BILIARY ATRESIA ATRESIE DES VOIES BILAIRES

Update: 02 Sept 2001

BILIARY ATRESIA
Christophe Chardot, MD, PhD*

*Paediatric surgery unit,
Centre Hospitalier Universitaire de Bicêtre,
78 rue du Général Leclerc
94275 LE KREMLIN BICÊTRE
France
Tel : (33) 1 45 21 31 84
Fax : (33) 1 45 21 31 89

E-mail : christophe.chardot@bct.ap-hop-paris.fr

Epidemiology
Anatomy
Aetiology
Diagnosis
Treatment
Outcome
acknowledgments
References

Biliary atresia (BA) is characterized by biliary obstruction of unknown origin, occurring in the perinatal period . BA is the main cause of cholestatic jaundice in neonates. The common histopathologic picture is inflammatory damage of intra- and extrahepatic bile ducts, and sclerosis with narrowing or obliteration of bile ducts . Untreated, this condition leads to cirrhosis and death within the first years of life. Surgical treatment usually involves two steps : the Kasai operation , a palliative bilio-intestinal derivation performed in the neonatal period, and subsequent liver transplantation, if needed because of failure of the Kasai operation to restore biliary flow and/or because of complications of cirrhosis . BA is the main indication for liver transplantation in infants and children.

Epidemiology:

The reported incidence of BA varies from 5 / 100000 live births in The Netherlands , 5.1 / 100000 in France , 6 / 100000 in the British Isles , 6.5 / 100000 in Texas , 7 / 100000 in Victoria Australia , 7.4 / 100000 in Atlanta USA and in Japan , 10.6 / 100000 in Hawaii , to 32 / 100000 in French Polynesia . Studies of time- and space-time distribution of BA cases did not produce convincing evidence of seasonal variations of incidence nor clustering, which were suspected only in studies with limited numbers of cases , but were not confirmed in studies with larger numbers of patients .

Anatomy:

Two different forms of BA are identified :

syndromic BA in which hepato-biliary disease is associated with various congenital anomalies such as polysplenia, cardiac or intra abdominal defects (situs inversus, median liver, pre-duodenal portal vein, absence of retro-hepatic inferior vena cava, intestinal malrotation).

Non-syndromic BA, in which the biliary damage is isolated.

Several surgical classifications of BA cases have been proposed. The French classification is based on the anatomical pattern of the extrahepatic biliary tract remnant :

Figure 1 : Anatomical types of biliary atresia

Type 1 (3%): Atresia limited to common bile duct

Type 2 (6%): Cyst in the liver hilum communicating with "hairy" intrahepatic bile ducts

Type 3 (19%): Gallbladder, cystic duct and common bile duct patent

Type 4 (72%): Complete extrahepatic biliary atresia

Aetiology:

The aetiology of BA is unknown. In sampling studies of digestive enzymes produced by foetal defecation in the amniotic fluid, gamma glutamyl transpeptidase levels were found to be low back to 18 weeks gestation in babies born with BA . Some cases of BA might be related to an anomaly of the morphogenesis of bile ducts, while others could be the result of an insult of normally developing bile ducts.

Human embryo studies showed similarities between the appearance of the developping bile ducts during the first trimester of pregnancy, and the residual ductules at the level of the porta hepatis in BA patients, suggesting that some forms of BA may be the result of an alteration of the remodeling process of the bile ducts originating from the ductal plate membrane . The persistence of foetal type bile ducts might lead to bile leak and severe secondary inflammatory reaction. Recent studies have focused on normal and altered bile duct morphogenesis and the mechanisms of hepatic fibrosis .

The role of viruses has been extensively studied. The association of BA with cytomegalovirus , respiratory syncitial virus , Epstein-Barr virus , and human papilloma virus has been reported, while no association with hepatitis A, B and C viruses has been found. Reovirus type 3 can cause cholangitis resembling BA in mice , and may be associated with spontaneous BA in the rhesus monkey . In human neonates, the association of reovirus type 3 and BA has been suggested in several studies but not supported in others . Rotavirus type A can cause biliary obstruction in newborn mice mimicking BA , and deleterious effects of rotavirus infection in mice can be prevented by interferon alpha . In humans, the role of rotavirus type C in the aetiology of BA is controversial .

