Pathogenesis and Outcome of Biliary Atresia: Current Concepts

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 the of this disorder in recent a in the of biliary atresia live births, with a in children in children a of with the in and a recent the of biliary atresia and with of 1 in live births Biliary atresia is most a clinical a of or to the hepatobiliary the and pathogenesis of the obliteration of the biliary tree are approximately of patients with biliary atresia, the of other that of the bile duct a in these and of the is to in to of all children with biliary atresia Biliary atresia that is with these and other has been the or may be a common of has been that these are by of or that bile duct that of and with may of the biliary The common in 80% of of biliary atresia is with other and has been the or in is that 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 of these two of biliary atresia may other the are on clinical neonatal is a term for neonatal intrahepatic cholestasis in the is on liver and for other or is idiopathic neonatal up to to of all neonatal cholestasis cases. during the past two to have idiopathic neonatal were to have metabolic and genetic diseases, neonatal of bile and infections with (e.g., and to of of idiopathic neonatal are to be and a may be by genetic or metabolic of are and to be the term idiopathic neonatal of of intrahepatic cholestasis for etiology has been The clinical of idiopathic neonatal and biliary atresia is patients with biliary atresia to be female and with idiopathic neonatal are for and to It has been that the of with biliary atresia may in a delay of is with biliary atresia have and The of liver and and the of may for the of a for and for on or acholic or stools, and within the first 3 months of life. there are other of biliary atresia or neonatal hepatitis, that may to diagnosis of other causes of neonatal cholestasis include and syndrome), and syndrome), and conjugated of total with of of and patients with biliary atresia to have with intrahepatic of cholestasis in the of this in patients with biliary atresia, total is may be and conjugated is complete bile duct may in patients with idiopathic neonatal with biliary atresia may to have if have bile are for patients with these disorders and intrahepatic and extrahepatic or bile a in of bile and should for these disorders biliary atresia and idiopathic neonatal are the two most common of cholestatic liver that in there are other disorders that be in the diagnosis (Table causes and be to progressive liver injury and to other of the genetic and causes of of (e.g., in for and has for the etiology of these disorders has to the of bile and This has our of of bile to and the of of these and other in or other hepatobiliary diseases The of the genetic of Alagille in the that for a to the has the of and of the intrahepatic bile ducts and the of the etiology and pathogenesis of liver and bile duct injury in patients with biliary atresia and idiopathic neonatal has recent in this is to a for the of and preventative biliary atresia is to be a common of the neonatal liver and bile ducts to a variety of and genetic and (viral, that the or of the biliary tree and that during a to 3 months of the of a genetic or to this 1). Biliary atresia and idiopathic neonatal are to be disorders for the of familial of idiopathic neonatal and of biliary for biliary atresia have been and of biliary atresia within the is this the that during of of these may be or that there is a genetic to that is on to during a of that in the of biliary to progressive of the extrahepatic bile of the etiology of the injury and to the may be the of bile with the a The of this first in by and the term have the of bile in bile duct of patients with biliary atresia, in the biliary the This group further that there a of biliary and of of of the could to in the of developing bile could be to the of bile flow to of bile in to and obliteration and of the extrahepatic bile The pathogenesis of injury and of intrahepatic bile ducts after portoenterostomy is to bile flow even after a portoenterostomy that eventually to biliary a if bile flow is or that intrahepatic bile or of and that to the intrahepatic bile duct are of a of and that and and of cholestasis to the of bile in the of and in injury and this may in the of fibrosis in patients with biliary atresia of and that in The the current theories of the etiology of biliary atresia (Table of biliary a etiology to biliary atresia and idiopathic neonatal has been of of to of in to biliary atresia a pediatric that biliary atresia, idiopathic neonatal hepatitis, and choledochal the of of injury to the hepatobiliary tree by a common and the term of have association the common and and biliary recent has on the of has been a a of with biliary atresia and idiopathic neonatal have been with are a recent a of in of patients with biliary atresia, and in 50% of with biliary atresia, a group could in bile duct children with biliary The of has been in a with The two most are and in the that in of the intrahepatic and extrahepatic bile ducts and the liver to of biliary atresia even after or could be group in bile duct with biliary atresia and in with biliary atresia these in a of with biliary atresia of in with biliary atresia have been The of may have these of have hepatobiliary with biliary atresia for to in biliary atresia idiopathic neonatal and a of in liver or bile duct of patients with the of biliary atresia and in to of and 1 year with other liver in patients with the of biliary The these two may in the of of the of and the of for is to be strategies may be the the of this be of patients and and has on group of the in the etiology of biliary to extrahepatic bile duct in with to biliary atresia further characterized this and that the of 3 in to after in