You are in: eMedicine Specialties > Pediatrics: Surgery > Transplantation History of Pediatric Liver TransplantationArticle Last Updated: Jun 13, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Beth A Carter, MD, Assistant Professor of Pediatrics, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital and Baylor College of Medicine Beth A Carter is a member of the following medical societies: American Gastroenterological Association, American Liver Foundation, and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Coauthor(s): Murat Kilic, MD, Associate Professor of Surgery, Department of Liver Transplantation and Hepatobiliary Surgery, Ege University Medical School, Turkey; Saul Karpen, MD, PhD, Director, Texas Children's Liver Center, Children's Hospital of Houston, Associate Professor, Departments of Pediatrics and Molecular/Cellular Biology, Baylor College of Medicine; John Goss, MD, Director of Liver Transplantation, Texas Children's Hospital, Associate Director of Liver Transplantation, Baylor/Methodist Liver Center, Associate Professor, Department of Surgery, Baylor College of Medicine Editors: Casimir F Firlit, MD, PhD, Consulting Staff, Department of Urology, Cardinal Glennon Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Brian F Gilchrist, MD, Chief, Division of Pediatric Surgery, Tufts-New England Medical Center; Associate Professor, Department of Surgery, Tufts University School of Medicine; Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center; Stuart M Greenstein, MD, Professor of Surgery, Albert Einstein College of Medicine; Consulting Surgeon, Department of Surgery, Division of Transplantation, Montefiore Medical Center Author and Editor Disclosure Synonyms and related keywords: history of pediatric liver transplantation, reduced-sized liver transplantation, RSLT, living donor liver transplantation, LDLT, split-liver transplantation, SLT INTRODUCTIONSection 2 of 11
  Forty years ago, during the developmental era of liver transplantation, liver recipients' prospects for long-term survival were dismal, and few transplants were attempted (Starzl, 1963). Over the years, refinements in patient selection, surgical techniques, and intensive care management, combined with the evolution of more effective immunosuppressive regimens, have resulted in dramatic gains in posttransplant survival rates. As of April 28, 2001, the United Network for Organ Sharing (UNOS) database reported that 17,564 patients in the United States were awaiting liver transplantation. A total of 4934 liver transplants were performed in the United States in 2000, and approximately 1000 individuals died that year while waiting for a liver (UNOS data). The pioneers of liver transplantation probably never envisioned the current scenario, in which the demand for donor livers far exceeds the supply. ANIMAL AND HUMAN TRIALSSection 3 of 11
In 1955, Welch published results of liver transplantation in an unspecified breed of dog. Although details of his technique remain unclear, he described transplanting livers into the right paravertebral gutters of immunocompetent mongrel dogs. The allografts atrophied rather quickly, which Welch attributed to rejection. In 1958, Moore developed a standard technique for canine orthotopic liver transplantation that was published in the Annals of Surgery (1960). Concurrently, Starzl was working on a similar liver transplantation technique. Prior to his landmark contributions to human liver transplantation, Starzl refined his technique by performing more than 200 canine transplants. Phase 1: 1963-1979 The history of human liver transplantation began within pediatrics, and many of the advances in liver transplantation techniques resulted from efforts to tailor the procedure to a pediatric recipient. In 1963, Starzl performed the first human liver transplant at the University of Colorado Health Sciences Center (UCHSC) on a 3-year-old male afflicted with biliary atresia (Starzl, 1963). This child had undergone multiple previous surgeries, and he died before the transplantation was completed. Initial enthusiasm for the new procedure was muted somewhat by postoperative complications, most notably sepsis and bleeding. Summary of the First 7 Orthotopic Liver Transplantation Attempts*