Several observations support a genetic component in the pathogenesis of BA. Familial cases of BA have been reported although discordant sets of monozygotic twins have also been observed . Variations in the incidence of BA among different races have been reported in Hawaii and in Atlanta . The incidence of HLA B12 and haplotypes A9-B5 and A28-B35 was found to be higher in infants with BA as opposed to a control group in UK .

Diagnosis:

Since the early diagnosis is essential for effective surgical treatment , every neonatal jaundice which lasts more than two weeks should be explored, and BA searched for urgently .

Prenatal diagnosis: Prenatal diagnosis of BA remains exceptional. Types 1 and 2 of BA, which are rare, can be suspected on prenatal US scans if a cystic structure is detected in the liver hilum : post-natal check-up has to distinguish a cystic form of BA, which requires urgent surgery, and a choledocal cyst, whose treatment can usually be delayed.

Clinical features: After birth, the clinical triad of BA is : 1) jaundice which lasts after 2 weeks of life. 2) decoloured (white) stools, and dark urines . 3) hepatomegaly. The general condition of the child is usually good, as well as growth in weight and height. Late symptoms are: splenomegaly (portal hypertension), ascitis, hemorrhage, which can be intracranial (lack of absorption of vitamine K).

Ultrasonography: Ultrasonography of the liver is performed after 12 hours fasting (with IV fluids infusion): it shows no bile duct dilatation. BA can be suspected if the gallbladder is shrunken despite fasting, if the liver hilum appears exceedingly hyperechogenic ("triangular chord sign"), if there is a cyst in the liver hilum, if features of the polysplenia syndrome are identified: multiples spleens, preduodenal portal vein, absence of retrohepatic vena cava.

Cholangiography: In the cases where the gallbladder seems normal on US scans, a cholangiography is needed to assess the morphology and permeability of the biliary tree. The cholangiogram can be percutaneous (puncture of the gallbladder), endoscopic (ERCP) or operative.

Liver biopsy: The main features suggesting BA are biliary plugs, ductular proliferation, portal oedema and/or fibrosis. As in any other cause of neonetal cholestasis, giant cell transformation may be observed.

Others: Liver function tests show cholestasis (with elevated cholesterol and g GTs). Hepatobiliary scintigraphy (HIDA scans) shows failure to excrete the marker in the intestine, but this can also be observed in any severe neonatal cholestasis. Moreover, scintigraphy can be falsely reassuring in the early stage of BA.

Absence of medical causes of neonatal cholestasis: Medical causes of neonatal cholestasis have to be ruled out. The most common differential diagnosis are: Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), a 1 antitrypsine deficiency, cystic fibrosis.

In the experience of the Bicêtre team, the diagnosis of BA can be highly suspected in most cases with the analysis of clinical features, US scans, and after having ruled out the main medical causes of neonatal cholestasis. Cholangiography and/or liver biopsy are indicated only in cases where the diagnosis remains uncertain, especially when the gallbladder seems normal on US scans .

Treatment:

The current management of BA patients involves two steps: 1) in the neonatal period, the Kasai operation, which aims at restoring a biliary flow to the intestine. 2) subsequent liver transplantation in case of failure of the Kasai operation to restore the biliary flow and/or complications of the biliary cirrhosis.

The Kasai operation: hepatoporto-enterostomy:

After transverse supra-ombilical laparotomy, the diagnosis of biliary atresia is confirmed by inspection of the liver and biliary tract: in most cases (type 4: complete extrahepatic biliary atresia), the diagnosis is obvious with cholestatic +/- fibrotic liver, shrunken and fibrous gallbladder; if the gallbladder is still patent, or if there is a cyst of the liver hilum, the color of its content is noticed, and a cholangiography is performed. Features of the polysplenia syndrome, as well as any other intra-abdominal anomaly, are looked at. The portal pressure is measured through a small catheter introduced via the umbilical vein. After section of the falciform and left triangular ligaments, the liver is exteriorised through the incision. The extrahepatic biliary tree is excised together with the fibrous tissue situated inside the bifurcation of the portal vein at the level of the porta hepatis. A 45 cm Roux en Y loop is prepared and passed through the mesocolon to the liver hilum. An anastomosis is fashioned between the cut edge of the transsected tissue in the porta hepatis and the antimesenteric side of the Roux loop. A liver biopsy is performed.

