Liver Transplantation in the Neonate and Young Infant

Abstract

After completing this article, readers should be able to: Prior to 1980, liver transplantation in the pediatric age group was characterized by poor outcomes, with high rates of mortality and complications and poor quality of life for the survivors. With improved surgical techniques and immunosuppressive medications, the average survival rate for children has increased to 85% at 1 year and 77% at 5 years after surgery. In addition, complications have become less frequent and are less severe. Because of these advancements, liver transplantation has become standard therapy for life-threatening liver disease in children. Nonetheless, liver transplantation in neonates and young infants remains challenging due to factors such as paucity of donor organs and technical difficulties related to small body size and small graft size. Recent data from United Network of Organ Sharing (UNOS) show that although infants younger than 1 year of age comprise a relatively small group of children waiting on the liver transplant list (<10%), they have the longest waiting times and highest mortality rates while awaiting an organ. This review focuses on the indications, timing, and common complications of liver transplantation pertinent to this high-risk population of children as well as a discussion of recent clinical advances that have resulted in improved outcomes.The most common indications for liver transplantation in the pediatric patient are biliary atresia (43%), metabolic liver disease (13%), and fulminant hepatic failure due to acute hepatic necrosis (11%). Other, less common liver diseases include idiopathic or cryptogenic cirrhosis (6%), biliary hypoplasia (5%), neonatal hepatitis (3%), autoimmune hepatitis (2%), and tumor (2%). However, the frequency of indications varies substantially according to age. At our center, the most frequent indications for liver transplantation in neonates and young infants are neonatal hepatitis (80% of transplants among children younger than 4 months of age), biliary atresia (80% of transplants among children 4 months to 3 years of age), and fulminant hepatic failure (children older than 3 years of age).Neonatal hepatitis is a pathophysiologic process associated with inflammatory changes in the liver. Although neonatal hepatitis may be due to an infectious process or a metabolic disease such as alpha-1-antitrypsin deficiency or inborn errors of bile acid metabolism, the cause is generally not identifiable. Jaundice, hepatomegaly, and splenomegaly are the usual presenting features. The clinical course of infants who have neonatal hepatitis is highly variable, ranging from complete recovery to end-stage liver disease. Liver transplantation is indicated for those who develop growth failure or end-stage liver disease. The care of such children is primarily supportive, with close follow-up because the pace of the disease may vary from slowly progressive to fulminant acute liver failure.If diagnosed by 2 months of age, the initial treatment of choice for biliary atresia is portoenterostomy (Kasai procedure). However, despite timely surgery, 80% of children undergoing a portoenterostomy require liver transplantation within 10 years of the procedure. The pace of the progression to cirrhosis and end-stage liver disease is highly variable and requires close follow-up. Primary liver transplantation should be considered for children who present with biliary atresia at more than 3 months of age with evidence of advanced liver disease.The third most common indication for liver transplantation in the neonate and young infant is fulminant hepatic failure caused by acute liver necrosis. Unlike adults, the cause of the acute liver failure usually cannot be determined and may represent an unknown infectious or abnormal metabolic process. Standard diagnostic investigations, such as percutaneous liver biopsy, may not be possible due to the profound uncorrectable coagulopathy such infants frequently develop, despite administration of large volumes of clotting factors and fresh frozen plasma. Open or surgical liver biopsy should be considered in such situations. Such children are at high risk for intracranial hemorrhage and require intensive management. Development of encephalopathy or rapidly progressive ascites portends a poor outcome, as does development of failure of other organ systems, such as kidney failure or hepatorenal syndrome.Prior to reduced-size and living-related donor options, 25% to 50% of children died due to lack of appropriate-sized donors. With the current wide range of liver donor possibilities, including whole graft, reduced-size, and split cadaver livers, living-related and unrelated livers, and blood-type mismatched livers, most children have donors available, and the transplant can be performed at the optimal time. Neonates and young infants as well as children who have fulminant hepatic failure continue to experience high morbidity and mortality due to an inability to secure a timely donor. Early referral of potential candidates to transplant centers is becoming increasingly important to optimize the opportunities for timely identification of an appropriate donor.Children who have fulminant hepatic failure have the highest risk of death, particularly if