* Adapted from "History of Liver and Other Splanchnic Organ Transplantation" by Starzl and published in Transplantation of the Liver in 1996. Despite these early failures, experimental efforts to improve transplantation remained constant in the late 1960s, and the search continued for more sophisticated immunosuppressive agents. Development of antilymphocyte globulin from horse serum permitted the evolution of triple therapy immunosuppression (ie, azathioprine, prednisone, antilymphocyte globulin) (Starzl, 1967). Also in the late 1960s, the long-term survival rate of canine liver recipients bolstered efforts in human clinical liver transplantation (Starzl, 1996). In 1967, the first successful liver transplantation was performed on a pediatric patient, an 18-month-old child with a malignant liver tumor. She survived for 400 days before succumbing to disseminated malignancy. More successful transplants followed in 1967 and 1968, but all of these patients eventually died. Over the next 12 years, the 1-year mortality rate at the UCHSC transplant center never fell below 50% (Starzl, 1996). Phase 2: 1979 to present Cyclosporine revolutionized human orthotopic liver transplantation. This drug was originally developed in 1963-1973 from a fungus sample cultured from soil. It was first used in animal trials of transplantation in Calne's laboratory at Cambridge, where it improved success rates in ectopic heart transplantation in rats (Calne, 1991). Calne's successes led to the first use of cyclosporine in human transplant recipients in 1978. Of the first 12 liver recipients treated by Starzl with cyclosporine and prednisone in the first 8 months of 1980, 11 lived longer than 1 year and 7 survived at least 12 years (Starzl, 1981). The US Federal Drug Administration (FDA) approved cyclosporine for human use in 1983. June 20-23, 1983, became milestone dates in pediatric liver transplantation when the National Institutes of Health (NIH) held its consensus development conference on liver transplantation. Prior to this meeting, many insurance companies, and even some healthcare professionals, considered liver transplantation risky and experimental. After reviewing 296 cases from 4 countries, conference participants resoundingly declared liver transplantation to be a valid therapy for end-stage liver disease (ESLD) (Schafer, 2001). When another promising immunosuppressive agent, tacrolimus (Prograf, FK506), was introduced in 1989, 1-year survival rates for liver transplantation surpassed 70%, and new liver transplant programs proliferated worldwide (Starzl, 1996). International 1-year success rates for pediatric liver transplantation now exceed 90%, and 5- to 10-year survival rates are 80%. A summary of historic milestones in pediatric liver transplantation from 1963 to the present is as follows:
UNOS data show more that approximately 500 pediatric deceased donor liver transplants were performed in 2002 by more than 100 US transplant centers. Image 1 summarizes UNOS data on the number of deceased donor transplants by recipient age in the United States between 1993 and 2002 (data includes multi-organ transplants in which a deceased donor liver was one of the transplanted organs). Unlike adults, many children receive liver transplants because of liver damage from metabolic or congenital diseases. For example, between 1991 and March 2000, UNOS reported that 1123 children with extrahepatic biliary atresia underwent liver transplantation. ALLOCATION OF LIVERSSection 4 of 11
In early 2000, OPTN/UNOS (Organ Procurement and Transplantation Network and United Network for Organ Sharing) developed a system for prioritizing patients awaiting a liver transplant. The goal was to base allocation on statistical formulas that were accurate for predicting who was most likely to die soon from end-stage liver disease. After approval in November 2001, the MELD (Model for End Stage Liver Disease) and PELD (Pediatric End Stage Liver Disease Model) went into effect for adults and children respectively in February 2002. Both the MELD and PELD systems allow patients to be ranked according to the need for liver transplant. The PELD score applies to patients younger than 18 years. The higher the PELD score, the greater the risk of dying from liver disease. The PELD score formula includes bilirubin, INR, albumin, growth failure, and the patient's age when placed on the waiting list. The calculated score can range from a negative value (ie, -10) to very high values (ie, 40-50). Image 2 illustrates the PELD score calculation. The UNOS status 1 designation for gravely ill patients in need of a liver transplant remains in place as it was prior to implementation of the PELD score. Status 7 designates a patient that is not suitable for a transplant because of medical reasons. Image 3 summarizes the sequence of liver allocation under the current system. PEDIATRIC LIVER TRANSPLANT SURGERYSection 5 of 11
Background Pediatric patients had unacceptably high morbidity and mortality rates while awaiting liver transplantation because of a severe shortage of whole-organ cadaveric liver allografts that were blood type compatible and size-matched. This donor-recipient disparity in children reportedly caused pretransplant mortality rates as high as 25-50%. To maximize the number of donor organs available to children, 3 surgical procedures have evolved. All 3 are based upon the fundamental principle that a component of the liver with a suitable vascular pedicle, bile duct, venous drainage, and sufficient functional hepatocyte mass can sustain hepatic function as well as a whole-organ liver allograft. In general, liver transplantation involves the following 3 stages:
