppression, successful steroid withdrawal has been described in more than 90% of children. There also appears to be less steroid-resistant rejection in more recent immunosuppressive regimens that use tacrolimus as primary therapy. Monoclonal antibody therapy with OKT3 has been used to treat steroid resistant rejection; however, its use may lead to a high risk of viral complications. For cyclosporine-treated children, steroid-resistant rejection is now more often treated with conversion to tacrolimus rather than with OKT3, with success rates of up to 80%. Mycophenolate mofetil is the other major new immunosuppressant currently available. Unfortunately, there have not yet been pharmacokinetic studies in pediatric liver recipients. Mycophenolate is generally added to regimens either containing tacrolimus or cyclosporine, either to control resistant rejection or as means of lowering the doses of tacrolimus, cyclosporine, or steroids to obviate toxicity. The combination of tacrolimus and mycophenolate may prove to be beneficial in cases of vanishing bile duct syndromes caused by chronic rejection. Other new immunosuppressive agents such as the humanized and chimeric IL-2 receptor monoclonal antibodies, sirolimus, or CTLA4-Ig have not yet been studied in pediatric liver transplant recipients. Each of these modalities holds considerable promise; however, appropriately designed pharmacokinetic studies followed by clinical trials in pediatric patients are needed. III. PLAN TO ACHIEVE GOALS Support Local Programs in Developing Countries Although finite resources devoted to health care may preclude development of liver tran

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