Figure 2: Operative view of complete extra-hepatic biliary atresia

Figure 3 : Hepatoporto-enterostomy (Kasai procedure)

Many technical variants are possible, according to the anatomical pattern of the biliary remnant:

in type 1 BA: cholecysto-enterostomy, or hepatico-enterostomy.

in type 2 BA: kysto-enterostomy. This operation can be performed only if the hilar cyst communicates with the dystrophic intra-hepatic bile ducts (cholangiography).

in type 3 BA: hepatoporto-cholecystostomy. The patent galbladder, cystic duct and common bile duct are preserved. The gallbladder is mobilised with preservation of its pedicle. An anastomosis is performed between the gallbladder and the transsected tissue in the porta hepatis. Since there is no direct contact between the porta hepatis and the intestine, this operation is expected to reduce the risk of post operative cholangitis . Its specific complications are: bile leaks and post-operative biliary ascitis, kinking and obstruction of cystic duct and common bile duct

Figure 4: Hepatoporto-cholecystostomy

Post operative course:

Post-operatively, different drugs have been proposed either to reduce the inflammatory process at the liver hilum, which might lead to granulation and fibrous scar obstructing the biliary ductules, or to increase the biliary flow. Although recommended by several surgeons , the indication of corticosteroids remains controversial since a long-term benefit has not been proven and the risk of severe cholangitis could be increased.

Outcome after successful Kasai operation:

If the Kasai operation succeeds to restore the biliary flow, the stools become coloured, and jaundice progressively clears. This process may last several weeks or months. The evolution of the biliary cirrhosis is stopped or markedly delayed, and survival with native liver have been reported up to 20 or 30 years of life. Nevertheless, several complications may occur:

Cholangitis: Direct communication of the intestine to the dystrophic intrahepatic bile ducts, with poor biliary flow, can trigger ascending cholangitis, especially in the first weeks or months after the Kasai procedure, in 30 to 60% of cases . This infection may be severe and sometimes fulminant. It is revealed by signs of sepsis (fever, hypothermia, poor haemodynamics), recurrent jaundice (with biological cholestasis), white stools, liver pain. The diagnosis can be confirmed by cultures of blood and/or liver biopsies . The treatment requires IV antiobiotics, and non specific resuscitation measures. In case of recurrent and/or late cholangitis, digestive reflux in a short Roux en Y loop, obstruction of the Roux en Y loop, as well as infected intrahepatic biliary cavities, have to be ruled out. Recurrent cholangitis without "surgical" aetiology may require continuous antibioprophylaxis.

Portal hypertension: Portal hypertension occurs in at least two thirds of the chidren after portoenterostomy , even in case of complete restoration of the biliary flow. The most common localisation of the varices are: esophagus, stomach, Roux en Y loop, rectum. In case of failed Kasai operation, portal hypertension is treated by liver transplantation, but often require sclerotherapy or variceal ligation before liver replacement. In case of complete clearance of jaundice after the Kasai operation, conservative treatments are indicated: usually sclerotherapy or variceal ligation . Transjugular intrahepatic portosystemic shunts (TIPS) are rarely used in this indication due to the young age of these patients, the common hypoplasy of the portal vein in BA patients, the possible development of intrahepatic biliary cavities, and the risk of intimal proliferation in the shunt and secondary obstruction . Surgical porto-systemic shunts keep rare indications, when portal hypertension is isolated, with normal liver function and no sign of progressing liver disease, and varices not accessible to sclerotherapy or ligation . Severe hypersplenism may rarely require splenic artery embolisation .