Although details of each surgical stage are beyond the scope of this article, important technical refinements have led to significant improvement in survival rates and deserve mention. These include the following:
Techniques for liver transplantation differ between children and adults in a few significant ways. First, the common bile duct in children is often either small or congenitally absent, making end-to-end (ie, donor-to-recipient) anastomoses of the bile ducts impossible and requiring a hepaticojejunostomy or choledochojejunostomy for bile drainage. Most pediatric liver transplant candidates weigh fewer than 30 kg. Aged-matched allografts are often unavailable. These factors have led to development of reduced-sized liver transplantation (RSLT), living donor liver transplantation (LDLT), and split-liver transplantation (SLT) procedures. Reduced-size liver transplantation A child's small size is an inherent disadvantage in the competition for a donor liver because most organ donations occur after a traumatic death of an adult or school-aged child. Yet more than 75% of ESLD occurs in children younger than 2 years. This donor-recipient size mismatch prompted the development of RSLT. In RSLT, the liver allograft can be tailored on the back table to a variety of functional lobes or segments. Segments most commonly used in children are 2 and 3 (ie, left lateral segment) or 2, 3, and 4 (ie, left lobe). Because of size discrepancy, segments 4-8 (ie, right lobe) and segments 1 and 4-8 (ie, right trisegment) allografts are rarely used in pediatric patients. When either a left lateral segment allograft or a left lobe allograft is used in RSLT, the remaining right-sided liver parenchyma is discarded. The first transplantation of part of a liver was performed in a heterotopic fashion and was reported by Fortner in 1979. Orthotopic transplantation of a reduced-size allograft was first reported by Bismuth in 1984. In 1988, Broelsch reported his experience with 14 children who received reduced-size liver allografts, 12 of whose cases were urgent. These transplants used 3 right lobe allografts, 9 left lobe allografts, and 2 left lateral segments. Although the 50% overall patient survival rate was similar to survival rates among high-risk recipients who received full-sized liver allografts, allograft-related and extrahepatic complication rates were 71% and 93%, respectively. A study of 54 patients by Otte and associates reported that the overall 1-year patient survival rate was 82% for whole-organ allografts versus 68% for reduced-size allografts, although children who underwent elective transplantation exhibited a 1-year survival rate of 77% (Otte, 1990). In 1992, Langnas et al demonstrated no significant difference in patient survival rates between RSLT and whole-organ liver transplantation in urgent recipients, although these patients had lower survival rates than patients who had undergone elective transplantation (Langnas, 1992). The results of this report demonstrated a 53% incidence of allograft-related complications, compared to a 75% incidence reported by Broelsch and associates in 1990. RSLT has become a safe and effective method of obtaining a liver allograft for critically ill children, and RSLT significantly reduces the waiting period for liver transplantation. RSLT increases the number of allografts available to the pediatric population, but it does not increase the total number of allografts available for transplantation. Living donor liver transplantation LDLT is an extension of RSLT. Raia et al were first to attempt use of a portion of the liver from a living donor in 1988 (Raia, 1988). The donor operation was without complication, but the recipient died. The first successful LDLT was performed in 1989 by Strong (Strong, 1990). Worldwide, more than 1000 LDLTs have been performed over the past 10 years. The prevalence of donor complications has been low, and patient and allograft survival rates have equalled or bettered rates achieved with cadaveric whole-organ transplantation or RSLT (Shackleton, 1995; Millis, 1995; Kiuchi, 1998). LDLT advantages include the ability to schedule the transplant as elective surgery and to select an ideal living donor. Donor selection was previously complicated by limiting the prospective donor pool to those who were brain dead and was further complicated by the events that caused the brain death. The potential advantage of increased histocompatibility between the donor and recipient (ie, lower incidents of allograft rejection) is unproved. Despite the success of LDLT for pediatric patients, unresolved safety issues remain that involve the donor, usually a parent of the recipient. Split-liver transplantation SLT