- Email: [email protected]
Pediatric liver transplantation
Seminars in Pediatric Surgery (2006) 15, 218-227
Pediatric liver transplantation Gregory M. Tiao, MD, Maria H. Alonso, MD, Frederick C. Ryckman, MD From the Department of Pediatric Surgery, Pediatric Liver Care Center, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio. INDEX WORDS Pediatric liver transplantation; Biliary atresia; Fulminant liver failure; Hepatoblastoma; Chronic immunosuppression; Tyrosinemia
Liver transplantation has become the accepted standard of care in the treatment of a child with a failing liver. Advances in the management of critical care and immunosuppression along with the development of innovative operative procedures have improved outcome such that 5-year survival rates of 80% to 90% are expected following liver transplantation. Organ allocation schemes have evolved in an effort to better stratify recipient risk thereby more appropriately distributing deceased donor grafts. A persistent shortage of appropriate donors continues to contribute to patient mortality. The consequences of long-term immunosuppression have become increasingly apparent such that health care providers need to be aware of the side effects of chronic immunosuppression. New strategies need to be defined to minimize the need of continuous immunosuppression. The continued success of pediatric liver transplantation will require multi-disciplinary health care teams comprised of general pediatricians, pediatric hepatologists, transplant surgeons, and transplant coordinators who focus on the complex needs of the transplant recipient. © 2006 Elsevier Inc. All rights reserved.
The outcome of children who have end-stage liver disease has improved markedly over the last 20 years. Liver transplantation (LTx) has evolved from a heroic experimental effort to the standard treatment for a child who faces the complex clinical problem of a failing liver. The marked improvement in outcomes has occurred because of advances in pediatric critical care, the management of immunosuppression, and the development of innovative operative procedures. The success of liver transplantation has bred unique problems that must be met in the future. The potential benefits of expanding indications for liver transplantation have been limited by a persistent lack of appropriate donors. The increasing number of long-term survivors after transplantation present unique challenges related to lifelong immunosuppression. The continued success of pediatric liver transplantation will require a national focus on donor Address reprint requests and correspondence: Gregory M. Tiao, MD, Department of Pediatric Surgery, Pediatric Liver Care Center, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: [email protected].
1055-8586/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2006.03.008
organ shortages and recognition of the complex needs of this population of patients.
Indications The most common clinical presentations prompting transplant evaluation in children can be classified as follows: (1) progressive primary liver disease, (2) hepatic based metabolic disease, (3) fulminant hepatic failure, and (4) unresectable primary liver tumors. Table 1 lists the indications for children who have undergone liver transplantation at Cincinnati Children’s Hospital and Medical Center over the last 15 years.
Primary liver disease The most common primary liver disease that manifests in childhood and causes end-stage liver disease (ESLD) is biliary atresia. Children with biliary atresia (BA) comprise at least 50% of the pediatric liver transplant population.
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219
Table 1 Indications for liver transplantation at Cincinnati Children’s Hospital and Medical Center (CCHMC)* Cholestatic liver disease Biliary atresia Alagille syndrome Familial cholestasis Primary sclerosing cholangitis Idiopathic Metabolic disease Alpha-1 antitrypsin defeciency Tyrosinemia Urea cycle defect Glycogen storage disease Wilson’s disease 1o hyperoxaluria Cystic fibrosis Fulminant liver failure CIRRHOSIS/HEPATITIS Cryptogenic cirrhosis Autoimmune Neonatal hepatitis Hepatitis C Congenital hepatic fibrosis Tumor Hepatoblastoma Hepatocellular carcinoma Sarcoma Other Hemangioendothelioma Hemachromatosis Budd-Chiari TPN related Short gut syndrome (L/SI) NEC (L/SI) Megacystis/microcolon
149 129 8 1 7 4 49 26 7 7 4 2 2 1 44 27 14 7 4 1 1 11 9 1 1 12 2 2 1 3 2 1 1
51%
Other primary liver diseases that are causes of ESLD in childhood include Alagille’s syndrome, sclerosing cholangitis, and the Progressive Familiar Intra-hepatic Cholestasis (PFIC) syndromes. The degree of liver injury varies such that only some affected patients develop end-stage liver disease and require LTx in childhood.6-8 Hepatitis C, the most common adult indication for LTx, is rare at present in children.
17%
Hepatic-based metabolic disease
15% 9%
4%
4%
*n ⫽ 292 primary liver transplants.
Urea cycle defects (UCD), alpha-one antitrypsin (␣1aT) deficiency, and tyrosinemia are several examples of hepaticbased metabolic diseases that manifest in the pediatric population. In patients with UCD and tyrosinemia, LTx is not only lifesaving but it also accomplishes a cure of the underlying disease. Hepatic replacement should be considered before the consequences of the defect results in complications that may prove to be contraindications for transplantation. For example, patients with UCD who have repetitive hyperammonemic crisis sustain significant neurologic injury with resulting mental retardation. Early transplantation eliminates episodes of hyperammonemic crisis preserving neurologic function.9,10 The use of living donors or carriers of UCD has been successful and allows planned early transplantation.11 Patients with tyrosinemia develop hyperplastic nodules which have a high risk of evolving into a hepatocellular carcinoma (HCC). They required LTx before extrahepatic spread of the tumor occurred. Recently, intervention with NTBC has been successful in preventing dysplasia, and may avoid the need for LTx when treatment is begun in early infancy.
Fulminant hepatic failure (FHF) Kasai portoenterostomy should be the primary surgical intervention for all infants with BA. In patients who present in late infancy (⬎120 days of age) and whose liver biopsy shows advanced cirrhosis, primary LTx is indicated1,2 In children who fail to achieve adequate biliary drainage following a Kasai, cirrhosis with manifestations of ESLD such as ascites, progressive portal hypertension, malnutrition, and/or progressive hepatic synthetic failure will become apparent. Approximately 40% to 50% of infants who undergo Kasai will suffer these complications and require LTx within the first 2 years of life. Some children have successful establishment of biliary drainage with normal postoperative serum bilirubin levels but still develop progressive cirrhosis and manifestations of ESLD. These children typically do not require LTx until late childhood. Another subset of children with stable synthetic liver function will develop hepatopulmonary syndrome that will dictate the need for LTx. Currently, it is estimated that only 15% to 20% of all BA patients who undergo the Kasai procedure will survive without LTx.3,4 The sequential use of the Kasai procedure followed by LTx is still indicated as it optimizes overall survival and organ utilization.2,5
Patients who develop FHF without recognized antecedent liver disease present diagnostic and prognostic difficulties. Rapid clinical deterioration frequently makes establishment of a primary diagnosis impossible before the need for urgent transplantation. The most common cause of fulminant liver failure is viral hepatitis of undefined type, followed by drug toxicity, toxin exposure, and previously unrecognized metabolic disease. There are several causes of fulminant liver disease that are unique to pediatrics. One of these, neonatal hemachromatosis, presents a particularly difficult challenge. Affected infants present in the neonatal period with fulminant hepatic failure. The use of antoxidant cocktails has improved some patients, but a failure to respond within 48 to 72 hours mandates transplantation.12 Liver transplantation is life-saving, but success rates of ⬃50% are reported.13 Recently, we have treated several children with hemophagocytic lymphohistiocytosis (HLH)-induced fulminant liver failure. In children who have HLH, inappropriate activation of macrophages and natural killer cells causes severe hepatocyte injury. The role of liver transplantation in the treatment of patients with HLH has not been clearly
220 established, as recurrence in the graft has been shown to occur.14 The primary treatment is hematologic, rather then organ replacement. Mitochondrial respiratory chain abnormalities representing disorders in the electron transport proteins present both as FHF or progressive liver disease with sudden decompensation.14 These disorders are especially important to recognize during the evaluation process, as they represent multi-organ progressive diseases; transplantation is not curative, nor indicated. Selection of FHF candidates for transplantation is difficult, as the natural history of each disease is not clearly established. The King’s College Institute of Liver Studies has developed a scoring system for children with FHF, stratifying their risk.15 Predictive factors included INR, bilirubin ⬎235 æmoles/L, age ⬍2 years, and WBC ⬎ 9000/ mm3. Although these criteria are helpful, careful observation for progression and clinical change is essential. For short-term stabilization, we have utilized repetitive courses of plasmapheresis to ameliorate the clinical manifestations of fulminant liver failure. Neurologic improvement is common but not sustained, and no suggestion of enhanced native liver recovery has occurred; ultimately, transplantation is the only effective treatment modality.16,17
Malignancy Hepatoblastoma and hepatocellular carcinoma (HCC) are the two most common primary hepatic malignancies found in children. Recent experience has documented the efficacy of liver transplantation in a subset of patients who have a hepatoblastoma, and have established transplantation as an integral part of the treatment strategy of these children.18-23 In children who present with a hepatoblastoma, complete surgical resection of the primary liver lesion remains the most crucial intervention required to achieve long-term survival. Adjuvant chemotherapy and conventional resection should be employed where feasible; however, some children have lesions that remain un-resectable after chemotherapy. In these children, liver transplantation is the only option that can achieve complete resection.18-23 Unlike the adult population, the frequency of HCC in the pediatric population is low; therefore, the experience in the application of liver transplantation in the pediatric population for HCC is limited.19,23-25 In patients whose disease is confined to the liver, the use of liver transplantation is indicated. Because chemotherapy is not beneficial at present in this group, results in patients with more extensive disease are poor.