Hepatopulmonary syndrome and pulmonary hypertension: As in patients with other causes of spontaneous (cirrhosis or prehepatic portal hypertension) or acquired (surgical) portosystemic shunts, pulmonary arteriovenous shunts or pulmonary hypertension may occur in BA patients, even after complete clearance of jaundice. They could be due to vasoactive substances released from the intestine and not cleared by the liver due to porto-systemic shunts. Pulmonary shunting is responsible for hypoxia, cyanosis, dyspnea, digital clubbing, while pulmonary hypertension is responsible of malaises and sudden death. The diagnosis is confirmed by pulmonary scintigraphy and echocardiography, respectively. Liver transplantation reverses pulmonary shunts , and can reverse pulmonary hypertension at its early stage .

Intrahepatic biliary cavities: Large intrahepatic biliary cysts may develop several months to years after the Kasai operation, even in patients with complete clearance of jaundice. These cavities may become infected and/or compress portal vein, requiring external drainage. Cystoenterostomy or liver transplantation may eventually be required.

Malignancies: Hepatocarcinomas, hepatoblastomas and cholangiocarcinomas have been described in the cirrhotic livers of patients with BA, in childhood or adulthood. Screening for malignancy has to be performed regularly in the follow-up of patients with successful Kasai operations.

Outcome after unsuccessfull Kasai operation

In case of failure of the Kasai operation to restore the biliary flow, biliary cirrhosis continues its progression and liver transplantation is required. Biliary atresia represents more than half of the indications of liver transplantation in children. In patients with primary failure of the Kasai operation, liver transplantation is usually performed in the second year of life, but may be necessary earlier (from 6 months of life) in case of rapid progression of the liver disease. In case of initial success of the Kasai operation, liver transplantation can be necessary later in childhood or adulthood, either due to recurrence of jaundice (secondary failure of the Kasai operation), or to various complications of cirrhosis despite complete clearance of jaundice.

The liver graft can be procured from a cadaveric donor: rarely a full size liver graft, procured from a size-matched paediatric donor; more often a left lobe (segments 2+3) or left liver (2+3+4) obtained after reduction or splitting of an adult liver graft. The liver graft can also be procured in a living related donor, usually one of the parents of the child.

Five and 10 year survival after liver transplantation for BA nowadays exceeds 80% . In most cases, quality of life of the transplanted patients is close to normal, regarding growth in height and weight as well as physical, intellectual and sexual development .

Overall outcome of BA patients

In a national study including all children with BA born in France between 1986 and 1996 , 5- and 10-year survival with native liver were 32% and 27 %, respectively. Overall survival of BA patients at 5 and 10 years was 71%. Independent prognostic factors at diagnosis for both survival with native liver and overall patient survival were : anatomical pattern of biliary remnant (worse from type 1 to type 4), polysplenia syndrome, early realisation of the Kasai operation, experience of the treating centre in the management of BA patients. With improvements of the overall management of BA patients, an overall survival of 90% is nowadays realistic .

Acknowledgments:

To paediatricians and surgeons of the 45 centres participating to the French observatory of biliary atresia.

To Pr Olivier Bernard and Frédéric Gauthier for their critical review of this manuscript.

References :

1. Alagille D. Extrahepatic biliary atresia. Hepatology 1984;4:7S-10S.

2. Gautier M, Eliot N. Extrahepatic biliary atresia: morphological study of 98 biliary remnants. Arch Path Lab Med 1981;105:397-402.

3. Kasai M, Kimura S, Asakura Y, Suzuki Y, Taira Y, Obashi E. Surgical treatment of biliary atresia. J Pediatr Surg 1968;3:665-675.

4. Otte JB, de Ville de Goyet J, Reding R, Hausleithner V, Sokal E, Chardot C, et al. Sequential treatment of biliary atresia with Kasai portoenterostomy and liver transplantation: a review. Hepatology 1994;20(1 Pt 2):41S-48S.

5. Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard JL, Auvert B. Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996. Hepatology 1999;30(3):606-11.

6. Houwen RH, Kerremans I, van Steensel-Moll HA, van Romunde LK, Bijleveld CM, Schweizer P. Time-space distribution of extrahepatic biliary atresia in The Netherlands and West Germany. Z Kinderchir 1988;43(2):68-71.

7. Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard JL, Auvert B. Epidemiology of biliary atresia in France: a national study 1986-96. J Hepatol 1999;31(6):1006-13.

8. McKiernan PJ, Baker AJ, Kelly DA. The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 2000;355(9197):25-9.

9. Strickland AD, Shannon K. Studies in the aetiology of extrahepatic biliary atresia: time-space clustering. Pediatrics 1982;100:749-53.

10. Danks DM, Campbell PE, Jack I, Rogers J, Smith AL. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child 1977;52:360-7.

11. Yoon PW, Bresee JS, Olney RS, James LM, Khoury MJ. Epidemiology of biliary atresia: a population-based study. Pediatrics 1997;99(3):376-82. 12. Chiba T, Ohi R, Kamiyama T, Nio M, Ibrahim M. Japanese biliary atresia registry. In: Ohi R, editor. Biliary atresia. Tokyo (Japan): ICOM Associates; 1991. p. 79-86.

13. Shim WK, Kasai M, Spence MA. Racial influence on the incidence of biliary atresia. Prog Pediatr Surg 1974;6:53-62.

14. Vic P, Gestas P, Mallet EC, Arnaud JP. Atrésie des voies biliaires en Polynésie française. Etude rétrospective de 10 ans. Arch Pediatr 1994;1(7):646-51.

15. Ayas MF, Hillemeier AC, Olson AD. Lack of evidence for seasonal variation in extrahepatic biliary atresia during infancy. J Clin Gastroenterol 1996;22(4):292-4.

16. Davenport M, Dhawan A. Epidemiologic study of infants with biliary atresia. Pediatrics 1998;101(4 Pt 1):729-30.

17. Howard ER. Biliary artesia. In: Stringer MD, Oldham KT, Mouriquand PDE, Howard ER, editors. Pediatric surgery and urology: long trem outcomes. London: WB Saunders; 1998. p. 402-16.

18. Gauthier F, Luciani JL, Chardot C, Branchereau S, de Dreuzy O, Lababidi A, et al. Determinants of life span after Kasai operation at the era of liver transplantation. Tohoku J Exp Med 1997;181(1):97-107.

19. Muller F, Oury JF, Dumez Y. Microvillar enzymes assays in amniotic fluid and fetal tisssues at different stages of development. Prenatal Diagnosis 1988;8:189-98.

20. Tan CE, Driver M, Howard ER, Moscoso GJ. Extrahepatic biliary atresia: a first-trimester event? Clues from light microscopy and immunohistochemistry. J Pediatr Surg 1994;29(6):808-14.

21. Desmet VJ. Ludwig symposium on biliary disorders--part I. Pathogenesis of ductal plate abnormalities. Mayo Clin Proc 1998;73(1):80-9.

22. Mazziotti MV, Willis LK, Heuckeroth RO, LaRegina MC, Swanson PE, Overbeek PA, et al. Anomalous development of the hepatobiliary system in the Inv mouse. Hepatology 1999;30(2):372-8.

23. Ramm GA, Nair VG, Bridle KR, Shepherd RW, Crawford DH. Contribution of hepatic parenchymal and nonparenchymal cells to hepatic fibrogenesis in biliary atresia. Am J Pathol 1998;153(2):527-35.

24. Fischler B, Ehrnst A, Forsgren M, Orvell C, Nemeth A. The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1998;27(1):57-64.

25. Hart MH, Kaufman SS, Vanderhoof JA, Erdman S, Linder J, Markin RS, et al. Neonatal hepatitis and extrahepatic biliary atresia associated with cytomegalovirus infection in twins. Am J Dis Child 1991;145(3):302-5.

26. Nadal D, Wunderli W, Meurmann O, Briner J, Hirsig J. Isolation of respiratory syncytial virus from liver tissue and extrahepatic biliary atresia material. Scand J Infect Dis 1990;22(1):91-3.

27. Weaver LT, Nelson R, Bell TM. The association of extrahepatic bile duct atresia and neonatal Epstein Barr virus infection. Acta Paediatr Scand 1984;73:155-7.

