Biliary atresia and idiopathic neonatal hepatitis are two cholestatic disorders occurring in the first 3 months of life that account for 60-70% of all infants with neonatal cholestasis, which have similar clinical presentations but disparate outcomes. Diagnosis of biliary atresia is frequently delayed; the Kasai portoenterostomy procedure may extend an infant's life, but in most cases is not curative. Thus liver transplantation becomes necessary in 70% of infants with biliary atresia in North America, accounting for 40-50% of all pediatric liver transplants. In idiopathic neonatal hepatitis, on the other hand, recovery occurs in 80% of patients with supportive care alone. The etiology and pathogenesis of these two disorders is currently poorly understood; consequently few effective therapies have been developed over the past three decades. The development of new therapeutic strategies will require a thorough understanding of the causes and mechanisms of tissue injury in these disorders. Because both these disorders are rare, a network of centers will be essential to achieve effective investigation. Consequently, the objective of this grant application is to be chosen as one of the Clinical Centers in the Biliary Atresia Clinical Research Consortium and participate in all investigations initiated by this consortium. We specifically will test the hypothesis that perinatal/acquired cases of biliary atresia and idiopathic neonatal hepatitis are distinct phenotypes caused by similar viral-induced immune injury of extrahepatic and entrahepatic bile ducts and hepatocytes in the genetically and immunologically susceptible infant.
The specific aims of this proposal are: (1) To develop a database and tissue/serum bank of human specimens from infants with biliary atresia, idiopathic neonatal hepatitis, and appropriate control cholestatic and non-cholestatic infants, in order to define the natural history and better understand the pathogenesis of these disorders. (2) To determine the role of specific viral infections in the etiology of biliary atresia and idiopathic neonatal hepatitis. (3) To conduct a Phase I/Phase II study of treatment with an antioxidant solution designed to reduce injury, and ultimately fibrosis, in infants with biliary atresia. Our Center has extensive experience in clinical care, investigation, and development of novel therapies for biliary atresia and related cholestatic disorders, and is committed to the scientific development of and participation in clinical investigations and trials initiated by the Biliary Atresia Clinical Research Consortium.
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