Contraindications Contraindications to transplantation include: (1) primary extra-hepatic unresectable malignancy, (2) progressive terminal nonhepatic disease, (3) uncontrolled systemic sepsis, and (4) irreversible neurologic injury. Relative contraindi-
Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 cations to transplantation, which need to be individually evaluated, include: (1) HIV positive serology, (2) advanced or partially treated systemic infection, (3) advanced hepatic encephalopathy-Grade IV, (4) severe psychosocial abnormalities, and (4) malignancy metastatic to the liver.
Preoperative preparation Efforts to correct abnormalities noted during candidate evaluation will decrease both the operative risk and postoperative complications. In children, optimizing the nutritional status of the recipient is vital; the use of calorie enhanced formula and the placement of nasogastric feeding tubes is often necessary in small children. Assessment of prior viral exposure, and meticulous attention to the delivery of all normal, well-child immunizations, particularly the live-virus vaccines, is imperative if time allows before LTx.
Organ allocation In the early 1980s, the Organ Procurement and Transplantation Network (OPTN) was established by the US Government to develop a system to distribute organs in an equitable fashion. Organ allocation was based primarily on severity of illness, as indicated by patient location (home, hospital, ICU) and time accrued waiting on the pretransplant list. It was shown that waiting time had no relationship to death, except for Status 1 patients, leading to dissatisfaction with the existing system.24 In response to this the HRSA established the “Final Rule” in 1998, requiring allocation policies to be based on sound medical judgment using defined criteria to achieve the best use of donated organs.25 Using knowledge gained from the Mayo End-stage Liver Disease model, the MELD (Model for End-stage Liver Disease) was established for adults. Based on similar information derived from the Studies of Pediatric Liver Transplantation (SPLIT), a pediatric-specific score (PELD) was established using bilirubin, INR, serum albumin, age ⬍1 year, and growth failure. The preferential policy to direct pediatric organs (⬍18-year-old donor) to pediatric recipients was maintained, and Status 1 priority was maintained for children with chronic or acute liver disease. Additional PELD points could be obtained for specific risk factors not identified in the PELD equation, such as hepatopulmonary syndrome, urea cycle defects, and hepatic neoplasms. Although the PELD system improved numerical quantification of candidates, and removed waiting time from the scoring equation, the PELD score has not proven to be a successful predictor of 30 day or long-term outcome following transplantation.26,27 Concerns that identification and transplantation of “sicker patients first” would lead to decreased survival have not proven correct.27 In a review of the first year of PELD, graft and patient survival remained unchanged from the prior allocation system.28 Although the PELD
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system was designed to better quantify risk, there is a perceived failure of the PELD system in its current form. The majority of infants and children allocated organs have achieved a PELD score sufficient for transplantation through special exception points, or Status 1. Further modeling and analysis will allow this system to be modified to reflect identified predictive factors and continually improve access and equity to all potential recipients.
Graft options The limited availability of pediatric donor organs and high waiting list mortality stimulated the development of innovative surgical procedures to increase donor options for children. Whole organ transplantation remains the ideal option; however, many children undergo reduced-size transplantation (RSLTx), where a whole organ from an adult donor is surgically reduced ex vivo such that only the left lobe or left lateral segment is transplanted. Although operative reduction of a larger sized donor liver expanded the number of donor organs available to small recipients it merely shifted donor resources rather than increasing donor availability. The success of the operative techniques perfected doing reduced-size transplantation allowed the development of both split-liver transplantation (SLTx), where a single liver is used to transplant two recipients, and livingdonor transplantation (LD). The selection of a donor organ or segment with appropriate parenchymal mass for adequate function is critical to success. Unfortunately, the minimal hepatic mass necessary for recovery is not clearly established. Any calculation must take into account the temporary loss of function due to the donor’s injury or treatment, as well as the possibility of preservation damage, early acute rejection, or technical problems. The normal liver volume in a child can be calculated using the following formula: Estimated Liver Volume ⫽ 706.2 ⫻ BSA (m2) ⫹ 2.4.29 When selecting donor segments, transplantation of ⱖ40% to 50% of this ideal calculated volume is recommended.30,31 Estimates of donor graft to recipient body weight ratio (GRWR) may prove to be the most accurate predictor of adequate graft volume. A minimum graft fraction of 1% recipient body mass meets this need.32 A GRWR of 1% to 3% is optimum. In cases where the GRWR ⬍0.7%, overall allograft and patient survival suffered due in part to excessive portal flow that leads to hemorrhagic necrosis of the graft. Large for size allografts (GRWR ⬎ 5.0%) have a better outcome compared with small allografts.31,33 The success of liver transplantation is related to the stability and quality of the donor. Assessment of donor organ suitability is primarily undertaken by evaluating clinical information and static biochemical tests. Clinical factors of concern include donors who are at the limits of age, have had prolonged intensive care hospitalization with potential sepsis, and have vasomotor instability requiring ex-
221 cessive inotropic agents. Severe electrolyte disturbances identify increased risk. Although nonideal (extended criteria) donor organs can be used as whole allografts, especially when ischemic time is limited, they are high risk when used as donors for reduced-size or split liver allografts. Donor liver biopsy at the time of organ harvest, or during evaluation, is helpful in questionable cases to identify preexisting liver disease or donor liver steatosis. Donor age can affect the long-term results of pediatric liver transplantation; however, the spectrum of influence is not completely clear. When the UNOS database was used with the UNOS Liver Allocation Model, Kaplan-Meier graft survivals showed that pediatric patients receiving livers from pediatric aged donors had an 81% 3-year graft survival compared with 63% if children received livers from donors ⱖ18 years. In contrast, adult recipients had similar 3-year graft survivals irrespective of donor age. In the multivariate analysis, the odds of graft failure were reduced to 0.66 if pediatric recipients received livers from pediatric aged donors. The odds of graft failure were not affected at any time point for adults whether they received an adult or pediatric-aged donor.34 If a deceased donor liver is used, these data strongly support the use of pediatric donors. The primary distribution of pediatric donor livers to pediatric recipients is further supported by evaluating adult experience with pediatric donor organs. In the Mount Sinai Hospital adult series, adult (⬎18 year age) recipients of pediatric donor organs had an increased risk of hepatic artery thrombosis (HAT) and poor function compared with recipients of adult donors, an effect that corelated with increasing donor:recipient size discrepancy.35 This was confirmed in the Mayo Clinic series, where the 1-year graft survival rate in adult transplant recipients receiving donors from donor ⬍12 years of age was 64.3% compared with 87.5% when the donor was 12 to 18 years of age (P ⫽ 0.015).36 The main cause of graft loss was again vascular complications. Because the outcome of small pediatric donor livers in adult recipients is poor, and small pediatric donors are the only source of lifesaving organs for the infant recipient, the use of small pediatric donor livers in adults should be avoided.
Donor procurement Whole organ procurement is now a well described procedure. The principles of minimum mobilization to define vascular structures, in situ perfusion with 4øC preservation solution, and sequential en bloc harvest of organs yield good allograft preservation. When reduction hepatectomy is needed for reduced-size grafts, this is accomplished following en bloc procurement. The operative techniques for this reduction are well described.37,38 “Split liver” grafting involves the preparation of two allografts from a single donor.32,39 In most cases, the extended right lobe allograft (segments 4-8) is used in an adult or large child, while the left lateral segment allograft (seg-
222 ments 2,3) is transplanted into a small recipient. Conventional techniques for implanting the respective allografts are used. The use of in situ division of the left lateral segment (LLS), as during living donor liver procurement, is our preferred method for split-liver donor preparation at the present time, although comparable results using ex vivo division have also been achieved.39
Liver transplantation The technical details of these pediatric liver transplant procedures are well described.40,41 The most underestimated portion of this complex operative procedure entails the removal of the native liver. Multiple prior operations or revisions for biliary atresia, or multiple episodes of spontaneous bacterial peritonitis, lead to extensive vascularized adhesions. These increase the risk of intestinal perforation and bleeding at transplantation. Optimal arterial inflow is essential for donor liver recovery. When the native hepatic artery is ⬍4 to 5 mm in diameter, we prefer to directly implant the celiac axis of the donor liver into the infrarenal aorta. When adequate length is lacking, a donor iliac arterial vascular interposition graft is used to accomplish this anastomosis. Access to the infrarenal aorta is provided by mobilizing the right colon and duodenum. A large experience has also indicated that microvascular reconstructive techniques for the hepatic artery are a very successful.42 Allograft venous outflow must be unimpeded. This is especially important in “piggyback” implantation to the native IVC in small children, where a confluence of all three hepatic venous orifices is our preference to achieve wide and effective outflow. Impaired outflow leads to allograft swelling, increased vascular resistance, and subsequent inflow thrombosis. Immediate postoperative and daily Doppler ultrasound will assist in recognizing correctable blood flow abnormalities before graft compromise. Bile duct reconstruction as an end-to-side choledochojejunostomy into an isoperistaltic Roux-en-Y jejunal limb is our preference in young recipients. Older children without primary biliary pathology can undergo direct stent-free choledochal reconstruction. When closing the abdomen, increased intraabdominal pressure should be avoided. In many cases, avoidance of fascial closure and the use of mobilized skin flaps and running monofilament skin closure, is advisable. Musculofascial abdominal wall closure can be completed approximately 1 week posttransplant.
