Biliary atresia; Mark Davenport, ChM FRCS (Paeds), FRCPS (Glas), FRCS (Eng) Recent advances in molecular pathology. Etiology

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1 Seminars in Pediatric Surgery (2005) 14, Biliary atresia Mark Davenport, ChM FRCS (Paeds), FRCPS (Glas), FRCS (Eng) From the Department of Paediatric Surgery, Kings College Hospital, London, UK. KEYWORDS Biliary atresia; Splenic Malformation; Kasai portoenterostomy Biliary atresia (BA) remains a devastating disease of infants. It is still a disease of largely unknown etiology although many hypotheses such as an aberrant early bile duct development, perinatal viral infection, aberrant immune response, and abnormalities of bile acids have all been suggested as possibly etiologically important. Although recent studies, using the techniques of molecular biology and immunohistochemistry, have improved the understanding of some of the inflammatory elements of BA, there is a lack of understanding of how many such disparate elements interact and relate. Clinically, the management in the majority of cases should consist of a primary portoenterostomy (Kasai procedure) to try and restore bile flow and alleviate jaundice. Transplantation should be reserved for those who develop chronic liver disease and its attendant complications. Recent series would suggest that over 50% of infants in large centers will be able to clear their jaundice and therefore have a reasonable expectation of long-term survival with a good quality-of-life Elsevier Inc. All rights reserved. Biliary atresia (BA) can be a devastating disease in infants invariably leading, if untreated, to cirrhosis, liver failure and death. It remains, still, the most common indication for pediatric liver transplantation throughout the developed world. The incidence is consistently greater in Japan (1 in 9600) 1 than in the UK (1 in 15,000), 2 Sweden (1 in 14,000), 3 or the USA (1 in 14,000). 4 There is usually a female preponderance. About 10% ( 3% in Japanese series 1 ) of cases have other congenital abnormalities, specifically a syndromic association which we have termed the Splenic Malformation (BASM) (formerly polysplenia) syndrome. 5 Table 1 illustrates the range of abnormalities and their incidence. Etiology The cause of BA is not known with any degree of certainty, though there are a number of hypotheses which have been Address reprint requests and correspondence: Mr. M. Davenport, Department of Paediatric Surgery, King s College Hospital, Denmark Hill, London SE5 9RS, UK. address: Markdav2@ntlworld.com. advanced (Figure 1). These range from a defect or derangement in early bile duct development (ie, a first trimester event), which may 5 or may not 6 be associated with the other congenital anomalies typical of BASM: excretion of an abnormal and toxic component in bile; 7 a perinatal infection with a variety of hepatotropic viruses; 8,9 an abnormality of the hepatic arterial supply 10 and mucosal destruction secondary to a common pancreatobiliary channel. Recent advances in molecular pathology Whatever the cause, the macroscopic appearance of the extrahepatic biliary tree ranges from an inflamed, hypertrophic occluded biliary tract to an atrophic negligible remnant with absent parts. The histological appearance within the liver appears consistent with early portal tract inflammation, a small-cell infiltrate, bile duct plugging and proliferation and latterly fibrosis giving way to overt biliary cirrhosis. The small cell infiltrate is largely composed of CD4 T lymphocytes and CD56 natural killer (NK) cells 11,12 which exhibit markers for proliferation (CD71 ) and activation (particularly LFA-1 but also CD25 ). Infiltrating CD8 cells, where found, 13 appear to lack markers of /$ -see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.sempedsurg

2 Davenport 43 Table 1 Biliary atresia splenic malformation syndrome Component Frequency* Notes Polysplenia, double spleen etc. 90% Asplenia 10% Situs inversus 50% Preduodenal portal vein 40-60% Other variants include congenital porto-caval shunt Absent vena cava 40-50% Azygous venous drainage of lower body Malrotation 30-40% Cardiac anomalies 30-40% Of all types including Fallot s, hypoplastic left heart, valvular anomalies and septal defects. Annular/short pancreas 5% Immotile cilia syndrome 2% Abnormal maternal history 40% e.g., maternal diabetes (10% of cases), first trimester drug ingestion * Incidence taken from King s College Hospital series ( ) (unpublished). activation such as perforin, granzyme B and Fas ligand, in contrast to other diseases such as primary biliary cirrhosis. Although still controversial, the inflammatory response appears to be specific to biliary atresia, rather than in neonatal cholestasis per se. 12 Macrophages may play an important role both in the presentation of antigenic material and in the initiation of fibrosis, the hallmark of chronic liver disease. 