they present in young infancy. A recent study reported survival was 8% without a transplant and 22% with a transplant in affected children younger than 2 years of age compared with 50% and 65%, respectively, in children older than age 2 years. Worsening encephalopathy, rising serum bilirubin, falling transaminases, and progressive coagulopathy are considered indications for urgent transplantation. The degree or severity of coagulopathy may be a predictor of outcome; the same study reported 73% survival among children who had an International Normalized Ratio (INR) of less than 4 compared with 14% survival of those who had INRs greater than 4.The prognosis also may depend on the etiology of the hepatic necrosis. Acetaminophen toxicity generally has a better prognosis for recovery than does viral hepatitis. The etiology of fulminant hepatic failure in children is unknown in most cases. Affected children generally have a very poor prognosis without liver transplantation. Several reports have shown a 50% to 68% survival among children who underwent liver transplantation for fulminant hepatic failure.A major constraint in the care of these children is the lack of clinical markers by which to determine whether the liver will recover or progress to complete irreversible failure. Liver biopsy specimens can be assessed for extent of hepatocyte injury, death, and drop-out if available, but this may not be feasible to obtain due to the profound coagulopathy commonly seen in these children. Serum proteins of hepatic origin, such as factor V or alpha-fetoprotein, are used as markers of hepatic function and recovery, but they are not reliable prognostic indicators for hepatic recovery. Our group has developed an approach in selected instances in which the patient who has fulminant hepatic failure is taken to the operating room when an organ becomes available. A laparotomy is performed, the liver inspected grossly, and an open liver biopsy is obtained and examined by frozen section. If extensive hepatocyte death with minimal or no regeneration is noted, the patient undergoes liver transplantation. If significant regeneration is occurring, the patient is returned to the intensive care unit and is spared the transplant.The UNOS is the major agency regulating allocation of donor organs according to length of waiting time and severity of liver disease, with children in intensive care settings having the highest priority. Specific manifestations of liver disease are also recognized as warranting high priority for transplant, including bleeding unresponsive to medical therapy, spontaneous bacterial peritonitis, hepatorenal syndrome, refractory ascites, recurrent cholangitis, growth failure, hyperbilirubinemia (>4 mg/dL [68.4 mcmol/L]), low albumin (<3 g/dL [30 g/L]), coagulopathy (INR >1.7), and malnutrition. Encephalopathy, which may be difficult to detect in children, is another important indication to proceed with transplantation.When signs of end-stage liver disease are present, a delay in transplantation, which at times is unavoidable due to difficulties in locating an appropriate donor, may result in an increased risk of death as well as greater morbidity after transplantation. As an example, timing of liver transplantation may have important implications for neurodevelopment of the child. Our group recently published data showing a relationship between neurodevelopmental delay and several pre- and posttransplant parameters in children who underwent liver transplantation for biliary atresia. These factors included low serum albumin, longer length of hospital stay after transplantation, younger age at transplant, and low weight for age. Such factors may be particularly pertinent to the neonate and young infant; young infants have a higher risk of developmental delay and higher mortality rates following transplantation. This may be due to the effects of end-stage liver disease on brain maturation or effects of the primary disease, such as neonatal hepatitis, which may be caused by an infectious or metabolic process that involves the brain.Graft rejection is an obvious major concern after liver transplantation. In the 1970s, the introduction of cyclosporine, an immunosuppressive drug derived from the fungus Tolypocladium infantum Gams, markedly improved liver transplant outcomes. In the early 1990s, tacrolimus, a more potent immunosuppressive agent derived from the actinomycete Streptomyces tsukubaensis, was introduced. Our group has accumulated substantial experience with this relatively new agent. We have seen less acute and chronic rejection among children treated with tacrolimus compared with cyclosporine. Our rate of biopsy-proven acute rejection was 58% among 106 children receiving tacrolimus compared with 74% among 138 children treated with cyclosporine. With cyclosporine, chronic rejection had been a common indication for retransplantation, but since changing to tacrolimus as our primary immunosuppressive medication, our rate of retransplantation has fallen from 11% to 5%, with retransplantation due to chronic rejection falling from 4% to 0. In addition, use of tacrolimus has resulted in shorter lengths of hospital stay posttransplant and the ability to wean the child completely off steroids by 6 months after transplantation. Weaning from steroids