Immunosuppression A complete discussion on the management of immunosuppression can be found elsewhere in this series. Currently, most liver transplant centers use an immunosuppressive protocol based on the administration of multiple complementary medications. The calcineurin inhibitor tacrolimus has become the mainstay of most of these regimens. Corticosteroids are a well established component of many regi-
Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 mens; however, recently, there has been significant interest in steroid minimization protocols. The antimetabolites mycophenolate mofetil and on occasion azathioprine are also used by in many protocols. Induction with antilymphocyte antibodies such as OKT3 or Thymoglobulin can be considered in conditions where calcineurin inhibitor toxicity precludes their early use. One of the most significant developments in field of transplantation has been the recognition of the consequences of long-term immunosuppression. Calcineurin inhibitors cause chronic renal insufficiency, diabetes mellitus, arterial hypertension, and atherosclerosis/coronary artery disease; as a result, many centers are developing protocols designed to avoid prolonged exposure to decrease future complications.43,44
Complications Vascular thrombosis is the most common cause of early postoperative allograft loss. Hepatic artery thrombosis occurs in 1% to 2% of children who undergo LTx. The overall incidence of vascular thrombosis is similar in whole, SLTx, and LD transplants in experienced centers.32,39 A variable clinical picture may be seen including: (1) fulminant allograft failure, (2) biliary disruption or obstruction, or (3) systemic sepsis. When identified early, successful thrombectomy and allograft salvage is possible if reconstruction is undertaken before allograft necrosis.45 Acute HAT with allograft failure requires immediate transplantation. Biliary complications are particularly common following HAT and may be temporized by percutaneous drainage and biliary stenting to control bile leakage and infection until re-transplantation is undertaken. Portal vein thrombosis occurs in 5% to 10% of recipients. In infant recipients with biliary atresia, preexisting portal vein hypoplasia often requires replacement of the entire portal vein to the SMV/Splenic Vein confluence with donor portal vein to avoid low flow related thrombosis. In LD allografts, size mismatch between donor and recipient and short venous pedicles may require grafting with donor gonadal or inferior mesenteric vein segments.46 Preexisting portal vein thrombosis in the recipient can be overcome by thrombectomy or portal vein replacement or extra-anatomic venous bypass using donor portal/iliac vein. Early thrombosis following transplantation, detected by Doppler screening, requires immediate anastomotic revision and thrombectomy. Later thrombosis is detected by decreased platelet counts and increasing spleen size or gastrointestinal bleeding. Interventional radiographic stent placement or balloon dilation has been successful in patients with portal anastomotic stenosis, but is less successful when occlusion has occurred.46 Portal venous shunting may be needed in selected patients with progressive portal hypertensive complications. Primary nonfunction (PNF) of the hepatic allograft implies the impairment of metabolic and synthetic activity
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following transplantation. Complete nonfunction requires immediate re-transplantation. Lesser degrees of allograft dysfunction occur more frequently but may be reversible. Biliary complications have been referred to as the “Achilles Heel” of liver transplantation, occurring in about 10% of pediatric whole organ liver transplant recipients. Their spectrum and treatment is determined by the status of the hepatic artery and the type of allograft used. Although whole and surgically reduced allografts (RSLTx, SLTx, and LD) as a group have an equivalent risk of biliary complications, the spectrum of complications differs.32,47,48 Late complications following any type of primary duct-to-duct biliary reconstruction include anastomotic stricture, biliary sludge formation, and recurrent cholangitis. Endoscopic dilation and internal stenting of anastomotic strictures or minimal biliary leaks has been successful in early postoperative cases. With recurrent stenosis or persistent postoperative leak, Roux-en-Y choledochojejunostomy is the preferred treatment. This is also the reconstruction method of choice in small children and in all patients with biliary atresia. The complexity of the biliary reconstruction is increased in both SLTx and LD allograft, which often require the anastomosis of two individual segmental bile ducts. The presence of multiple bile ducts in surgically reduced allografts has a documented increased risk for biliary leak following reimplantation. Parenchymal bile leaks and anastomotic leaks were slightly more common in SLTx, whereas anastomotic strictures are more common in LD.32 These complications seem most related to graft type rather then patient illness (UNOS Status). This increased complexity and risk of complications is the known trade-off for increased organ availability. Acute rejection is characterized by the histologic triad of endothelialitis, portal triad lymphocyte infiltration with bile duct injury, and hepatic parenchymal cell damage.49 Acute rejection occurs in approximately two-thirds of patients following LTx using tacrolimus or cyclosporine based immunotherapy.50 Allograft biopsy is essential to establish the diagnosis of acute rejection before treatment. The primary treatment of rejection is a short course of high dose steroids. Bolus doses administered over a several day period with a rapid taper to baseline therapy is successful in 75% to 80% of cases.51 When refractory or recurrent rejection occurs, antilymphocyte therapy using the monoclonal antibody OKT-3 is successful in 90% of cases.52 Chronic rejection occurs in 5% to 10% of transplanted patients. The primary clinical manifestation is a progressive rise in alkaline phosphatase, gamma glutamyl transpeptidase and progressive cholestasis. This course can be initially asymptomatic. Chronic rejection can follow one of the two clinical forms.53 In the first, the injury is primarily to the biliary epithelium; the clinical course is characterized as “acute vanishing bile duct syndrome” where severe ductopenia is seen in at least 20 portal tracts.54 Spontaneous resolution in nearly half of affected patients when they were administered tacrolimus therapy has led to the development
223 of enhanced immunosuppression protocols for this patient subgroup. Retransplantation is occasionally necessary but rarely emergent. The second subtype is characterized by the early development of progressive ischemic injury to both bile ducts and hepatocytes leading to ductopenia and ischemic necrosis with fibrosis. The clinical course is relentlessly progressive and nearly always requires retransplantation. Recurrence of chronic rejection in the retransplanted allograft is a common event.53 Infectious complications now represent the most common source of morbidity and mortality following transplantation. A complete discussion of this topic can also be found elsewhere in this series. Bacterial infections occur in the immediate post transplant period and are most often caused by Gram-negative enteric organisms, Enterococcus, or Staphylococcus species. Antibacterial prophylactixis is discontinued as soon as possible to prevent the development of resistant organisms. Fungal sepsis represents a significant potential problem in the early posttransplant period. Aggressive protocols for pretransplant prophylaxis are based on the concept that fungal infections originate from organisms colonizing the GI tract of the recipient. Selective preoperative bowel decontamination was successful in eliminating pathogenic Gram-negative bacteria from the GI tract in 87% of adult patients; in all cases, Candida was eliminated.55 However, these protocols have not been practical in pediatric patients because there is a long waiting time for pediatric organs and the taste of the antibiotics used is poorly accepted. All patients undergoing LTx receive antifungal prophylaxis with fluconazole at our center. The majority of early and severe viral infections are caused by viruses of the Herpes family, including EpsteinBarr Virus (EBV), Cytomegalovirus (CMV), and Herpes Simplex Virus (HSV).56 The likelihood of developing either CMV or EBV infection is influenced by the preoperative serologic status of the transplant donor and recipient.57,58 Seronegative recipients receiving seropositive donor organs are at greatest risk. Use of various immune-based prophylactic protocols including IV IgG, hyperimmune anti-CMV IgG, coupled with acyclovir or ganciclovir have all achieved success in decreasing the incidence of symptomatic CMV and EBV infection, although seroconversion in naive recipients inevitably occurs.57,59 Posttransplant lymphoproliferative disease (PTLD), a potentially fatal abnormal proliferation of B lymphocytes, can occur in any situation in which immunosuppression is undertaken. The increased frequency of PTLD in pediatric liver transplantation results from the intensity of the immunosuppression required, its lifetime duration, and the absence of prior exposure to EBV infection in 60% to 80% of pediatric recipients. PTLD is the most common tumor in children following transplantation representing 52% of all tumors compared with 15% and adults. About 80% occur within the first 2 years following transplantation.60 Many studies analyzing the associations between immunosuppressive therapy and the development of PTLD have shown a
224
Seminars in Pediatric Surgery, Vol 15, No 3, August 2006
CCHMC Patient Survival by Age @ First LT 100 90
% Survival Probability
80 70 60 50 0
3
6
12
18
24
36
48
Months
0-6 months
6-12 months
1-5 years
5-13 years
> 13 years
CCHMC Graft Survival by Age @ First LT 100 90 80 % Survival Probability 70 60 50 0
3
6
12
18
24
36
48
Months 0-6 months
6-12 months
1-5 years
5-13 years
> 13 years
Figure 1 Liver transplant patient and graft survival: Cincinnati Children’s Hospital Medical Center Experience. (Color version of figure is available online.)
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progressive increase in the incidence of PTLD with: (1) an increase in total immunosuppression load; (2) EBV naive recipients; and (3) the intensity of active viral load.61,62 No single immunosuppressive agent has been directly related to PTLD. The second pathogenic feature encouraging PTLD appears to be EBV infection. Treatment of PTLD is stratified according to the immunologic cell typing and clinical presentation.63 Documented PTLD requires an immediate decrease or discontinuation of immunosuppression and institution of anti-EBV therapy. Patients with polyclonal Bcell proliferation frequently show regression with this treatment.64,65 If tumor cells express B cell surface marker CD20 at histology, then the anti-CD20 monoclonal antibody rituximab (Genentech, Biogen-IDEC) has been used with increasing success. When given alone, its response rate was 46%, and it has a 54% relapse/progression rate. The combination of cyclophosphamide/prednisone yielded a response rate exceeding 80%, but 2-year event-free survival was only 58%. Recently, chemoimmunotherapy using cyclophosphamide, prednisone, and rituximab has shown response rate of 100%, with minimal toxicity. Further use of this combination will clarify it’s future role.66,67 Patients with aggressive monoclonal malignancies have poor survival even with immunosuppressive reduction, acyclovir, and conventional chemotherapy or radiation therapy.