of cholestasis and biliary atresia in to of cholestasis or biliary atresia of the by with in to developing hepatobiliary with that the of the biliary and in the of bile duct in with with that the of the system is in this hepatobiliary patients for of group of patients with biliary atresia and of liver of to for or in patients with biliary atresia and liver patients a almost half the patients were months were there is that may be in up to 50% of of biliary atresia, to the of in the of The of other has been in liver of patients with biliary atresia and patients to of in patients with biliary atresia or idiopathic neonatal the United in patients with neonatal and biliary The of and in biliary atresia is and further and of in the liver of patients with biliary and a in a of patients with biliary this to to related or to to in this of and pediatric biliary disorders is injury in biliary atresia and that biliary atresia the of a in a or to biliary to or on the of bile duct in the are by to a bile duct injury, eventually in fibrosis and of the extrahepatic bile duct of and that are in may in this disorder within the first 3 months of life and in a of with the could and of and in liver injury in the neonatal of to of bile duct in patients with biliary The injury to the bile duct a other to of or by during further to the to of with of and and or or bile duct this injury are to further of this and progressive of bile duct with of biliary that a variety of in the of or injury to biliary of liver diseases, hepatitis, and biliary are with this have in biliary that biliary atresia patients and and were with biliary atresia in a population. Other could these a of biliary atresia with in with and a group of could any association in patients with biliary atresia of children with biliary atresia for and that been in the pathogenesis of biliary atresia could be these and biliary atresia, with a of a 1 of a association may have been by this It should be noted that the complete and were in this are and in the is that other may be a of patients of and patients in children with biliary atresia, of the are of the and are in patients with and The that and may to biliary atresia or idiopathic neonatal to be in of is to the of a in the pathogenesis of biliary in the of the in patients with biliary atresia, and noted the of with in bile duct further that of intrahepatic bile ducts with bile duct of patients with biliary atresia the of to by a are for the of the with the and that with on the of with the of in the of and in the of on this have that bile duct may in patients with biliary are by bile duct that by bile duct in liver patients with biliary further that and in the liver and extrahepatic bile duct of patients with biliary atresia, that the and and that in are with the that and and in the extrahepatic bile duct and obliteration in patients with biliary The liver in the recent and of in liver patients with biliary atresia the of diagnosis that in in and biliary patients with biliary atresia a after the portoenterostomy procedure, with the of to and that may to and and other of is the to and may be in the of and these have that of intrahepatic bile duct is in the liver of patients with biliary atresia with liver or that patients with choledochal a in bile duct and the of in patients with biliary is in bile duct this to be to biliary Bile after the portoenterostomy in patients with for on bile duct in patients with This that of may in in bile duct other or bile duct are by a a to the pathogenesis of biliary the were on liver with biliary atresia and with patients with intrahepatic neonatal in the patients with biliary atresia by the of a of in and that the with of with of a bile duct and other in the liver that should the for in biliary atresia Biliary atresia with diseases, the female by and in bile duct has been that injury in patients with biliary atresia may represent have in patients with biliary have that of patients with biliary atresia were for and with of the in patients with biliary atresia with children and with other liver our in of children with biliary atresia and idiopathic neonatal to the that of be in liver and bile duct were in of with biliary atresia and idiopathic neonatal in and were common in of with liver The of on bile duct injury is a in for has been the of in that of to of and have that are with to of patients of in in the have been with and in patients with biliary have been to in patients with and the that in that and the could to biliary this have the of in the of the two and and in the of the in of children with biliary atresia in the United with and were in the of or for any of these the patients with biliary atresia and these for to biliary there are to be other that will be to a in biliary injury and will be for may be that that and of bile and or could a in and bile duct injury in patients with biliary etiology etiology for biliary atresia has been on and extrahepatic bile ducts the thus, causes bile duct after liver transplantation. the of biliary after of in have in of the in the extrahepatic biliary tree of patients with biliary atresia It has been that the may be the in patients with biliary atresia; the or of these of that of biliary atresia are by of the biliary of are with biliary atresia, is of that a in the of or complete of the in the to of the hepatobiliary system in this the and patients with in this were there were in patients with biliary atresia and that the is in the of of biliary Other that and have been with a of for of the the in patients with familial and of of the patients of this with biliary atresia and the this by in two with biliary atresia, were It that these of may be for this may for a that a genetic or to the the of is to a in the that of this and other related that may in the on or or are for of biliary