is of major benefit because it allows increased linear growth, lessened bone demineralization, and diminished risk of infection.Because of its potent immunosuppressive action, initial experiences with tacrolimus were associated with a high incidence of Epstein-Barr virus (EBV) infection and EBV-associated posttransplant lymphoproliferative disorder (PTLD). PTLD results from persistent EBV infection in the setting of potent immunosuppressive therapy, causing the emergence of B lymphocyte proliferations that sometimes act like aggressive lymphomas. The incidence of PTLD at our center has been reduced considerably by use of lower doses of tacrolimus and use of this medication as primary therapy rather than as rescue therapy for rejection.Frequent infections are common among children after transplantation due to the highly invasive nature of the procedure, the intensity of the subsequent care, and most importantly, the use of potent immunosuppressive medications to prevent rejection of the newly placed liver graft. Immediately following liver transplantation, bacterial infections due to gram-negative and enterococcal pathogens are common and are usually due to surgical complications such as cholangitis, bowel perforation, and biliary ischemia secondary to hepatic artery thrombosis. Viral upper respiratory and gastrointestinal infections are also common in children following liver transplantation. The three most common and potentially life-threatening pathogens are EBV, cytomegalovirus (CMV), and varicella viruses. Administration of intravenous gancyclovir prophylactically for 14 days posttransplant has reduced the incidence of symptomatic CMV infection from 21% to 6% in our patients. Because most neonates and young infants have not yet been exposed to either EBV or CMV, we routinely treat them with prophylactic acyclovir (10 mg/kg per dose four times per day) for at least 1 year posttransplant. The primary EBV infection may be severe and progress rapidly to PTLD, which requires that young children who have no antibody titers to EBV be continued indefinitely on prophylactic acyclovir and monitored frequently until there is an EBV exposure with subsequent development of anti-EBV antibody titers.PTLD due to EBV infection has been the leading cause of death in our patients after the first 3 posttransplant months. Fifty-four children who had EBV infection had symptoms of fever (100%), lymphadenopathy (57%), gastrointestinal symptoms (39%), rash (31%), and airway obstruction (24%). Eleven also had PTLD. We have recently reported that gastrointestinal symptoms of diarrhea and bleeding were common among children who had EBV infection and often were manifestations of PTLD. Children who are younger than 5 years of age, particularly neonates and young infants, are at the greatest risk of developing a primary infection with EBV, which has, in turn, the highest risk of resulting in PTLD. Monitoring of EBV serology and EBV by polymerase chain reaction allows early detection and reduction of immunosuppression if infection is found and discontinuance of immunosuppression if PTLD develops. Other therapies for PTLD include gancyclovir and gamma globulin therapy with preparations that have high antibody titers to CMV and EBV and chemotherapy. With the use of these therapies, the incidence of PTLD has fallen dramatically, although it remains a leading cause of death after liver transplantation.As mentioned previously, although neonates and small infants comprise a small portion of children on the UNOS waiting list for liver transplantation, a high proportion (approximately 15%) die while awaiting a donor organ. Because of this high death rate, various modalities have been developed to increase the pool of potential donors, including reduced-size liver transplantation, ABO-incompatible transplantation, and living-related transplantation. These techniques and options have resulted in decreased waiting times for high-risk infants. However, these infants are subject to unique problems after the transplant procedure. Because of small vessel size, vascular thromboses, such as hepatic artery thrombosis and portal vein thrombosis, are of major concern and are clearly associated with poorer survival. This has resulted in aggressive postoperative use of anticoagulants, such as heparin, dextran, dipyridamole, and aspirin.Immunosuppression is a challenge in these small infants, who require higher levels of medication on a per body weight basis than older children and adults but are more prone to infectious complications, including PTLD, as discussed previously. Meticulous monitoring by an experienced transplant team is required for good outcomes.With newer surgical techniques and immunosuppressive therapies and heightened vigilance for complications, neonatal and young infant candidates for liver transplantation who have donors available at the appropriate time can expect a greater than 80% chance for 5-year survival, with few complications and adverse effects from medications. Increased survival rate and improved quality of life are expected with better timing for transplantation and newer, more selective immunosuppressive medications that have fewer adverse effects as well as therapies to prevent and more effectively treat infectious complications, such as EBV infection.