Outcome Although the potential complications following liver transplantation are frequent and occasionally severe, the overall results are rewarding. Overall 1-year patient and graft survival has reached 88%/82% in the SPLIT registry,68 92%/ 84% in our own center (Figure 1). The highest risk of mortality occurs in all groups during the first year, with the majority of this risk within the first 3 months following transplantation. Long-term survival beyond 1 year is excellent, 83%/74% in SPLIT (4 years), and is similar in all ages, and for all diagnostic groups. Survival has improved dramatically in infants and small children over the past years. Infants ⬍1 year of age or ⬍10 kg have reported survival of 65% to 88% overall, an improvement over previously reported rates of 50% to 60%.69 Improved survival in these small recipients is consistent throughout all levels of medical urgency and results from both technical innovations in graft preparation, and avoidance of life and graft threatening complications such as HAT and PNF. Donor factors associated with decreased patient and graft survival include donor age ⬍6 months or ⬎50 years. In the combined SPLIT registry, whole organ recipients had better patient and graft survival than any surgically reduced/split/LD recipients.70 These results may be influenced by the diverse nature of the experience accumulated in these registries. When whole organ, living donor, and split liver recipients were directly compared in experienced centers, there was no difference in patient or graft survival, biliary or vascular complica-
225 tions.32,71-73 These combined results suggest that best results will be achieved at centers with extensive experience with all age groups and allograft types, allowing transplantation to be tailored to the needs of the recipient and family, rather then identifying specific graft types for patient subgroups.
References 1. Kasai M, Mochizuki I, Ohkohchi N, et al. Surgical limitation for biliary atresia: indication for liver transplantation. J Pediatr Surg 1989; 24:851-4. 2. Ryckman F, Fisher R, Pedersen S, et al. Improved survival in biliary atresia patients in the present era of liver transplantation. J Pediatr Surg 1993;28:382-6. 3. Nio M, Ohi R, Hayashi Y, et al. Current status of 21 patients who have survived more than 20 years since undergoing surgery for biliary atresia. J Pediatr Surg 1996;31:381-4. 4. Altman RP, Lilly JR, Greenfeld J, et al. A multivariable risk factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia: twenty-five years of experience from two centers. Ann Surg 1997;226: 348-53;discussion 353-5. 5. Otte JB, de Ville de Goyet J, Reding R, et al. Sequential treatment of biliary atresia with Kasai portoenterostomy and liver transplantation: a review. Hepatology 1994;20:41S-8S. 6. Cardona J, Houssin D, Gauthier F, et al. Liver transplantation in children with Alagille syndrome–a study of twelve cases. Transplantation 1995;60:339-42. 7. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, et al. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995;127:220-4. 8. Tzakis AG, Reyes J, Tepetes K, et al. Liver transplantation for Alagille’s syndrome. Arch Surg 1993;128:337-9. 9. Ryckman FC, Alonso MH. Transplantation for hepatic malignancy in children. In: Busuttil RW, Klintmalm G, eds. Transplanatation of the Liver.Philadelphia, PA: WB Sanders, 1996;216-26. 10. McBride KL, Miller G, Carter S, et al. Developmental outcomes with early orthotopic liver transplantation for infants with neonatalonset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics 2004;114:e523-6. 11. Morioka D, Kasahara M, Takada Y, et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transplant 2005;11:1332-42. 12. Flynn DM, Mohan N, McKiernan P, et al. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed 2003;88:F124-7. 13. Rodrigues F, Kallas M, Nash R, et al. Neonatal hemochromatosis medical treatment vs. Transplantation: the king’s experience. Liver Transplant 2005;11:1417-24. 14. McClean P, Davison SM. Neonatal liver failure. Semin Neonatol 2003;8:393-401. 15. Dhawan A, Cheeseman P, Mieli-Vergani G. Approaches to acute liver failure in children. Pediatr Transplant 2004;8:584-8. 16. Kondrup J, Almdal T, Vilstrup H, Tygstrup N. High volume plasma exchange in fulminant hepatic failure. Int J Artif Organs 1992;15:66976. 17. Singer AL, Olthoff KM, Kim H, et al. Role of plasmapheresis in the management of acute hepatic failure in children. Ann Surg 2001;234: 418-24. 18. Pimpalwar AP, Sharif K, Ramani P, et al. Strategy for hepatoblastoma management: Transplant versus nontransplant surgery. J Pediatr Surg 2002;37:240-5. 19. Srinivasan P, McCall J, Pritchard J, et al. Orthotopic liver transplantation for unresectable hepatoblastoma. Transplantation 2002;74:652-5.
226 20. Molmenti EP, Nagata D, Roden J, et al. Liver transplantation for hepatoblastoma in the pediatric population. Transplant Proc 2001;33: 1749. 21. Tiao GM, Bobey N, Allen S, et al. The current management of hepatoblastoma: a combination of chemotherapy, conventional resection, and liver transplantation. J Pediatr 2005;146:204-11. 22. Penn I. Hepatic transplantation for primary and metastatic cancers of the liver. Surgery 1991;110:726-34; discussion 734-35. 23. Tagge EP, Tagge DU, Reyes J, et al. Resection, including transplantation, for hepatoblastoma and hepatocellular carcinoma: impact on survival. J Pediatr Surg 1992;27:292-6; discussion 297. 24. Freeman RB Jr, Edwards EB. Liver transplant waiting time does not correlate with waiting list mortality: implications for liver allocation policy. Liver Transplant 2000;6:543-52. 25. Organ Procurement and Transplantation Network–HRSA. Final rule with comment period. Fed Regist 1998;63:16296-338. 26. McDiarmid SV, Merion RM, Dykstra DM, Harper AM. Selection of pediatric candidates under the PELD system. Liver Transplant 2004; 10(10):S23-30 (suppl 2). 27. Bourdeaux C, Tri TT, Gras J, et al. PELD score and posttransplant outcome in pediatric liver transplantation: a retrospective study of 100 recipients. Transplantation 2005;79:1273-6. 28. Freeman RB Jr, Wiesner RH, Roberts JP, et al. Improving liver allocation: MELD and PELD. Am J Transplant 2004;4:114-31, 2004 (suppl 9). 29. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology 1995; 21:1317-21. 30. Ozawa K. Living Related Donor Liver Transplantation. Basel: Kargers, 1994:58-60. 31. Higashiyama H, Yamaguchi T, Mori K, et al. Graft size assessment by preoperative computed tomography in living related partial liver transplantation. Br J Surg 1993;80:489-92. 32. Yersiz H, Renz JF, Farmer DG, et al. One hundred in situ split-liver transplantations: a single-center experience. Ann Surg 2003;238:496505; discussion 506-7. 33. Morimoto T, Ichimiya M, Tanaka A, et al. Guidelines for donor selection and an overview of the donor operation in living related liver transplantation. Transplant Int 1996;9:208-13. 34. McDiarmid SV, Davies DB, Edwards EB. Improved graft survival of pediatric liver recipients transplanted with pediatric-aged liver donors. Transplantation 2000;70:1283-91. 35. Emre S, Soejima Y, Altaca G, et al. Safety and risk of using pediatric donor livers in adult liver transplantation. Liver Transplant 2001;7: 41-7. 36. Yasutomi M, Harmsmen S, Innocenti F, et al. Outcome of the use of pediatric donor livers in adult recipients. Liver Transplant 2001;7:3840. 37. Broelsch CE, Emond JC, Whitington PF, et al. Application of reducedsize liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg 1990;212:368-75; discussion 375-7. 38. Ryckman FC, Flake AW, Fisher RA, et al. Segmental orthotopic hepatic transplantation as a means to improve patient survival and diminish waiting-list mortality. J Pediatr Surg 1991;26:422-7; discussion 427-8. 39. Renz JF, Yersiz H, Reichert PR, et al. Split-liver transplantation: a review. Am J Transplant 2003;3:1323-35. 40. Ryckman FC, Fisher RA, Pedersen SH, Balistreri WF. Liver transplantation in children. Semin Pediatr Surg 1992;1:162-72. 41. Otte JB, de Ville de Goyet J, Sokal E, et al. Size reduction of the donor liver is a safe way to alleviate the shortage of size-matched organs in pediatric liver transplantation. Ann Surg 1990;211:146-57. 42. Inomoto T, Nishizawa F, Sasaki H, et al. Experiences of 120 microsurgical reconstructions of hepatic artery in living related liver transplantation. Surgery 1996;119:20-6. 43. Burdelski MM, Rogiers X. What lessons have we learned in pediatric liver transplantation? J Hepatol 2005;42:28-33.
Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 44. Reding R, Webber SA, Fine R. Getting rid of steroids in pediatric solid-organ transplantation? Pediatr Transplant 2004;8:526-30. 45. Langnas AN, Marujo W, Stratta RJ, et al. Hepatic allograft rescue following arterial thrombosis. Role of urgent revascularization. Transplantation 1991;51:86-90. 46. Ueda M, Egawa H, Ogawa K, et al. Portal vein complications in the long-term course after pediatric living donor liver transplantation. Transplant Proc 2005;37:1138-40. 47. Heffron TG, Emond JC, Whitington PF, et al. Biliary complications in pediatric liver transplantation. A comparison of reduced-size and whole grafts. Transplantation 1992;53:391-5. 48. Peclet MH, Ryckman FC, Pedersen SH, et al. The spectrum of bile duct complications in pediatric liver transplantation. J Pediatr Surg 1994;29:214-9; discussion 219-20. 49. Snover DC, Sibley RK, Freese DK, et al. Orthotopic liver transplantation: a pathological study of 63 serial liver biopsies from 17 patients with special reference to the diagnostic features and natural history of rejection. Hepatology 1984;4:1212-22. 50. Mor E, Solomon H, Gibbs JF, et al. Acute cellular rejection following liver transplantation: clinical pathologic features and effect on outcome. Semin Liver Dis 1992;12:28-40. 51. Adams DH, Neuberger JM. Treatment of acute rejection. Semin Liver Dis 1992;12:80-8. 52. Ryckman FC, Schroeder T, Pedersen S. Use of monoclonal antibody immunosuppressive therapy in pediatric renal and liver transplantation. Clin Transplant 1991;5:186-90. 53. Freese DK, Snover DC, Sharp HL, et al. Chronic rejection after liver transplantation: a study of clinical, histopathological and immunological features. Hepatology 1991;13:882-91. 54. Ludwig J, Wiesner RH, Batts KP, et al. The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation. Hepatology 1987;7:476-83. 55. Wiesner RH, Hermans PE, Rakela J, et al. Selective bowel decontamination to decrease gram-negative aerobic bacterial and Candida colonization and prevent infection after orthotopic liver transplantation. Transplantation 1988;45:570-4. 56. Singh N, Carrigan DR, Gayowski T, Marino IR. Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity. Transplantation 1997;64:674-8. 57. Patel R, Snydman DR, Rubin RH, et al. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation 1996;61:1279-89. 58. Fox AS, Tolpin MD, Baker AL, et al. Seropositivity in liver transplant recipients as a predictor of cytomegalovirus disease. J Infect Dis 1988;157:383-5. 59. Darenkov IA, Marcarelli MA, Basadonna GP, et al. Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy. Transplantation 1997;64: 848-52. 60. Smets F, Sokal EM. Lymphoproliferation in children after liver transplantation. J Pediatr Gastroenterol Nutr 2002;34:499-505. 61. Guthery SL, Heubi JE, Bucuvalas JC, et al. Determination of risk factors for Epstein-Barr virus-associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment. Transplantation 2003;75:987-93. 62. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101-13. 63. Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL. Epstein-Barr virus, immunodeficiency, and B cell lymphoproliferation. Transplantation 1985;39:461-72. 64. Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant 2002;6:456-64. 65. Holmes RD, Orban-Eller K, Karrer FR, et al. Response of elevated Epstein-Barr virus DNA levels to therapeutic changes in pediatric liver transplant patients: 56-month follow up and outcome. Transplantation 2002;74:367-72. 66. Orjuela M, Gross TG, Cheung YK, et al. A pilot study of chemoimmunotherapy (cyclophosphamide, prednisone, and rituximab) in pa-
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68. 69. 70.
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tients with post-transplant lymphoproliferative disorder following solid organ transplantation. Clin Cancer Res 2003;9:39450S-39452S. Gross TG. Low-dose chemotherapy for children with post-transplant lymphoproliferative disease. Recent Results Cancer Res 2002;159:96103. Studies of Pediatric Liver Transplantation (SPLIT). Annual Report. 2004;6:1-6.27. Sokal EM, Veyckemans F, de Ville de Goyet J, et al. Liver transplantation in children less than 1 year of age. J Pediatr 1990;117:205-10. Lozanov J, Millis JM, Anand R, Group TSR. Surgical outcomes in
227 primary pediatric liver transplantation:SPLIT database report - Abstract #1453. American Transplant Congress. Seattle, WA. 2005 (abstr). 71. Deshpande RR, Bowles MJ, Vilca-Melendez H, et al. Results of split liver transplantation in children. Ann Surg 2002;236:248-53. 72. Kim JS, Broering DC, Tustas RY, et al. Split liver transplantation: past, present and future. Pediatr Transplant 2004;8:644-8. 73. Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a singlecenter experience. Ann Surg 2005;241:905-18.
Pediatric liver transplantation Gregory M. Tiao, MD, Maria H. Alonso, MD, Frederick C. Ryckman, MD From the Department of Pediatric Surgery, Pediatric Liver Care Center, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio. INDEX WORDS Pediatric liver transplantation; Biliary atresia; Fulminant liver failure; Hepatoblastoma; Chronic immunosuppression; Tyrosinemia
Liver transplantation has become the accepted standard of care in the treatment of a child with a failing liver. Advances in the management of critical care and immunosuppression along with the development of innovative operative procedures have improved outcome such that 5-year survival rates of 80% to 90% are expected following liver transplantation. Organ allocation schemes have evolved in an effort to better stratify recipient risk thereby more appropriately distributing deceased donor grafts. A persistent shortage of appropriate donors continues to contribute to patient mortality. The consequences of long-term immunosuppression have become increasingly apparent such that health care providers need to be aware of the side effects of chronic immunosuppression. New strategies need to be defined to minimize the need of continuous immunosuppression. The continued success of pediatric liver transplantation will require multi-disciplinary health care teams comprised of general pediatricians, pediatric hepatologists, transplant surgeons, and transplant coordinators who focus on the complex needs of the transplant recipient. © 2006 Elsevier Inc. All rights reserved.
The outcome of children who have end-stage liver disease has improved markedly over the last 20 years. Liver transplantation (LTx) has evolved from a heroic experimental effort to the standard treatment for a child who faces the complex clinical problem of a failing liver. The marked improvement in outcomes has occurred because of advances in pediatric critical care, the management of immunosuppression, and the development of innovative operative procedures. The success of liver transplantation has bred unique problems that must be met in the future. The potential benefits of expanding indications for liver transplantation have been limited by a persistent lack of appropriate donors. The increasing number of long-term survivors after transplantation present unique challenges related to lifelong immunosuppression. The continued success of pediatric liver transplantation will require a national focus on donor Address reprint requests and correspondence: Gregory M. Tiao, MD, Department of Pediatric Surgery, Pediatric Liver Care Center, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: [email protected].
1055-8586/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2006.03.008
organ shortages and recognition of the complex needs of this population of patients.
Indications The most common clinical presentations prompting transplant evaluation in children can be classified as follows: (1) progressive primary liver disease, (2) hepatic based metabolic disease, (3) fulminant hepatic failure, and (4) unresectable primary liver tumors. Table 1 lists the indications for children who have undergone liver transplantation at Cincinnati Children’s Hospital and Medical Center over the last 15 years.
Primary liver disease The most common primary liver disease that manifests in childhood and causes end-stage liver disease (ESLD) is biliary atresia. Children with biliary atresia (BA) comprise at least 50% of the pediatric liver transplant population.
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219
Table 1 Indications for liver transplantation at Cincinnati Children’s Hospital and Medical Center (CCHMC)* Cholestatic liver disease Biliary atresia Alagille syndrome Familial cholestasis Primary sclerosing cholangitis Idiopathic Metabolic disease Alpha-1 antitrypsin defeciency Tyrosinemia Urea cycle defect Glycogen storage disease Wilson’s disease 1o hyperoxaluria Cystic fibrosis Fulminant liver failure CIRRHOSIS/HEPATITIS Cryptogenic cirrhosis Autoimmune Neonatal hepatitis Hepatitis C Congenital hepatic fibrosis Tumor Hepatoblastoma Hepatocellular carcinoma Sarcoma Other Hemangioendothelioma Hemachromatosis Budd-Chiari TPN related Short gut syndrome (L/SI) NEC (L/SI) Megacystis/microcolon
149 129 8 1 7 4 49 26 7 7 4 2 2 1 44 27 14 7 4 1 1 11 9 1 1 12 2 2 1 3 2 1 1
51%
Other primary liver diseases that are causes of ESLD in childhood include Alagille’s syndrome, sclerosing cholangitis, and the Progressive Familiar Intra-hepatic Cholestasis (PFIC) syndromes. The degree of liver injury varies such that only some affected patients develop end-stage liver disease and require LTx in childhood.6-8 Hepatitis C, the most common adult indication for LTx, is rare at present in children.
17%
Hepatic-based metabolic disease
15% 9%
4%
4%
*n ⫽ 292 primary liver transplants.
Urea cycle defects (UCD), alpha-one antitrypsin (␣1aT) deficiency, and tyrosinemia are several examples of hepaticbased metabolic diseases that manifest in the pediatric population. In patients with UCD and tyrosinemia, LTx is not only lifesaving but it also accomplishes a cure of the underlying disease. Hepatic replacement should be considered before the consequences of the defect results in complications that may prove to be contraindications for transplantation. For example, patients with UCD who have repetitive hyperammonemic crisis sustain significant neurologic injury with resulting mental retardation. Early transplantation eliminates episodes of hyperammonemic crisis preserving neurologic function.9,10 The use of living donors or carriers of UCD has been successful and allows planned early transplantation.11 Patients with tyrosinemia develop hyperplastic nodules which have a high risk of evolving into a hepatocellular carcinoma (HCC). They required LTx before extrahepatic spread of the tumor occurred. Recently, intervention with NTBC has been successful in preventing dysplasia, and may avoid the need for LTx when treatment is begun in early infancy.