is the culminating step in the progression from RSLT and LDLT. This technique divides a whole adult cadaveric liver into 2 functioning allografts—segments 2 and 3 for children (ie, left lateral segment) and segments 1 and 4-8 for adults (ie, right trisegment). The donor liver may be split either ex vivo on the back table after removal from the cadaver or in situ with division of the liver in the cadaver, similar to the LDLT procedure prior to procurement of the allograft. SLT both overcomes the drawbacks of RSLT and LDLT and increases the total number of cadaveric donor liver allografts. Some authorities predict that if SLT were developed to its full potential the technique would eliminate the need for RSLT and LDLT procedures except in emergent circumstances. Ex vivo split-liver transplantation Pichlmayr et al reported in 1988 the first clinical attempt at SLT by procuring a single cadaveric liver, splitting it into a right and left allograft on the back table, then placing the right-sided allograft into a 63-year-old woman with primary biliary cirrhosis and the left-sided allograft into a small child with congenital biliary atresia. In 1989, Bismuth and associates described 2 patients with fulminant hepatic failure who each received a split-liver allograft. Although both patients recovered from hepatic coma and had improved liver function, both died, the first on postoperative day 20 from multiple organ failure and the second on postoperative day 45 from diffuse cytomegalovirus disease. Bismuth attributed neither patient's demise to poor allograft function or technical complications. Broelsch and associates, in 1990, reported the first series of 30 SLT procedures in 21 children and 5 adults. In this early experience, the patient survival rate was inferior to reported series of whole-organ cadaveric liver transplants; only 67% of children and 20% of adults who received split-liver allografts survived. Technical complication rates were also high, with a 35% retransplantation rate and a 27% biliary complication rate. Despite reservations about SLT, several European transplant centers, faced with increasing waiting list mortality because of donor allograft shortage, cautiously pursued the procedure. De Ville de Goyet's 1995 study of European Split Liver Registry data reported the collective experience of 50 donor livers that supplied 100 allografts over a 5-year period. This series reported stratified 6-month survival rates for allografts and patients as follows, based upon whether the patient's need for transplantation status was elective or urgent:
Of the 100 original split-liver allografts in this series, 20 were lost because of complications involving the allograft itself. In addition, 11.5% of recipients had hepatic artery thrombosis, 4% had portal vein thrombosis, and 18.7% had biliary complications. When these results were compared to European Liver Transplant Registry data on whole-organ liver transplants performed during the same period, whole-liver allografts were not significantly different in regard to allograft or patient survival rates. Survival rates for adult patients receiving a split allograft electively were higher than for those who received a whole-organ allograft (ie, 88.9% versus 80.3%). Also, children who received an elective split-liver allograft experienced lower allograft loss rates and lower rates of retransplantation than those who received whole-organ allografts. These results stimulated renewed interest in SLT, as shown in more recent studies by Azoulay et al in 1996, Kalayoglu et al in 1996, and Rela et al in 1998. All showed improved allograft and patient survival rates in nonurgent transplantations, despite a continuing high rate of biliary complications. In situ split-liver transplantation In situ SLT is a modification of the ex vivo technique. In addition to being completed in the cadaveric donor while the heart is still beating, the in situ method is based upon the techniques established in living donor liver procurement. The first report of a successful in situ SLT was published in 1996 by Rogiers et al. They summarized their initial experience with 14 in situ split-liver allografts that resulted in a 92.8% 6-month patient survival rate and an 85.7% 6-month allograft survival rate. These researchers also reported right-sided allografts with lower rates of biliary complications, intra-abdominal hemorrhage, and primary allograft nonfunction than the rates reported in other series involving ex vivo split-liver techniques. Because in situ SLT was introduced in 1996, only a small number of reports of solely in situ split-liver techniques have been published to date (Rogiers, 1995; Rogiers, 1996; Goss, 1997). All of these series, however, have shown improved results over the ex vivo technique: higher patient and allograft survival rates and fewer incidents of technical complications