14 Such macrophage/monocytes may either be resident (Kupffer cells) or systemic/recruited and when activated and proliferating appear to be key components in the prolongation of the inflammatory response. Tracy and coworkers in showed increases in resident macrophages (CD68 ) in 5 of 6 cases of BA with marked expression of the lipopolysaccharide receptor, CD14. Kobayashi and coworkers 16 in 15 infants and ourselves in a series of 29 infants 11 have also shown a negative prognostic relationship with increased levels of CD68 cells. The infiltrate in the biliary tree remnant appears to be less marked than the liver and this is rather surprising as intuitively the extrahepatic biliary tree is often thought of as the focus and target of the inflammatory process. It may be that by the time of study the inflammatory process in the biliary tree is effectively burnt out. Cell adhesion molecules are proteins involved in cell cell binding. There are three dominant molecular families: the immunoglobulin superfamily, the integrin family and the selectin family. Intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) are members of the immunoglobulin superfamily which are Congenital hepatic embryopathy Postnatal Hepatotropic Viral Insult (ie first trimester "insult" to developing bile ducts) < 35 days gestation Genetic predisposition Candidate genes jagged 1 mutation CFC HNF-6 INV BASM Candidates REOvirus rotavirus cytomegalovirus Immune dysregulation? T H 1 response CD4+ T cells NK cells?? CD8 cells > 35 days gestation Anatomical Factors Candidates Arterial abnormalites Common channel "Toxic " bile acids Figure 1 Etiological factors in biliary atresia: Real or imagined?

3 44 Seminars in Pediatric Surgery, Vol 14, No 1, February 2005 expressed on cell surfaces and are believed to be important in binding circulating leukocytes by interaction with cellsurface integrins and hence facilitating transendothelial migration. Selectins are involved in the earliest phase of adhesion of circulating leukocytes, inducing a characteristic rolling motion. Dillon and coworkers, 17 originally identified abnormal expression of the inflammatory adhesion molecules, ICAM-1 and VCAM-1 but not E-selectin (then known as ELAM), in six infants with BA. This suggested that an inflammatory reaction could be occurring in BA by attraction, retention and activation of circulating leukocytes. Later studies 11 have confirmed ICAM-1 staining of sinusoidal endothelium in virtually all and VCAM-1 staining in about 80% of cases. An interesting and possibly clinically relevant addendum to the adhesion molecule story is that it is possible to measure such molecules in the circulation. High values of sicam-1 and svcam-1 have been shown in other immunologically mediated liver diseases such as primary biliary cirrhosis and sclerosing cholangitis. This has also been shown in BA at the time of initial surgery 18 and in relation to older children with treated BA. 19 Our own study (unpublished) shows that, at the time of Kasai, s-icam-1 and s-vcam-1 (but not s-e-selectin) are grossly elevated with significant correlation of s-icam-1 with increasing age at surgery and total bilirubin and of s-vcam-1 with total bilirubin and aspartate aminotransferase levels. One of the putative causes, either as an indirect trigger of an abnormal immune-mediated reaction or as an actual pathological agent, is infection with hepatotropic viruses. Animal models where intraperitoneal inoculation on the first day of life is able to mimic postnatal biliary inflammation have been described. 20 Serological evidence in humans is contradictory 21 and isolation of both viral RNA and DNA have 8,22 and have not 23,24 been identified by sophisticated RT-PCR and PCR techniques. Those proponents of the viral hypothesis, however, fail to explain why such ubiquitous organisms, perfectly able to cause gastrointestinal lesions in millions of infants and children, only damage the biliary tree in what is, relatively, a handful. A possible genetic predisposition may explain this observation, although, as yet, there is no actual evidence. Nevertheless key genes that are important in both bile duct development (eg, Jagged 1, 25 HNF-6), and visceral and somatic symmetry (eg, CFC-1) 26 have been described. Macroscopic pathology The lumen of the extrahepatic duct is obliterated at a variable level and this forms the basis for the commonest classification in clinical use. Type 1 ( 5%): where the level of obstruction is within the common bile duct (the gallbladder therefore contains bile). Type 2 ( 3%): where the level is within the common hepatic duct. The gallbladder will not contain bile but a transection of the proximal remnant should show two distinct bile-containing lumens. Type 3 ( 90%): where there is no visible bile-containing proximal lumen and the obstruction is within the porta hepatis. The other main macroscopic variation is that of cystic change, seen in about 5% of cases, within some part of the extrahepatic biliary tree. Some cysts contain mucus, while others contain bile. If it is the latter there may be some diagnostic confusion with that of a true choledochal cyst. However, in cystic biliary atresia, the wall is invariably thickened and communicates poorly with abnormal nondilated intrahepatic ducts. This should be obvious on a cholangiogram (operative or percutaneous). Clinical features All infants with biliary atresia will be jaundiced and will have pale stools and dark urine when looked for. This is due to the inability to excrete conjugated (ie, water-soluble) bilirubin into the gastrointestinal tract, which is then excreted into the urine causing its color to darken. Some infants will have had an abnormal antenatal maternal ultrasound scan ( 5%), because of the cystic change in the biliary tree 27 or may present because of other anomalies (typically the cardiac abnormalities associated with BASM. 5 Most infants presenting within 80 days will not show clinical features of cirrhosis or irretrievable liver damage, such as ascites, splenomegaly or heterogeneity on the liver ultrasound. 