Fulminant hepatic failure (FHF) Kasai portoenterostomy should be the primary surgical intervention for all infants with BA. In patients who present in late infancy (⬎120 days of age) and whose liver biopsy shows advanced cirrhosis, primary LTx is indicated1,2 In children who fail to achieve adequate biliary drainage following a Kasai, cirrhosis with manifestations of ESLD such as ascites, progressive portal hypertension, malnutrition, and/or progressive hepatic synthetic failure will become apparent. Approximately 40% to 50% of infants who undergo Kasai will suffer these complications and require LTx within the first 2 years of life. Some children have successful establishment of biliary drainage with normal postoperative serum bilirubin levels but still develop progressive cirrhosis and manifestations of ESLD. These children typically do not require LTx until late childhood. Another subset of children with stable synthetic liver function will develop hepatopulmonary syndrome that will dictate the need for LTx. Currently, it is estimated that only 15% to 20% of all BA patients who undergo the Kasai procedure will survive without LTx.3,4 The sequential use of the Kasai procedure followed by LTx is still indicated as it optimizes overall survival and organ utilization.2,5
Patients who develop FHF without recognized antecedent liver disease present diagnostic and prognostic difficulties. Rapid clinical deterioration frequently makes establishment of a primary diagnosis impossible before the need for urgent transplantation. The most common cause of fulminant liver failure is viral hepatitis of undefined type, followed by drug toxicity, toxin exposure, and previously unrecognized metabolic disease. There are several causes of fulminant liver disease that are unique to pediatrics. One of these, neonatal hemachromatosis, presents a particularly difficult challenge. Affected infants present in the neonatal period with fulminant hepatic failure. The use of antoxidant cocktails has improved some patients, but a failure to respond within 48 to 72 hours mandates transplantation.12 Liver transplantation is life-saving, but success rates of ⬃50% are reported.13 Recently, we have treated several children with hemophagocytic lymphohistiocytosis (HLH)-induced fulminant liver failure. In children who have HLH, inappropriate activation of macrophages and natural killer cells causes severe hepatocyte injury. The role of liver transplantation in the treatment of patients with HLH has not been clearly
220 established, as recurrence in the graft has been shown to occur.14 The primary treatment is hematologic, rather then organ replacement. Mitochondrial respiratory chain abnormalities representing disorders in the electron transport proteins present both as FHF or progressive liver disease with sudden decompensation.14 These disorders are especially important to recognize during the evaluation process, as they represent multi-organ progressive diseases; transplantation is not curative, nor indicated. Selection of FHF candidates for transplantation is difficult, as the natural history of each disease is not clearly established. The King’s College Institute of Liver Studies has developed a scoring system for children with FHF, stratifying their risk.15 Predictive factors included INR, bilirubin ⬎235 æmoles/L, age ⬍2 years, and WBC ⬎ 9000/ mm3. Although these criteria are helpful, careful observation for progression and clinical change is essential. For short-term stabilization, we have utilized repetitive courses of plasmapheresis to ameliorate the clinical manifestations of fulminant liver failure. Neurologic improvement is common but not sustained, and no suggestion of enhanced native liver recovery has occurred; ultimately, transplantation is the only effective treatment modality.16,17
Malignancy Hepatoblastoma and hepatocellular carcinoma (HCC) are the two most common primary hepatic malignancies found in children. Recent experience has documented the efficacy of liver transplantation in a subset of patients who have a hepatoblastoma, and have established transplantation as an integral part of the treatment strategy of these children.18-23 In children who present with a hepatoblastoma, complete surgical resection of the primary liver lesion remains the most crucial intervention required to achieve long-term survival. Adjuvant chemotherapy and conventional resection should be employed where feasible; however, some children have lesions that remain un-resectable after chemotherapy. In these children, liver transplantation is the only option that can achieve complete resection.18-23 Unlike the adult population, the frequency of HCC in the pediatric population is low; therefore, the experience in the application of liver transplantation in the pediatric population for HCC is limited.19,23-25 In patients whose disease is confined to the liver, the use of liver transplantation is indicated. Because chemotherapy is not beneficial at present in this group, results in patients with more extensive disease are poor.
Contraindications Contraindications to transplantation include: (1) primary extra-hepatic unresectable malignancy, (2) progressive terminal nonhepatic disease, (3) uncontrolled systemic sepsis, and (4) irreversible neurologic injury. Relative contraindi-
Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 cations to transplantation, which need to be individually evaluated, include: (1) HIV positive serology, (2) advanced or partially treated systemic infection, (3) advanced hepatic encephalopathy-Grade IV, (4) severe psychosocial abnormalities, and (4) malignancy metastatic to the liver.
Preoperative preparation Efforts to correct abnormalities noted during candidate evaluation will decrease both the operative risk and postoperative complications. In children, optimizing the nutritional status of the recipient is vital; the use of calorie enhanced formula and the placement of nasogastric feeding tubes is often necessary in small children. Assessment of prior viral exposure, and meticulous attention to the delivery of all normal, well-child immunizations, particularly the live-virus vaccines, is imperative if time allows before LTx.
Organ allocation In the early 1980s, the Organ Procurement and Transplantation Network (OPTN) was established by the US Government to develop a system to distribute organs in an equitable fashion. Organ allocation was based primarily on severity of illness, as indicated by patient location (home, hospital, ICU) and time accrued waiting on the pretransplant list. It was shown that waiting time had no relationship to death, except for Status 1 patients, leading to dissatisfaction with the existing system.24 In response to this the HRSA established the “Final Rule” in 1998, requiring allocation policies to be based on sound medical judgment using defined criteria to achieve the best use of donated organs.25 Using knowledge gained from the Mayo End-stage Liver Disease model, the MELD (Model for End-stage Liver Disease) was established for adults. Based on similar information derived from the Studies of Pediatric Liver Transplantation (SPLIT), a pediatric-specific score (PELD) was established using bilirubin, INR, serum albumin, age ⬍1 year, and growth failure. The preferential policy to direct pediatric organs (⬍18-year-old donor) to pediatric recipients was maintained, and Status 1 priority was maintained for children with chronic or acute liver disease. Additional PELD points could be obtained for specific risk factors not identified in the PELD equation, such as hepatopulmonary syndrome, urea cycle defects, and hepatic neoplasms. Although the PELD system improved numerical quantification of candidates, and removed waiting time from the scoring equation, the PELD score has not proven to be a successful predictor of 30 day or long-term outcome following transplantation.26,27 Concerns that identification and transplantation of “sicker patients first” would lead to decreased survival have not proven correct.27 In a review of the first year of PELD, graft and patient survival remained unchanged from the prior allocation system.28 Although the PELD
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system was designed to better quantify risk, there is a perceived failure of the PELD system in its current form. The majority of infants and children allocated organs have achieved a PELD score sufficient for transplantation through special exception points, or Status 1. Further modeling and analysis will allow this system to be modified to reflect identified predictive factors and continually improve access and equity to all potential recipients.
Graft options The limited availability of pediatric donor organs and high waiting list mortality stimulated the development of innovative surgical procedures to increase donor options for children. Whole organ transplantation remains the ideal option; however, many children undergo reduced-size transplantation (RSLTx), where a whole organ from an adult donor is surgically reduced ex vivo such that only the left lobe or left lateral segment is transplanted. Although operative reduction of a larger sized donor liver expanded the number of donor organs available to small recipients it merely shifted donor resources rather than increasing donor availability. The success of the operative techniques perfected doing reduced-size transplantation allowed the development of both split-liver transplantation (SLTx), where a single liver is used to transplant two recipients, and livingdonor transplantation (LD). The selection of a donor organ or segment with appropriate parenchymal mass for adequate function is critical to success. Unfortunately, the minimal hepatic mass necessary for recovery is not clearly established. Any calculation must take into account the temporary loss of function due to the donor’s injury or treatment, as well as the possibility of preservation damage, early acute rejection, or technical problems. The normal liver volume in a child can be calculated using the following formula: Estimated Liver Volume ⫽ 706.2 ⫻ BSA (m2) ⫹ 2.4.29 When selecting donor segments, transplantation of ⱖ40% to 50% of this ideal calculated volume is recommended.30,31 Estimates of donor graft to recipient body weight ratio (GRWR) may prove to be the most accurate predictor of adequate graft volume. A minimum graft fraction of 1% recipient body mass meets this need.32 A GRWR of 1% to 3% is optimum. In cases where the GRWR ⬍0.7%, overall allograft and patient survival suffered due in part to excessive portal flow that leads to hemorrhagic necrosis of the graft. Large for size allografts (GRWR ⬎ 5.0%) have a better outcome compared with small allografts.31,33 The success of liver transplantation is related to the stability and quality of the donor. Assessment of donor organ suitability is primarily undertaken by evaluating clinical information and static biochemical tests. Clinical factors of concern include donors who are at the limits of age, have had prolonged intensive care hospitalization with potential sepsis, and have vasomotor instability requiring ex-
221 cessive inotropic agents. Severe electrolyte disturbances identify increased risk. Although nonideal (extended criteria) donor organs can be used as whole allografts, especially when ischemic time is limited, they are high risk when used as donors for reduced-size or split liver allografts. Donor liver biopsy at the time of organ harvest, or during evaluation, is helpful in questionable cases to identify preexisting liver disease or donor liver steatosis. Donor age can affect the long-term results of pediatric liver transplantation; however, the spectrum of influence is not completely clear. When the UNOS database was used with the UNOS Liver Allocation Model, Kaplan-Meier graft survivals showed that pediatric patients receiving livers from pediatric aged donors had an 81% 3-year graft survival compared with 63% if children received livers from donors ⱖ18 years. In contrast, adult recipients had similar 3-year graft survivals irrespective of donor age. In the multivariate analysis, the odds of graft failure were reduced to 0.66 if pediatric recipients received livers from pediatric aged donors. The odds of graft failure were not affected at any time point for adults whether they received an adult or pediatric-aged donor.34 If a deceased donor liver is used, these data strongly support the use of pediatric donors. The primary distribution of pediatric donor livers to pediatric recipients is further supported by evaluating adult experience with pediatric donor organs. In the Mount Sinai Hospital adult series, adult (⬎18 year age) recipients of pediatric donor organs had an increased risk of hepatic artery thrombosis (HAT) and poor function compared with recipients of adult donors, an effect that corelated with increasing donor:recipient size discrepancy.35 This was confirmed in the Mayo Clinic series, where the 1-year graft survival rate in adult transplant recipients receiving donors from donor ⬍12 years of age was 64.3% compared with 87.5% when the donor was 12 to 18 years of age (P ⫽ 0.015).36 The main cause of graft loss was again vascular complications. Because the outcome of small pediatric donor livers in adult recipients is poor, and small pediatric donors are the only source of lifesaving organs for the infant recipient, the use of small pediatric donor livers in adults should be avoided.