associated with hepatic artery anastomosis, biliary reconstruction, and postoperative intra-abdominal bleeding. Unlike ex vivo SLT reports, cases requiring urgent transplants had allograft and patient survival rates equivalent to similar patients who received whole-organ liver allografts. Waiting time and pretransplant morbidity and mortality rates have also improved with in situ SLT. Infants younger than 1 year have had the waiting time for transplantation decrease from 128 days to 24 days, and waiting times for children older than 1 year have dropped from 192 days to 30 days (Goss, 1997). Splitting the cadaveric liver expands the donor pool and may eliminate the need for LDLT in all but emergent pediatric cases. Recent experience with ex vivo SLT, if applied to elective cases, provides patient and allograft survival rates comparable to whole-organ transplantation, although postoperative complication rates are higher. In situ SLT provides 2 allografts of optimal quality that can be used by the entire spectrum of transplant recipients. This technique may evolve into the procedure of choice to expand the cadaveric liver donor pool. IMMUNOSUPPRESSIONSection 6 of 11
Background The aim of immunosuppression is to abrogate the host's immune response to the liver allograft and to allow allograft survival. In the early years of liver transplantation, immunosuppression was based upon corticosteroid and azathioprine use. The development and introduction of additional immunosuppressive agents have given transplant physicians a powerful armamentarium of medications to manipulate the host immune system and to prevent allograft rejection. The modern era of immunosuppression began with Borel's discovery of cyclosporine (Borel, 1976). Calne first described the clinical application of cyclosporine in 1978. The selective effect of cyclosporine on the production of interleukin 2 (IL-2) and the IL-2 receptor reduced the incidence of acute allograft rejection and also tended to spare nonspecific host resistance. Tacrolimus was later introduced and proved to be even more potent, with a lower rate of steroid-resistant allograft rejection (Weisner, 1998). Cyclosporine In 1979, cyclosporine revolutionized immunotherapy and allowed solid organ transplantation to emerge as a recognized and viable option for patients with end-stage organ failure. Cyclosporine A is a cyclic 11–amino acid peptide isolated from the fungus Tolypocladium inflatum gams. This drug inhibits cell-mediated immunity and suppresses T-lymphocyte function without compromising phagocytosis or hematopoiesis. Adverse effects include, but are not limited to, renal toxicity, hypertension, fluid retention, gingival hyperplasia, and hirsutism. Cyclosporine and prednisone were first used in combination in the late 1970s as postoperative immunosuppressive agents, which dramatically improved survival rates. The original preparation of cyclosporine, Sandimmune, was in an ethanolic olive oil. This form was poorly absorbed in children with liver disease and poor bile flow, conditions that lessen the drug's bioavailability. Neoral is a newer oral formulation of cyclosporine that is prepared in a stable microemulsion. Even children with cholestasis can adequately absorb Neoral, so it has replaced Sandimmune in many transplant centers. Tacrolimus First introduced into clinical practice in 1989, tacrolimus emerged in the 1990s as an alternative immunosuppressive medication. Its mechanism of action is similar to that of cyclosporine. Tacrolimus is a macrolide lactone produced by the fungus Streptomyces tsukubaensis. Among the advantages of tacrolimus over cyclosporine are less gingival hyperplasia and hirsutism, better oral absorption, and higher potency. Disadvantages include a questionable increased prevalence of cardiomyopathy, which is not reported with cyclosporine use, and its association with lymphoproliferative disease, although all immunosuppressive agents share this association. At first, tacrolimus was used primarily as a rescue agent in patients with refractory rejection under cyclosporine. More recent tests have verified its utility and success as a primary immunosuppressive agent. A recent study suggests almost all children can be weaned off steroids by using tacrolimus as the primary immunosuppressive agent after liver transplantation (Jain, 2002). Cyclosporine versus tacrolimus Posttransplant induction protocols usually dictate use of a calcineurin inhibitor, either cyclosporine or tacrolimus, for children and adults. Most centers also use steroids for some time. A multicenter study showed tacrolimus has a lower rejection prevalence than Sandimmune, the nonmicroemulsion preparation of cyclosporine (McDiarmid, 1995). (Sandimmune also has less favorable pharmakinetics in children than Neoral, the microemulsion form of cyclosporine.) The choice between cyclosporine and tacrolimus