bile duct on and a of that a the intrahepatic bile and a the lumen to the bile ducts to the that is to be for the liver of fibrosis and other bile duct a of with biliary atresia to of the on liver that or and the may be in patients with biliary atresia and in of during a for or other in could for bile duct in patients with biliary atresia, there is of these The of is in and a in the developing extrahepatic bile duct and are in patients with biliary atresia and paucity of interlobular bile duct in of patients with biliary patients of Alagille Remarkably, for the group with that could be a in patients with biliary is that patients with biliary atresia have a of Alagille to the biliary The or of in the causes a with of the and the and intrahepatic bile duct and of of biliary atresia have to the that could be in other has been with biliary atresia or idiopathic neonatal in of biliary atresia in and in may have been related to a or other are and of bile that has the bile duct the of the extrahepatic bile It is to the of with have and to the diagnosis to the of therapies and to for after portoenterostomy for biliary this is that a be for all to 3 of or acholic or hepatomegaly. the common causes of cholestasis is biliary atresia and idiopathic neonatal hepatitis, with in the first of progressive of in stools, and of and Biliary atresia is in were for and to be idiopathic neonatal is common in were for and are to The most for biliary atresia other conditions is liver liver has a for biliary atresia by of to if is and will if are patients with biliary atresia bile and bile or and fibrosis with the of bile in bile ducts is in of patients with biliary atresia, if the is during the first of life. It is to that liver in patients with and in with Alagille and total parenteral nutrition all the of biliary atresia, the of other to these patients with idiopathic neonatal a with of and and bile bile in bile ducts are and bile is or fibrosis is is are to idiopathic neonatal and have been in patients with bile and other of liver and bile duct in biliary and and and with bile duct and bile in bile duct common duct in with and of biliary a and and of common bile duct with lumen and and are in biliary atresia intrahepatic causes of or these is of are of the during has 50% to for biliary atresia intrahepatic cholestasis and paucity of interlobular bile duct disorders may biliary of of the the biliary of the liver and biliary tree is for biliary may a biliary if intrahepatic cholestasis is may a in a with biliary atresia that is This is to or of the common and common bile ducts in is for the of with cholestasis to the of a choledochal and to the of of is with biliary have to the of two that may to be that a or the of the bile duct the is a for biliary recent that a may in and that are of biliary atresia The of these for with cholestasis will require further other that a for diagnosis of biliary atresia of for of intrahepatic cholestasis biliary atresia the to extrahepatic bile ducts on bile The of has been for of the extrahepatic biliary and and the is have the of a bile for of or bile a to of the extrahepatic biliary in diagnosis of biliary atresia is a in the United States neonatal may be to with biliary atresia may have and be are by health care and and of these diseases may be the with may be by a health care after the for of the for diagnosis of biliary atresia, and the portoenterostomy procedure, in and have developed in are to of have or of of acholic are 1 the are to with on the to in a and to the to the and the the of the acholic on the the or a to the The and pediatric are and the is for cholestasis and biliary The of this The diagnosis of biliary atresia is after of intrahepatic and causes of cholestasis and choledochal (Table 1). biliary atresia is by that to a lumen in of the extrahepatic biliary by of a extrahepatic bile and by on liver and bile duct in the of other known or are to the of the extrahepatic biliary be in the diagnosis of biliary atresia and the portoenterostomy if the are to the common duct and intrahepatic ducts on these may represent biliary in with Alagille The diagnosis of idiopathic neonatal is after and causes of are for intrahepatic cholestasis are to have neonatal may have diagnosis AND for patients with biliary atresia is the in a of is by to the of the liver after to bile duct in the performed within the first of life by pediatric the portoenterostomy should bile the liver the in 70% to 80% of in of the and of performed and of approximately to 50% of patients bile if performed after of up to and if performed after of to of of bile will the portoenterostomy in with biliary atresia after 3 to months is that after to 3 be for cholestasis if for biliary and be performed if biliary atresia be other is for of patients with biliary atresia in the United of or of of to of to bile flow and a of nutrition of a and of are there is in with in in and and with improved in with to liver transplantation may require or parenteral and of intrahepatic bile ducts in to of patients and may to progressive biliary and liver of the of and the in the pathogenesis of biliary atresia, (e.g., after portoenterostomy to and intrahepatic bile duct injury and fibrosis could be of there are of for patients with biliary has been in and to of after portoenterostomy to clinical with in a review in and with and bile and for up to months after portoenterostomy a of after is to with this this in is the a and transplantation be life and is for patients with biliary atresia portoenterostomy of in portoenterostomy has to bile and with and liver of after liver transplantation for biliary atresia 80% to The for patients with idiopathic neonatal is with of of and of and for improved and of to for are are and or is to up to of with idiopathic neonatal hepatitis, patients