28. Drut R, Gomez MA, Drut RM, Cueto RE, Lojo M. [Human papillomavirus, neonatal giant cell hepatitis and biliary duct atresia]. Acta Gastroenterol Latinoam 1998;28(1):27-31.

29. Balistreri WF, Tabor E, Gerety RJ. Negative serology for hepatitis A and B viruses in 18 cases of neonatal cholestasis. Pediatrics 1980;66:269-71.

30. A-Kader HH, Nowicki MJ, Kuramoto KL, Baroudy B, Zeldis JB, Balistreri WF. Evaluation of the role of hepatitis C virus in biliary atresia. Pediatr Infect Dis J 1994;13:657-9.

31. Bangaru B, Morecki R, Glaser JH, Gartner LM, Horwitz MS. Comparative studies of biliary atresia in the human newborn and reovirus-induced cholangitis in weanling mice. Lab invest 1980;43:456-62.

32. Rosenberg DP, Morecki R, Lollini LO, Glaser J, Cornelius CE. Extrahepatic biliary atresia in a rhesus monkey (macaca mulata). Hepatology 1983;3:577-80.

33. Morecki R, Glaser JH, Cho S, Balistreri WF, Horwitz MS. Biliary atresia and reovirus type 3 infection. New Engl J Med 1982;307:481-4.

34. Glaser JH, Balistreri WF, Morechi R. Role of reovirus type 3 in persistent infantile cholestasis. J Pediatr 1984;105:912-5.

35. Morecki R, Glaser JH, Johnson AB, Kress Y. Detection of reovirus type 3 in the porta hepatis of an infant with extrahepatic biliary atresia: ultrastructural and immunocytochemical study. Hepatology 1984;4:1137-42.

36. Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM, Narkewicz MR, et al. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 1998;27(6):1475-82.

37. Dussaix E, Hadchouel M, Tardieu M, Alagille D. Biliary atresia and reovirus type 3 infection. New Engl J Med 1984;310:658.

38. Brown WR, Sokol RJ, Levin MJ, Silverman A, Tamaru T, Lilly JR, et al. Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis. J Pediatr 1988;113(4):670-6.

39. Steele MI, Marshall CM, Lloyd RE, Randolph VE. Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease. Hepatology 1995;21(3):697-702.

40. Petersen C, Grasshoff S, Luciano L. Diverse morphology of biliary atresia in an animal model. J Hepatol 1998;28(4):603-7.

41. Petersen C, Bruns E, Kuske M, von Wussow P. Treatment of extrahepatic biliary atresia with interferon-alpha in a murine infectious model. Pediatr Res 1997;42(5):623-8.

42. Riepenhoff-Talty M, Gouvea V, Evans MJ, Svensson L, Hoffenberg E, Sokol RJ, et al. Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 1996;174(1):8-15.

43. Bobo L, Ojeh C, Chiu D, Machado A, Colombani P, Schwarz K. Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia. Pediatr Res 1997;41(2):229-34.

44. Cunningham ML, Sybert VP. Idiopathic extrahepatic biliary atresia: recurrence in sibs in two families. Am J Med Genet 1988;31(2):421-6.

45. Smith BM, Laberge JM, Schreiber R, Weber AM, Blanchard H. Familial biliary atresia in three siblings including twins. J Pediatr Surg 1991;26(11):1331-3.

46. Lachaux A, Descos B, Plauchu H, Wright C, Louis D, Raveau J, et al. Familial extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1988;7(2):280-3. 47. Gunasekaran TS, Hassall EG, Steinbrecher UP, Yong SL. Recurrence of extrahepatic biliary atresia in two half sibs. Am J Med Genet 1992;43(3):592-4.

48. Silveira TR, Salzano FM, Howard ER, Mowat AP. Extrahepatic biliary atresia and twinning. Braz J Med Biol Res 1991;24(1):67-71.

49. Hyams JS, Glaser JH, Leichtner AM, Morecki R. Discordance for biliary atresia in two sets of monozygotic twins. J Pediatr 1985;107:420-2.

