Pathogenesis and Outcome of Biliary Atresia: Current Concepts

Abstract

Neonatal cholestatic disorders are a group of hepatobiliary diseases occurring within the first 3 months of life. Bile flow is impaired, and patients have conjugated hyperbilirubinemia, acholic stools, and hepatomegaly. Overall, 1 in 2,500 live births is affected with a neonatal cholestatic disorder (1). The two most common causes of neonatal cholestasis are biliary atresia and idiopathic neonatal hepatitis, accounting for up to 50% to 70% of cases. Other causes include a variety of neonatal infections (viral, toxoplasmosis, syphilis, bacterial), metabolic and genetic diseases, progressive familial intrahepatic cholestatic disorders (PFIC), paucity of interlobular bile duct disorders (e.g., Alagille syndrome), choledochal cyst, ischemia-reperfusion injury, association with parenteral nutrition administration, and other conditions (Table 1). Despite clinical improvement after the portoenterostomy procedure, approximately 70% to 80% of children with biliary atresia will eventually require liver transplantation; thus, biliary atresia alone accounts for almost 50% of all liver transplants performed in children (1). It should be noted that $77 million is spent each year in the United States on liver transplantation for children and the ensuing hospitalizations (2). This sum of money covers 0.2% of total health care expenditures related to children, even though these children represent 0.0006% of the total pediatric population. Importantly, this disproportionate expenditure for liver transplantation in children could be cut in half if improved therapies for biliary atresia were developed that could abrogate or further delay the need for liver transplantation. Remarkably, little is known about the etiopathogenesis of biliary atresia; consequently, there has been slow progress in developing improved therapies or preventative strategies during the past decade. The purpose of this review is to summarize recent advances in the diagnosis and management of biliary atresia, examine the clinical outcome, describe the evolving theories of the etiology and pathogenesis of this disorder, and highlight gaps in our current knowledge.TABLE 1: Differential diagnosis of neonatal cholestasisDEFINITIONS AND CLINICAL FEATURES Biliary atresia is the most common neonatal cholestatic disorder, occurring in approximately 1 of 8,000 (Asian countries) to 1 of 18,000 (European countries) live births, with a female preponderance, characterized by complete fibrotic obliteration of the lumen of all or part of the extrahepatic biliary tree within 3 months of life (1). Fibrous obliteration may involve the entire extrahepatic biliary system or any part of the system, with concomitant injury and fibrosis of intrahepatic bile ducts (hence, the term extrahepatic has been dropped from the name of this disorder in recent years). In a prospective study conducted between 1968 through 1993 in Atlanta, Georgia, the calculated incidence of biliary atresia was 0.73 cases per 10,000 live births, with a higher prevalence in African-American children than in white children (3). There was also a considerable seasonal clustering of cases, with the incidence three times higher in infants born between December and March. In contrast, a recent study using the Swedish National Health Database found no seasonal occurrence of biliary atresia between 1987 and 1997, with an incidence of 1 in 14,000 live births (4). Biliary atresia is most likely a clinical phenotype resulting from a number of prenatal or perinatal insults to the hepatobiliary tree, although the etiologic factors and pathogenesis of the obliteration of the biliary tree are poorly understood (5). In approximately 20% of patients with biliary atresia, the presence of at least one other major congenital anomaly suggests that defective development of the bile duct apparatus played a role in these cases (5,6). In particular, polysplenia and of the is to in to of all children with biliary atresia Biliary atresia that is with these and other congenital has been the or although may be a common phenotype of prenatal has been that these are by of or that bile duct that of and development with polysplenia an may development of the biliary The common in 80% of of biliary atresia is with other congenital and has been the perinatal or in is that perinatal or progressive injury and fibrosis of a developed biliary tree during a in the first 3 months of life the of biliary atresia is with and acholic the first 3 of life a the of biliary atresia has of and acholic in the to of life after a of Despite these the clinical phenotype of these two of biliary atresia may other congenital the are on clinical neonatal is a term for neonatal intrahepatic cholestasis in the is on liver and for no other or is In idiopathic neonatal up to to of all neonatal cholestasis cases. during the past two infants to have idiopathic neonatal were found to have metabolic and genetic diseases, neonatal of bile and infections with (e.g., and to 20