as the primary immunosuppressive agent often depends upon the transplant physician's experience and familiarity with a particular medication. In recent years, tacrolimus has almost completely replaced cyclosporine in liver transplantations. An antiproliferative drug, either azathioprine or mycophenolate, is often added for triple therapy when cyclosporine is used as the primary posttransplant immunosuppressive agent in conjunction with steroids. Triple therapy is seldom used with tacrolimus. The advantage of mycophenolate mofetil (CellCept) over azathioprine (Imuran) is its superior ability to prevent rejection. Azathioprine also has a much more widespread antiproliferative effect than that produced by mycophenolate. Triple therapy in the cyclosporine protocol permits temporary reduction of cyclosporine if adverse effects develop. FUTURE ISSUESSection 7 of 11
Posttransplant lymphoproliferative disorder Posttransplant lymphoproliferative disorder (PTLD) is a serious complication in children that may occur as early as the first few months following transplantation. Despite some progress in its prevention and treatment, PTLD remains an important posttransplant complication. A series of 298 children who had received liver transplantation reported an overall prevalence of PTLD of 8.4% (Newell, 1996). The prevalence of PTLD rises with increased levels of immunosuppression because the disease depends on the suppression of T cells. As T cells decrease, Ebstein-Barr virus (EBV) stimulates clonal expansion of B cells. An infant who is EBV-negative and receives an organ from a seropositive donor has a significant risk of developing PTLD in the absence of prophylaxis. Symptoms of PTLD are extremely variable. Heightened suspicion for the disorder should occur when a child has lymphadenopathy, enlarged tonsils, unexplained fever, diarrhea, sinusitis, malaise, anorexia, headaches, new-onset seizures, or any mass lesion after transplantation. Serial polymerase chain reaction (PCR) tests for EBV should be performed for all posttransplant patients. Treatment options include temporary cessation or reduction of immunosuppression, surgical resection of mass lesions, chemotherapy, and administration of anti-CD20 monoclonal receptor antibodies. In recent years CTL (cytotoxic T lymphocyte) infusions have emerged as a promising therapy for PTLD, as well. This technique involves the transfer of EBV-specific cytotoxic T lymphocytes generated from the peripheral blood of the organ recipient. Future studies Laboratory research appears likely to change transplantation techniques in the new millennium. For example, hepatocyte transplantation is emerging as a technique that may someday become an adjunct treatment for acute hepatic failure. Furthermore, hepatic tissue culture models are currently being performed in many research laboratories. These models are designed to explore the mechanisms of in vitro hepatic injury; their goal is to develop therapeutic interventions. More frequent multiorgan transplantations are also likely in upcoming decades. Some centers already perform combined liver-intestinal transplantations. A novel treatment for fulminant liver failure that has emerged in recent years is molecular absorbant recirculating system (MARS). This technique involves pumping blood from the body through a thin membrane coated with albumin. Molecules (ie, toxins that accumulate with liver failure) can then bind to the albumin and are removed by passage through a charcoal column and anion exchange. Although this therapy has potential promise in the treatment of pediatric liver failure, it needs further testing in this population. In summary, the future of pediatric transplantation appears bright, but the following questions await answers in the new millennium:
RESOURCESSection 8 of 11
The following Web sites provide additional information on solid organ transplantation:
THE BILIARY ATRESIA RESEARCH CONSORTIUMSection 9 of 11
Biliary atresia is the single-most common reason for liver transplantation in children. It accounts for approximately 40% of liver transplants performed in children in the United States. Unfortunately, the cause of this disease remains unknown and, historically, relatively few scientific investigators have actively pursued animal models or basic science projects aimed at investigating the etiology or epidemiology of biliary atresia. Accordingly, in 2004, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) announced the establishment of the Biliary Atresia Research Consortium (BARC). This project consists of 10 US medical centers and is aimed at collecting data on newly diagnosed biliary atresia cases and conducting clinical trials. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
History of Pediatric Liver Transplantation excerpt Article Last Updated: Jun 13, 2006 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