50. Strickland AD, Shannon K, Coln CD. Biliary atresia in two sets of twins. J Pediatr 1985;107(418-20).

51. Poovorawan Y, Chongsrisawat V, Tanunytthawongse C, Norapaksunthorn T, Mutirangura A, Chandrakamol B. Extrahepatic biliary atresia in twins: zygosity determination by short tandem repeat loci. J Med Assoc Thai 1996;79 Suppl 1:S119-24.

52. Silveira TR, Salzano FM, Donaldson PT, Mieli-Vergani G, Howard ER, Mowat AP. Association between HLA and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1993;16(2):114-7.

53. Altman RP, Lilly JR, Greenfeld J, Weinberg A, van Leeuwen K, Flanigan L. A multivariable risk factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia: twenty-five years of experience from two centers. Ann Surg 1997;226(3):348-55.

54. Ibrahim M, Miyano T, Ohi R, Saeki M, Shiraki K, Tanaka K, et al. Japanese Biliary Atresia Registry, 1989 to 1994. Tohoku J Exp Med 1997;181(1):85-95.

55. Karrer FM, Lilly JR, Stewart BA, Hall RJ. Biliary atresia registry, 1976 to 1989. J Pediatr Surg 1990;25(10):1076-81.

56. Bernard O. Plaidoyer pour un diagnostic précoce de l'atrésie des voies biliaires. Douze erreurs à éviter. Arch Pediatr 1995;2(10):937-9.

57. Mieli-Vergani G, Howard ER, Portman B, Mowat AP. Late referral for biliary atresia--missed opportunities for effective surgery. Lancet 1989;1(8635):421-3.

58. Brunero M, de Dreuzy O, Herrera JM, Gauthier F, Valayer J. Diagnosi ecografica prenatale di una immagine cistica a carico dell'ilo epatico. Interpretazione per un adeguato trattamento. Minerva pediatr 1996;48:485-94.

59. Redkar R, Davenport M, Howard ER. Antenatal diagnosis of congenital anomalies of the biliary tract. J Pediatr Surg 1998;33(5):700-4.

60. Bernard O, Gauthier F. Progrès récents en hépatologie pédiatrique. Arch Fr Pediatr 1991;48(1):53-6.

61. Bernard O. Diagnostic précoce des cholestases néonatales. Arch Pediatr 1998;5(9):1031-5.

62. Valayer J. Atrésie des voies biliaires. Encyclopédie Médico Chirurgicale. 1990;Techniques chirurgicales. Appareil digestif:40980-9.

63. Lilly JR, Stellin G. Catheter decompression of hepatic portocholecystostomy. J Pediatr Surg 1982;17(6):904-5.

64. Lilly JR. Hepatic portocholecystostomy for biliary atresia. J Pediatr Surg 1979;14(3):301-4.

65. Freitas L, Gauthier F, Valayer J. Second operation for repair of biliary atresia. J Pediatr Surg 1987;22(9):857-60.

66. Kasai M, Suzuki H, Ohashi E, Ohi R, Chiba T, Okamoto A. Technique and results of operative management of biliary atresia. World J Surg 1978;2(5):571-9.

67. Altman RP, Anderson KD. Surgical management of intractable cholangitis following successful Kasai procedure. J Pediatr Surg 1982;17(6):894-900. 68. Karrer FM, Lilly JR. Corticosteroid therapy in biliary atresia. J Pediatr Surg 1985;20(6):693-5.

69. Valayer J. Conventional treatment of biliary atresia: long-term results. J Pediatr Surg 1996;31(11):1546-51. 70. Ohi R, Nio M, Chiba T, Endo N, Goto M, Ibrahim M. Long-term follow-up after surgery for patients with biliary atresia. J Pediatr Surg 1990;25(4):442-5.

71. Ecoffey C, Rothman E, Bernard O, Hadchouel M, Valayer J, Alagille D. Bacterial cholangitis after surgery for biliary atresia. J Pediatr 1987;111(6 Pt 1):824-9.

72. Burnweit CA, Coln D. Influence of diversion on the development of cholangitis after hepatoportoenterostomy for biliary atresia. J Pediatr Surg 1986;21(12):1143-6.