27 A small proportion of infants will present with features of Vitamin K-dependent coagulopathy and bleeding, particularly in those communities where routine neonatal administration of parenteral Vitamin K has been abandoned or was never present. The differential diagnosis of conjugated jaundice in infants is long and needs perseverance to work out. Surgical causes, other than biliary atresia, are uncommon but may include obstructed choledochal malformations, spontaneous perforation of the bile duct and the inspissated bile syndrome. 28 The common medical causes include neonatal hepatitis, 1-antitrypsin deficiency, giant-cell hepatitis, cytomegalovirus hepatitis and cystic fibrosis. Biliary hypoplasia may be a feature of Alagille s syndrome and cause diagnostic confusion. Such infants have a characteristic elfin face, butterfly vertebrae and cardiac valve (typically pulmonary stenosis) anomalies. A positive prelaparotomy diagnosis of biliary atresia is possible in over 80% of actual cases. 28 Important diagnostic elements should include biliary ultrasonography, biochemical exclusion of 1-antitrypsin deficiency and cystic fibrosis, viral serology, and, ideally, a percutaneous liver biopsy. However, in many centers, and particularly those in Japan, duodenal intubation and measurement of intralumenal bile remains the key test, rather than a biopsy.

4 Davenport 45 The role of other techniques such as ERCP (endoscopic retrograde cholangiopancreatography), MRCP (magnetic resonance cholangiopancreatography), percutaneous and laparoscopic cholangiography is more debatable. ERCP is technically difficult in infants for obvious reasons, though where it is available and the endoscopist is skilled, it can be useful for excluding many borderline cases due to medical or infective causes. The current generation of MRCP scanners do not appear to offer any advantage over skilled ultrasonography and we have tended to appreciate their worth in evaluation of choledochal malformations rather than atresia in infants. Radio-isotope hepatobiliary imaging (eg, using IDA derivatives) is still lacking sufficient discrimination in borderline cases to be really useful. Kasai portoenterostomy The aim of the surgery is to excise all extrahepatic biliary remnants to allow a wide portoenterostomy reconstruction onto a portal plate, denuded of all tissue. This should be the object not only in type 3 biliary atresia but also in those who do have a visible bile-containing proximal communication. It should be obvious therefore that frozen section, formerly used to confirm patent ductules, is not necessary because it should not be possible to resect any further biliary tissue. As with many operations, there are many variations in detail, and may explain wide variations in reported results. At King s College Hospital we have developed the original technique and believe the following as crucial elements. The liver should be fully mobilized by dividing its ligaments, so that the organ can then be everted outside of the abdominal cavity. This step allows full exposure of the portal hepatis and facilitates the subsequent detailed dissection. This maneuver does impair venous return to the heart by kinking the cava and may need a concomitant increase in intravenous volume support. The dissection itself must be wide. There are three key portal plate landmarks. Exposure of the origin of the umbilical vein from the left portal vein in the fossa of Rex; exposure of the (usual) extrahepatic bifurcation of the right portal pedicle and division of small veins to the plate directly from the portal vein to expose the caudate lobe posteriorly. It is important to realize that actually excising liver parenchyma ( coring ) does not improve bile drainage, presumably because any divided ductules simply become obliterated by subsequent scar tissue. A portoenterostomy using a measured retrocolic 40-cm Roux loop completes the surgery. Although formerly stomas and more latterly intussusception-valves have been advocated to reduce cholangitis, the evidence for benefit remains unconvincing and hasn t altered our practice. 29 There are a whole range of possible pharmacological therapies which have been suggested to improve postoperative results. However, none have been subjected to anything like acceptable scientific scrutiny. For instance, there are anecdotal small number studies suggesting benefit from corticosteroids, 30 ursodeoxycholic acid 31 and even Chinese herbs. 32 An early, interim analysis from our institution on a double blind, randomized study on postoperative prednisolone failed to show any benefit in terms of clearance of jaundice or need for transplantation (unpublished results). Prognostic factors There are many factors, which will influence surgical outcome in biliary atresia. Some are unalterable (eg, degree of cirrhosis at presentation, absence of, or paucity of, microscopic bile ductules at the level of section) and some are subject to change (eg, surgical experience, untreated cholangitis). In large centers with experienced surgeons, about 50 to 60% of all infants will clear their jaundice and achieve a normal ( 20 mol/l) bilirubin. 