will to and liver and may require liver transplantation. recent of these patients have been to of and 1 and bile or neonatal with 1 and may biliary with improvement in liver and liver AND the portoenterostomy is performed in patients with biliary atresia, 50% to 80% of children will liver biliary by 1 and to will by 3 of and cholestasis to the of these children performed to of is with approximately a to and with the most after portoenterostomy performed of in may (Table the of the for is of the most the portoenterostomy is in bile transplantation is to or that of patients care after portoenterostomy in that in the United It is if these in management or other (e.g., genetic or are for the improved in portoenterostomy for biliary atresia review of the of all children with biliary atresia in and the of portoenterostomy with liver for patients with biliary atresia The with the liver after portoenterostomy and after liver transplantation of were the of the portoenterostomy of with of atresia for atresia of the common bile duct for complete extrahepatic of for for and of the the portoenterostomy for patients for and for The and with the liver after with the liver portoenterostomy performed for patients year the United and in a in that of the portoenterostomy to the in the United the of the the portoenterostomy is of the most The of in children with biliary atresia by that children with liver with during the first year of life in and a of related these to of liver and of liver and there little improvement in these 1 year after liver transplantation the patients children with other liver diseases with (e.g., Alagille syndrome), to biliary atresia has been that children 1 year with biliary atresia were for liver transplantation a in the and a 1 of patients improvement 1 year after to be affected and with this delay were of for and transplantation. that improved may be a to liver to and transplantation the of the to the may be to other related to liver has been The most after the portoenterostomy is the of of the to of the biliary system is of the of the portoenterostomy the of this diagnosis and management of is to and of intrahepatic bile and to of the is after a portoenterostomy if any of the stools, liver the or or during or after infections of of bile flow and bile and of the of on bile may be to causes of and liver during the first to months after most with any of liver or in are if is our has been the most for management of in the of a have and to of or if liver for in to the is in 1 a of on by 1 and on to this the may be with 1 for to or should with and of the for or may require a of have the of in the is The of patients with biliary atresia will may by the of progressive with a to liver the of or or or has been in to of patients with biliary a the of of patients developed of the patients were a liver 1 of to by has on to by or of of has been in the of there a in and that on the of or on to is the of and to This in the of in with this has been in a in have been two of for and of in children on to the and of in children to be the management on on management with or and management with or these are in a or liver to be the of the of of a intrahepatic this has been the in for patients to most patients with biliary atresia, liver transplantation may be a and are common and have been in patients with biliary of the is and with is with and or may be for by progressive cholestasis is with and or and to or bile (e.g., for after a portoenterostomy of that the will and the or intrahepatic bile to after portoenterostomy include of the of atresia of the extrahepatic bile and and of of with a common duct atresia patients with atresia of the biliary tree the liver have to to and of liver transplantation for children with biliary The include of and and the of bile and a total and have been in of and are thus, these have in clinical developed a for of in pediatric patients for liver transplantation that of and of this is and has been in the of liver for patients with biliary atresia for liver transplantation. the system has been developed by the for of children for liver transplantation by total and 1 the in part and children with biliary atresia, has been for and children the of be for liver transplantation thus, may be of in the of biliary total of after the first of the of current 70% to 80% of patients with biliary atresia in will require liver transplantation during the first two of with portoenterostomy biliary atresia accounts for to 50% of all liver transplants performed in children It should be noted that there is liver in that accounts for a of liver that transplantation have been in the of improved and of life for patients with biliary atresia and other cholestatic disorders have been in a that are on the and the liver transplantation of children with biliary atresia in the that could be to the of patients with biliary health to care to all with the if and to a total and if the is to 3 or if the has stools, or of a to diagnosis of patients with biliary atresia and outcome, and to that the of a for 1 to the and to if will of patients with biliary atresia to in a of patients with biliary atresia, to with a care and pediatric or year to after of after portoenterostomy in patients with biliary atresia to the and of to and in the etiology and pathogenesis of biliary of the pathogenesis of bile duct injury in and genetic of biliary The Biliary for by the of and of the of is a of clinical and a in the United in with the of and that will on a of these The of are to and a clinical and the of and a of the etiology and pathogenesis of biliary atresia; to and clinical and and to to the and management of biliary this and other is that advances in our of biliary atresia and related diseases will the in improved health and for children with biliary The for the and for