Donor procurement Whole organ procurement is now a well described procedure. The principles of minimum mobilization to define vascular structures, in situ perfusion with 4øC preservation solution, and sequential en bloc harvest of organs yield good allograft preservation. When reduction hepatectomy is needed for reduced-size grafts, this is accomplished following en bloc procurement. The operative techniques for this reduction are well described.37,38 “Split liver” grafting involves the preparation of two allografts from a single donor.32,39 In most cases, the extended right lobe allograft (segments 4-8) is used in an adult or large child, while the left lateral segment allograft (seg-
222 ments 2,3) is transplanted into a small recipient. Conventional techniques for implanting the respective allografts are used. The use of in situ division of the left lateral segment (LLS), as during living donor liver procurement, is our preferred method for split-liver donor preparation at the present time, although comparable results using ex vivo division have also been achieved.39
Liver transplantation The technical details of these pediatric liver transplant procedures are well described.40,41 The most underestimated portion of this complex operative procedure entails the removal of the native liver. Multiple prior operations or revisions for biliary atresia, or multiple episodes of spontaneous bacterial peritonitis, lead to extensive vascularized adhesions. These increase the risk of intestinal perforation and bleeding at transplantation. Optimal arterial inflow is essential for donor liver recovery. When the native hepatic artery is ⬍4 to 5 mm in diameter, we prefer to directly implant the celiac axis of the donor liver into the infrarenal aorta. When adequate length is lacking, a donor iliac arterial vascular interposition graft is used to accomplish this anastomosis. Access to the infrarenal aorta is provided by mobilizing the right colon and duodenum. A large experience has also indicated that microvascular reconstructive techniques for the hepatic artery are a very successful.42 Allograft venous outflow must be unimpeded. This is especially important in “piggyback” implantation to the native IVC in small children, where a confluence of all three hepatic venous orifices is our preference to achieve wide and effective outflow. Impaired outflow leads to allograft swelling, increased vascular resistance, and subsequent inflow thrombosis. Immediate postoperative and daily Doppler ultrasound will assist in recognizing correctable blood flow abnormalities before graft compromise. Bile duct reconstruction as an end-to-side choledochojejunostomy into an isoperistaltic Roux-en-Y jejunal limb is our preference in young recipients. Older children without primary biliary pathology can undergo direct stent-free choledochal reconstruction. When closing the abdomen, increased intraabdominal pressure should be avoided. In many cases, avoidance of fascial closure and the use of mobilized skin flaps and running monofilament skin closure, is advisable. Musculofascial abdominal wall closure can be completed approximately 1 week posttransplant.
Immunosuppression A complete discussion on the management of immunosuppression can be found elsewhere in this series. Currently, most liver transplant centers use an immunosuppressive protocol based on the administration of multiple complementary medications. The calcineurin inhibitor tacrolimus has become the mainstay of most of these regimens. Corticosteroids are a well established component of many regi-
Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 mens; however, recently, there has been significant interest in steroid minimization protocols. The antimetabolites mycophenolate mofetil and on occasion azathioprine are also used by in many protocols. Induction with antilymphocyte antibodies such as OKT3 or Thymoglobulin can be considered in conditions where calcineurin inhibitor toxicity precludes their early use. One of the most significant developments in field of transplantation has been the recognition of the consequences of long-term immunosuppression. Calcineurin inhibitors cause chronic renal insufficiency, diabetes mellitus, arterial hypertension, and atherosclerosis/coronary artery disease; as a result, many centers are developing protocols designed to avoid prolonged exposure to decrease future complications.43,44
Complications Vascular thrombosis is the most common cause of early postoperative allograft loss. Hepatic artery thrombosis occurs in 1% to 2% of children who undergo LTx. The overall incidence of vascular thrombosis is similar in whole, SLTx, and LD transplants in experienced centers.32,39 A variable clinical picture may be seen including: (1) fulminant allograft failure, (2) biliary disruption or obstruction, or (3) systemic sepsis. When identified early, successful thrombectomy and allograft salvage is possible if reconstruction is undertaken before allograft necrosis.45 Acute HAT with allograft failure requires immediate transplantation. Biliary complications are particularly common following HAT and may be temporized by percutaneous drainage and biliary stenting to control bile leakage and infection until re-transplantation is undertaken. Portal vein thrombosis occurs in 5% to 10% of recipients. In infant recipients with biliary atresia, preexisting portal vein hypoplasia often requires replacement of the entire portal vein to the SMV/Splenic Vein confluence with donor portal vein to avoid low flow related thrombosis. In LD allografts, size mismatch between donor and recipient and short venous pedicles may require grafting with donor gonadal or inferior mesenteric vein segments.46 Preexisting portal vein thrombosis in the recipient can be overcome by thrombectomy or portal vein replacement or extra-anatomic venous bypass using donor portal/iliac vein. Early thrombosis following transplantation, detected by Doppler screening, requires immediate anastomotic revision and thrombectomy. Later thrombosis is detected by decreased platelet counts and increasing spleen size or gastrointestinal bleeding. Interventional radiographic stent placement or balloon dilation has been successful in patients with portal anastomotic stenosis, but is less successful when occlusion has occurred.46 Portal venous shunting may be needed in selected patients with progressive portal hypertensive complications. Primary nonfunction (PNF) of the hepatic allograft implies the impairment of metabolic and synthetic activity
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following transplantation. Complete nonfunction requires immediate re-transplantation. Lesser degrees of allograft dysfunction occur more frequently but may be reversible. Biliary complications have been referred to as the “Achilles Heel” of liver transplantation, occurring in about 10% of pediatric whole organ liver transplant recipients. Their spectrum and treatment is determined by the status of the hepatic artery and the type of allograft used. Although whole and surgically reduced allografts (RSLTx, SLTx, and LD) as a group have an equivalent risk of biliary complications, the spectrum of complications differs.32,47,48 Late complications following any type of primary duct-to-duct biliary reconstruction include anastomotic stricture, biliary sludge formation, and recurrent cholangitis. Endoscopic dilation and internal stenting of anastomotic strictures or minimal biliary leaks has been successful in early postoperative cases. With recurrent stenosis or persistent postoperative leak, Roux-en-Y choledochojejunostomy is the preferred treatment. This is also the reconstruction method of choice in small children and in all patients with biliary atresia. The complexity of the biliary reconstruction is increased in both SLTx and LD allograft, which often require the anastomosis of two individual segmental bile ducts. The presence of multiple bile ducts in surgically reduced allografts has a documented increased risk for biliary leak following reimplantation. Parenchymal bile leaks and anastomotic leaks were slightly more common in SLTx, whereas anastomotic strictures are more common in LD.32 These complications seem most related to graft type rather then patient illness (UNOS Status). This increased complexity and risk of complications is the known trade-off for increased organ availability. Acute rejection is characterized by the histologic triad of endothelialitis, portal triad lymphocyte infiltration with bile duct injury, and hepatic parenchymal cell damage.49 Acute rejection occurs in approximately two-thirds of patients following LTx using tacrolimus or cyclosporine based immunotherapy.50 Allograft biopsy is essential to establish the diagnosis of acute rejection before treatment. The primary treatment of rejection is a short course of high dose steroids. Bolus doses administered over a several day period with a rapid taper to baseline therapy is successful in 75% to 80% of cases.51 When refractory or recurrent rejection occurs, antilymphocyte therapy using the monoclonal antibody OKT-3 is successful in 90% of cases.52 Chronic rejection occurs in 5% to 10% of transplanted patients. The primary clinical manifestation is a progressive rise in alkaline phosphatase, gamma glutamyl transpeptidase and progressive cholestasis. This course can be initially asymptomatic. Chronic rejection can follow one of the two clinical forms.53 In the first, the injury is primarily to the biliary epithelium; the clinical course is characterized as “acute vanishing bile duct syndrome” where severe ductopenia is seen in at least 20 portal tracts.54 Spontaneous resolution in nearly half of affected patients when they were administered tacrolimus therapy has led to the development
223 of enhanced immunosuppression protocols for this patient subgroup. Retransplantation is occasionally necessary but rarely emergent. The second subtype is characterized by the early development of progressive ischemic injury to both bile ducts and hepatocytes leading to ductopenia and ischemic necrosis with fibrosis. The clinical course is relentlessly progressive and nearly always requires retransplantation. Recurrence of chronic rejection in the retransplanted allograft is a common event.53 Infectious complications now represent the most common source of morbidity and mortality following transplantation. A complete discussion of this topic can also be found elsewhere in this series. Bacterial infections occur in the immediate post transplant period and are most often caused by Gram-negative enteric organisms, Enterococcus, or Staphylococcus species. Antibacterial prophylactixis is discontinued as soon as possible to prevent the development of resistant organisms. Fungal sepsis represents a significant potential problem in the early posttransplant period. Aggressive protocols for pretransplant prophylaxis are based on the concept that fungal infections originate from organisms colonizing the GI tract of the recipient. Selective preoperative bowel decontamination was successful in eliminating pathogenic Gram-negative bacteria from the GI tract in 87% of adult patients; in all cases, Candida was eliminated.55 However, these protocols have not been practical in pediatric patients because there is a long waiting time for pediatric organs and the taste of the antibiotics used is poorly accepted. All patients undergoing LTx receive antifungal prophylaxis with fluconazole at our center. The majority of early and severe viral infections are caused by viruses of the Herpes family, including EpsteinBarr Virus (EBV), Cytomegalovirus (CMV), and Herpes Simplex Virus (HSV).56 The likelihood of developing either CMV or EBV infection is influenced by the preoperative serologic status of the transplant donor and recipient.57,58 Seronegative recipients receiving seropositive donor organs are at greatest risk. Use of various immune-based prophylactic protocols including IV IgG, hyperimmune anti-CMV IgG, coupled with acyclovir or ganciclovir have all achieved success in decreasing the incidence of symptomatic CMV and EBV infection, although seroconversion in naive recipients inevitably occurs.57,59 Posttransplant lymphoproliferative disease (PTLD), a potentially fatal abnormal proliferation of B lymphocytes, can occur in any situation in which immunosuppression is undertaken. The increased frequency of PTLD in pediatric liver transplantation results from the intensity of the immunosuppression required, its lifetime duration, and the absence of prior exposure to EBV infection in 60% to 80% of pediatric recipients. PTLD is the most common tumor in children following transplantation representing 52% of all tumors compared with 15% and adults. About 80% occur within the first 2 years following transplantation.60 Many studies analyzing the associations between immunosuppressive therapy and the development of PTLD have shown a
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CCHMC Patient Survival by Age @ First LT 100 90
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Figure 1 Liver transplant patient and graft survival: Cincinnati Children’s Hospital Medical Center Experience. (Color version of figure is available online.)