33,34 These should do well and have a good quality of long-term survival with their native liver. 35,36 In those with no effect from the Kasai (usually apparent within 2-3 months), then active consideration should be given to early liver transplantation. Children with BASM do less well in comparison to non-syndromic infants, although because of the unequal size of the two groups, this can be difficult to prove statistically. Larger studies from both the UK 5,34 and France 37 have been able to show this effect definitively. Of course, one of the reasons for the increased mortality in this group is related to the associated malformations especially severe congenital cardiac disease and sudden death seen with hepatopulmonary syndrome. 38,39 This latter complication is associated with BASM, and appears to be due to vasoactive substances derived from the mesenteric circulation bypassing sinusoidal inactivation (Table 2). 38 The age of the infant has an effect on outcome although this is not as clear-cut as was once thought. It is not a linear effect and it is difficult to determine real variation in outcome at anywhere up to 80 days of age. Beyond that fibrosis does begin to be detrimental although even beyond 100 days the Kasai can have advantages and even long-term jaundicefree survival. 27 Complications post-kasai Cholangitis Cholangitis occurs most commonly in the year following primary surgery in about 30 to 50% of children. 29,33,40 Paradoxically, it only occurs in children with some degree of bile flow, not in those with early failure. Clinically, it is characterized by worsening jaundice, fever and acholic stools. The diagnosis may be confirmed by blood culture or by percutaneous liver biopsy but it is important to treat suspected cases early with broad-spectrum antibiotics effective against Gram-negative organisms. Recalcitrant cholangitis can be a problem in some children. This can be asso-

5 46 Seminars in Pediatric Surgery, Vol 14, No 1, February 2005 Table 2 Surgical outcome of portoenterostomy (recent experience) Reference Period N 5-year native liver survival 5-year actuarial survival Davenport et al London , % 41% , % Chardot et al France % 70% 27% Altman et al New York &Denver % 35% Schweiser et al Tubingen, Germany % Nio et al Japan %* 69 78%* 66% Howard et al Sendai, Japan % 60% 60% % 68% 60% % 56% 51% Wildhaber et al. Ann Arbor, USA % Van Heurn et al Hong Kong % Davenport et al. England &Wales % 89% 10-year native liver survival * Expressed in yearly cohorts. Only survival statistics for Sendai series quoted. 66 patients used in calculation. 4-year estimate only. ciated with parenchymal cyst formation 41 and some authors have advocated percutaneous aspiration or internal drainage to overcome putative defects in bile drainage. 42 A brief course of high-dose steroids has also be been advocated by some institutions. 43 Portal hypertension Increased portal venous pressure has been shown in virtually all infants at the time of the Kasai operation, however subsequent portal hypertension depends both on the degree of established fibrosis and, most importantly, the response to surgery. 44 There is a relationship with biochemical liver function and variceal development and in those who fail and need early transplantation about 30% will have had a significant variceal bleed. In those who respond well to initial Kasai, but who have established fibrosis then variceal development can be delayed and presentation with bleeding perhaps only occurring at 2 to 3 years. Although injection sclerotherapy retains a role in treating varices in infants, 45 most older children are suitable for endoscopic variceal banding. 46 Where liver function is poor, then liver transplantation needs to be actively considered. jaundice rate was 57%. 34 The next unequivocal criterion of success is the 5-year native liver survival rate, which therefore regards the need for transplant or death as end-points. Recent figures have ranged from 29 to 68% in large centers 33,36,47-52 to 32 to 62% in national registries. 1,2,34,37 Long-term results (ie, 10 years or greater) are less readily available as Kasai s operation was not readily performed or even available to infants born in the 1970s and early 1980s. Table 1 summarizes some recently published series from around the world and Figure 2 illustrates the most recent experience in England and Wales with a national policy of centralizing the care of all infants born with biliary atresia to only three large surgical centers. Our own figures suggest that 10 to 15% will have a truly excellent long-term, symptom-free, hospital-free, normal liver biochemistry existence although even in those their liver histology is still very abnormal. 35 The prospect of native liver survival to adulthood is probably only available Recent results An excellent outcome following portoenterostomy can be characterized as clearance of jaundice (to normal levels), abbreviation of hepatic fibrosis (ie, absence of clinical portal hypertension) and minimization of the tendency to ascending cholangitis. Just how many actually achieve this is fiercely debated. In the recently published experience from the three designated centers in England and Wales, the clearance of Figure 2 Outcome of 148 infants born with biliary atresia in England and Wales between January 1999 to July 2002 (reproduced with permission 34 ).