73. Kasai M, Okamoto A, Ohi R, Yabe K, Matsumura Y. Changes of portal vein pressure and intrahepatic blood vessels after surgery for biliary atresia. J Pediatr Surg 1981;16(2):152-9.

74. Ohi R, Mochizuki I, Komatsu K, Kasai M. Portal hypertension after successful hepatic portoenterostomy in biliary atresia. J Pediatr Surg 1986;21(3):271-4.

75. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management of esophageal varices in 61 children with biliary atresia. J Pediatr Surg 1989;24(5):438-42.

76. Sasaki T, Hasegawa T, Nakajima K, Tanano H, Wasa M, Fukui Y, et al. Endoscopic variceal ligation in the management of gastroesophageal varices in postoperative biliary atresia. J Pediatr Surg 1998;33(11):1628-32.

77. Rossle M, Siegerstetter V, Huber M, Ochs A. The first decade of the transjugular intrahepatic portosystemic shunt (TIPS): state of the art. Liver 1998;18(2):73-89.

78. Valayer J, Branchereau S. Portal hypertension: porto systemic shunts. In: Stringer MD, Oldham KT, Mouriquand PDE, Howard ER, editors. Pediatric surgery and urology: long term outcomes. London: W.B. Saunders; 1998. p. 439-46.

79. Chiba T, Ohi R, Yaoita M. Partial splenic embolization for hypersplenism in pediatric patients with special reference to its long-term efficacy. In: Ohi R, editor. Biliary atresia. Tokyo: ICOM Associates Inc; 1991. p. 154-8.

80. Yonemura T, Yoshibayashi M, Uemoto S, Inomata Y, Tanaka K, Furusho K. Intrapulmonary shunting in biliary atresia before and after living-related liver transplantation. Br J Surg 1999;86(9):1139-43.

81. Losay J, Piot D, Bougaran J, Ozier Y, Devictor D, Houssin D, et al. Early liver transplantation is crucial in children with liver disease and pulmonary artery hypertension. J Hepatol 1998;28(2):337-42.

82. Tsuchida Y, Honna T, Kawarasaki H. Cystic dilatation of the intrahepatic biliary system in biliary atresia after hepatic portoenterostomy. J Pediatr Surg 1994;29(5):630-4.

83. Tatekawa Y, Asonuma K, Uemoto S, Inomata Y, Tanaka K. Liver transplantation for biliary atresia associated with malignant hepatic tumors. J Pediatr Surg 2001;36(3):436-9.

84. Kulkarni PB, Beatty E, Jr. Cholangiocarcinoma associated with biliary cirrhosis due to congenital biliary atresia. Am J Dis Child 1977;131(4):442-4.

85. Reding R, de Goyet J, Delbeke I, Sokal E, Jamart J, Janssen M, et al. Pediatric liver transplantation with cadaveric or living related donors: comparative results in 90 elective recipients of primary grafts. J Pediatr 1999;134(3):280-6.

86. Goss JA, Shackleton CR, Swenson K, Satou NL, Nuesse BJ, Imagawa DK, et al. Orthotopic liver transplantation for congenital biliary atresia. An 11-year, single-center experience. Ann Surg 1996;224(3):276-87.

87. Valayer J, Gauthier F, Yandza T, Lababidi A, De Dreuzy O, Hamada H. Biliary atresia: results of long-term conservative treatment and of liver transplantation. Transplant Proc 1993;25(6):3290-2.

88. Codoner-Franch P, Bernard O, Alvarez F. Long-term follow-up of growth in height after successful liver transplantation. J Pediatr 1994;124(3):368-73.

89. Asonuma K, Inomata Y, Uemoto S, Egawa H, Kiuchi T, Okajima H, et al. Growth and quality of life after living-related liver transplantation in children. Pediatr Transplant 1998;2(1):64-9.

90. Midgley DE, Bradlee TA, Donohoe C, Kent KP, Alonso EM. Health-related quality of life in long-term survivors of pediatric liver transplantation. Liver Transpl 2000;6(3):333-9.

91. Rudolph JA, Balistreri WF. Optimal treatment of biliary atresia: halfway there! Hepatology 1999;30(3):808-10.