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progressive increase in the incidence of PTLD with: (1) an increase in total immunosuppression load; (2) EBV naive recipients; and (3) the intensity of active viral load.61,62 No single immunosuppressive agent has been directly related to PTLD. The second pathogenic feature encouraging PTLD appears to be EBV infection. Treatment of PTLD is stratified according to the immunologic cell typing and clinical presentation.63 Documented PTLD requires an immediate decrease or discontinuation of immunosuppression and institution of anti-EBV therapy. Patients with polyclonal Bcell proliferation frequently show regression with this treatment.64,65 If tumor cells express B cell surface marker CD20 at histology, then the anti-CD20 monoclonal antibody rituximab (Genentech, Biogen-IDEC) has been used with increasing success. When given alone, its response rate was 46%, and it has a 54% relapse/progression rate. The combination of cyclophosphamide/prednisone yielded a response rate exceeding 80%, but 2-year event-free survival was only 58%. Recently, chemoimmunotherapy using cyclophosphamide, prednisone, and rituximab has shown response rate of 100%, with minimal toxicity. Further use of this combination will clarify it’s future role.66,67 Patients with aggressive monoclonal malignancies have poor survival even with immunosuppressive reduction, acyclovir, and conventional chemotherapy or radiation therapy.
Outcome Although the potential complications following liver transplantation are frequent and occasionally severe, the overall results are rewarding. Overall 1-year patient and graft survival has reached 88%/82% in the SPLIT registry,68 92%/ 84% in our own center (Figure 1). The highest risk of mortality occurs in all groups during the first year, with the majority of this risk within the first 3 months following transplantation. Long-term survival beyond 1 year is excellent, 83%/74% in SPLIT (4 years), and is similar in all ages, and for all diagnostic groups. Survival has improved dramatically in infants and small children over the past years. Infants ⬍1 year of age or ⬍10 kg have reported survival of 65% to 88% overall, an improvement over previously reported rates of 50% to 60%.69 Improved survival in these small recipients is consistent throughout all levels of medical urgency and results from both technical innovations in graft preparation, and avoidance of life and graft threatening complications such as HAT and PNF. Donor factors associated with decreased patient and graft survival include donor age ⬍6 months or ⬎50 years. In the combined SPLIT registry, whole organ recipients had better patient and graft survival than any surgically reduced/split/LD recipients.70 These results may be influenced by the diverse nature of the experience accumulated in these registries. When whole organ, living donor, and split liver recipients were directly compared in experienced centers, there was no difference in patient or graft survival, biliary or vascular complica-
225 tions.32,71-73 These combined results suggest that best results will be achieved at centers with extensive experience with all age groups and allograft types, allowing transplantation to be tailored to the needs of the recipient and family, rather then identifying specific graft types for patient subgroups.
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Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 44. Reding R, Webber SA, Fine R. Getting rid of steroids in pediatric solid-organ transplantation? Pediatr Transplant 2004;8:526-30. 45. Langnas AN, Marujo W, Stratta RJ, et al. Hepatic allograft rescue following arterial thrombosis. Role of urgent revascularization. Transplantation 1991;51:86-90. 46. Ueda M, Egawa H, Ogawa K, et al. Portal vein complications in the long-term course after pediatric living donor liver transplantation. Transplant Proc 2005;37:1138-40. 47. Heffron TG, Emond JC, Whitington PF, et al. Biliary complications in pediatric liver transplantation. A comparison of reduced-size and whole grafts. Transplantation 1992;53:391-5. 48. Peclet MH, Ryckman FC, Pedersen SH, et al. The spectrum of bile duct complications in pediatric liver transplantation. J Pediatr Surg 1994;29:214-9; discussion 219-20. 49. Snover DC, Sibley RK, Freese DK, et al. Orthotopic liver transplantation: a pathological study of 63 serial liver biopsies from 17 patients with special reference to the diagnostic features and natural history of rejection. Hepatology 1984;4:1212-22. 50. Mor E, Solomon H, Gibbs JF, et al. Acute cellular rejection following liver transplantation: clinical pathologic features and effect on outcome. Semin Liver Dis 1992;12:28-40. 51. Adams DH, Neuberger JM. Treatment of acute rejection. Semin Liver Dis 1992;12:80-8. 52. Ryckman FC, Schroeder T, Pedersen S. Use of monoclonal antibody immunosuppressive therapy in pediatric renal and liver transplantation. Clin Transplant 1991;5:186-90. 53. Freese DK, Snover DC, Sharp HL, et al. Chronic rejection after liver transplantation: a study of clinical, histopathological and immunological features. Hepatology 1991;13:882-91. 54. Ludwig J, Wiesner RH, Batts KP, et al. The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation. Hepatology 1987;7:476-83. 55. Wiesner RH, Hermans PE, Rakela J, et al. Selective bowel decontamination to decrease gram-negative aerobic bacterial and Candida colonization and prevent infection after orthotopic liver transplantation. Transplantation 1988;45:570-4. 56. Singh N, Carrigan DR, Gayowski T, Marino IR. Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity. Transplantation 1997;64:674-8. 57. Patel R, Snydman DR, Rubin RH, et al. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation 1996;61:1279-89. 58. Fox AS, Tolpin MD, Baker AL, et al. Seropositivity in liver transplant recipients as a predictor of cytomegalovirus disease. J Infect Dis 1988;157:383-5. 59. Darenkov IA, Marcarelli MA, Basadonna GP, et al. Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy. Transplantation 1997;64: 848-52. 60. Smets F, Sokal EM. Lymphoproliferation in children after liver transplantation. J Pediatr Gastroenterol Nutr 2002;34:499-505. 61. Guthery SL, Heubi JE, Bucuvalas JC, et al. Determination of risk factors for Epstein-Barr virus-associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment. Transplantation 2003;75:987-93. 62. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101-13. 63. Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL. Epstein-Barr virus, immunodeficiency, and B cell lymphoproliferation. Transplantation 1985;39:461-72. 64. Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant 2002;6:456-64. 65. Holmes RD, Orban-Eller K, Karrer FR, et al. Response of elevated Epstein-Barr virus DNA levels to therapeutic changes in pediatric liver transplant patients: 56-month follow up and outcome. Transplantation 2002;74:367-72. 66. Orjuela M, Gross TG, Cheung YK, et al. A pilot study of chemoimmunotherapy (cyclophosphamide, prednisone, and rituximab) in pa-
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tients with post-transplant lymphoproliferative disorder following solid organ transplantation. Clin Cancer Res 2003;9:39450S-39452S. Gross TG. Low-dose chemotherapy for children with post-transplant lymphoproliferative disease. Recent Results Cancer Res 2002;159:96103. Studies of Pediatric Liver Transplantation (SPLIT). Annual Report. 2004;6:1-6.27. Sokal EM, Veyckemans F, de Ville de Goyet J, et al. Liver transplantation in children less than 1 year of age. J Pediatr 1990;117:205-10. Lozanov J, Millis JM, Anand R, Group TSR. Surgical outcomes in
227 primary pediatric liver transplantation:SPLIT database report - Abstract #1453. American Transplant Congress. Seattle, WA. 2005 (abstr). 71. Deshpande RR, Bowles MJ, Vilca-Melendez H, et al. Results of split liver transplantation in children. Ann Surg 2002;236:248-53. 72. Kim JS, Broering DC, Tustas RY, et al. Split liver transplantation: past, present and future. Pediatr Transplant 2004;8:644-8. 73. Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a singlecenter experience. Ann Surg 2005;241:905-18.