6 Davenport 47 to a minority 36,52 and a successful liver transplant procedure at some later point in life should probably be a realistic aim for the majority of infants born with biliary atresia. 53,54 References 1. Nio M, Ohi R, Miyano T, et al: Five and 10-year survival rates after surgery for biliary atresia: A report from the Japanese Registry. J Pediatr Surg 38: , McKiernan PJ, Baker AJ, Kelly DA: The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 355:25-29, Fischler B, Haglund B, Ajern A: A population-based study on the incidence and possible pre- and perinatal etiological risk factors of biliary atresia. J Pediatr 141: , Yoon PW, Bresee JS, Olney RS, et al: Epidemiology of biliary atresia: A population based study. Pediatrics 101: , Davenport M, Savage M, Mowat AP, et al: The Splenic Malformation syndrome. Surgery 113: , Tan CEL, Driver M, Howard ER, et al: Extrahepatic biliary atresia: A first-trimester event? Clues from light microscopy and immunohistochemistry. J Pediatr Surg 29: , Jenner RE, Howard ER: Unsaturated monohydroxy bile acids as a cause of idiopathic obstructive cholangiopathy. Lancet 2: , Riepenhoff-Talty M, Gouvea V, Evans MJ, et al: Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 174:8-15, Fischler B, Rodensjo P, Nemeth A, et al: Cytomegalovirus DNA detection on Guthrie cards in patients with neonatal cholestasis. Arch Dis Child 80:F130-F134, Ho CW, Shioda K, Shirasaki K, et al: The pathogenesis of biliary atresia: A morphological study of the hepatobiliary system and the hepatic artery. J Pediatr Gastrol Nutr 16:53-60, Davenport M, Gonde C, Redkar R, et al: Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia. J Pediatr Surg 36: , Mack CL, Tucker RM, Sokol RL, et al: Biliary atresia is associated with CD4 Th1 cell-mediated portal tract inflammation. 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7 48 Seminars in Pediatric Surgery, Vol 14, No 1, February Price MR, Sartorelli KH, Karrer FM, et al: Management of esophageal varices in children by endoscopic variceal ligation. J Pediatr Surg 31: , Valayer J: Conventional treatment of biliary atresia: Long-term results. J Pediatr Surg 31: , Altman RP, Lilly JR, Greenfield J, et al: A multivariable risk factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia. Ann Surg 226: , Van Heurn LW, Saing H, Tam PK: Portoenterostomy for biliary atresia: Long-term survival and prognosis after esophageal variceal bleeding. J Pediatr Surg 39:6-9, Schweizer P, Schweizer M, Schellinger K, et al: Prognosis of extrahepatic bile duct atresia after hepatoportoenterostomy. Pediatr Surg Int 16: , Wildhaber BA, Coran AG, Dongowski RA, et al: The Kasai portoenterostomy for biliary atresia: A review of 27-year experience with 81 patients. J Pediatr Surg 38: , Kuroda T, Saeki M, Nakano M, et al: Biliary atresia, the next generation: A review of liver function, social activity, and sexual development in the late post-operative period. J Pediatr Surg 37: , Diem HV, Evrard V, Vinh HT, et al: Pediatric liver transplantation for biliary atresia: Results of primary grafts in 328 recipients. Transplantation 75:1692-7, Evrard V, Otte JB, Sokal E, et al: Impact of surgical and immunological parameters in pediatric liver transplantation: A multivariate analysis in 500 consecutive recipients of primary grafts. Ann Surg 239: , 2004