Semin Liver Dis 2007; 27(3): 233-242
DOI: 10.1055/s-2007-985068
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Pathogenesis of Biliary Atresia: Evidence for a Virus-Induced Autoimmune Disease

Cara L. Mack1
  • 1Pediatric Liver Center and Liver Transplant Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital, University of Colorado at Denver-Health Sciences Center, Denver, Colorado
Further Information

Publication History

Publication Date:
08 August 2007 (online)

ABSTRACT

Biliary atresia is a mystifying cause of neonatal cholestasis, manifested by progressive inflammation and fibrosis of both the extrahepatic and intrahepatic bile ducts. It is a devastating disease that leads to cirrhosis and the need for liver transplantation in the majority of children. The etiology is unknown, and one theory is that it may involve a primary perinatal hepatobiliary viral infection and a secondary generation of an autoimmune-mediated bile duct injury. This review will outline the evidence from both human and murine studies supporting a potential cholangiotropic viral infection as the initiator of bile duct injury in biliary atresia and the role of the adaptive immune response and autoimmunity in progression of disease. Delineating the pathways of immune and autoimmune-mediated bile duct injury within biliary atresia could stimulate development of new medical interventions aimed at suppressing the specific immune response, decreasing the inflammatory damage to bile ducts, and delaying or negating the need for liver transplantation.

REFERENCES

  • 1 Chen S M, Chang M H, Du J C et al.. Screening for biliary atresia by infant stool color card in Taiwan.  Pediatrics. 2006;  117 1147-1154
  • 2 Hung P Y, Chen C C, Chen W J et al.. Long-term prognosis of patients with biliary atresia: a 25 year summary.  J Pediatr Gastroenterol Nutr. 2006;  42 190-195
  • 3 Sokol R J, Mack C L. Etiopathogenesis of biliary atresia.  Semin Liver Dis. 2001;  21 517-524
  • 4 Balistreri W F, Grand R, Hoofnagle J et al.. Biliary atresia: current concepts and research directions. Summary of a symposium.  Hepatology. 1996;  23 1682-1692
  • 5 Gosseye S, Otte J B, De Meyer R, Maldague P. A histological study of extrahepatic biliary atresia.  Acta Paediatr Belg. 1977;  30 85-90
  • 6 Ohya T, Fujimoto T, Shimomura H et al.. Degeneration of intrahepatic bile duct with lymphocyte infiltration into biliary epithelial cells in biliary atresia.  J Pediatr Surg. 1995;  30 515-518
  • 7 Sokol R J, Mack C L, Narkewicz M R, Karrer F M. Pathogenesis and outcome of biliary atresia: current concepts.  J Pediatr Gastroenterol Nutr. 2003;  37 4-21
  • 8 Lykavieris P, Chardot C, Sokhn M et al.. Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver.  Hepatology. 2005;  41 366-371
  • 9 Bucuvalas J C, Ryckman F C, Atherton H et al.. Predictors of cost of liver transplantation in children: a single center study.  J Pediatr. 2001;  139 66-74
  • 10 Riepenhoff-Talty M, Houvea V, Evans M J et al.. Detection of group C rotavirus in infants with extrahepatic biliary atresia.  J Infect Dis. 1996;  174 8-15
  • 11 Morecki R, Glaser J H, Cho S, Balistreri W F, Horwitz M S. Biliary atresia and reovirus type 3 infection.  N Engl J Med. 1982;  307 481-484
  • 12 Tyler K L, Sokol R J, Oberhaus S M et al.. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts.  Hepatology. 1998;  27 1475-1482
  • 13 Jevon G P, Kimmick J E. Biliary atresia and cytomegalovirus infection: a DNA study.  Pediatr Dev Pathol. 1999;  2 11-14
  • 14 Schreiber R A, Kleinman R E. Genetics, immunology, and biliary atresia: an opening or a diversion?.  J Pediatr Gastroenterol Nutr. 1993;  16 111-113
  • 15 Tan C E, Driver M, Howard E R et al.. Extrahepatic biliary atresia: a first-trimester event? Clues from light microscopy and immunohistochemistry.  J Pediatr Surg. 1994;  29 808-814
  • 16 Oldstone M B. Molecular and cellular mechanisms, pathogenesis, and treatment of insulin-dependent diabetes obtained through study of a transgenic model of molecular mimicry.  Curr Top Microbiol Immunol. 2005;  296 65-87
  • 17 Marrack P, Kappler J, Kotzin B L. Autoimmune disease: why and where it occurs.  Nat Med. 2001;  7 899-905
  • 18 Fujinami R S, Oldstone M B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity.  Science. 1985;  230 1043-1045
  • 19 Naucler C S, Larsson S, Moller E. A novel mechanism for virus-induced autoimmunity in humans.  Immunol Rev. 1996;  152 175-192
  • 20 Fae K C, da Silva D D, Oshiro S E et al.. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease.  J Immunol. 2006;  176 5662-5670
  • 21 Ellis N M, Li Y, Hildebrand W, Fischetti V A, Cunningham M W. T cell mimicry and epitope specificity of cross-reactive T cell clones from rheumatic heart disease.  J Immunol. 2005;  175 5448-5456
  • 22 Poole B D, Scofield R H, Harley J B, James J A. Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus.  Autoimmunity. 2006;  39 63-70
  • 23 Wucherpfennig K W, Strominger J L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein.  Cell. 1995;  80 695-705
  • 24 Rao V P, Kajon A E, Spindler K R, Carayanniotis G. Involvement of epitope mimicry in potentiation but not initiation of autoimmune disease.  J Immunol. 1999;  162 5888-5893
  • 25 Olson J K, Croxford J L, Calenoff M A, Dal Canto M C, Miller S D. A virus-induced molecular mimicry model of multiple sclerosis.  J Clin Invest. 2001;  108 311-318
  • 26 Zhao Z S, Granucci F, Yeh L, Schaffer P A, Cantor H. Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection.  Science. 1998;  279 1344-1347
  • 27 Beisel K W, Srinivasappa J, Prabhakar B S. Identification of a putative shared epitope between Coxsackie virus B4 and alpha cardiac myosin heavy chain.  Clin Exp Immunol. 1991;  86 49-55
  • 28 Drut R, Drut R M, Gomez M A et al.. Presence of human papillomavirus in extrahepatic biliary atresia.  J Pediatr Gastroenterol Nutr. 1998;  27 530-535
  • 29 Domiati-Saad R, Dawson D B, Margraf L R et al.. Cytomegalovirus and human herpesvirus 6, but not human papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic biliary atresia.  Pediatr Dev Pathol. 2000;  3 367-373
  • 30 Fjaer R B, Bruu A L, Nordbo S A. Extrahepatic bile duct atresia and viral involvement.  Pediatr Transplant. 2005;  9 68-73
  • 31 Glaser J H, Balistreri W F, Morecki R. Role of reovirus type 3 in persistent infantile cholestasis.  J Pediatr. 1984;  105 912-915
  • 32 Richardson S C, Bishop R F, Smith A L. Reovirus serotype 3 infection in infants with extrahepatic biliary atresia or neonatal hepatitis.  J Gastroenterol Hepatol. 1994;  9 264-268
  • 33 Steele M I, Marshall C M, Lloyd R E, Randolph V E. Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease.  Hepatology. 1995;  21 697-702
  • 34 Saito T, Shinozaki K, Matsunaga T et al.. Lack of evidence for reovirus infection in tissues from patients with biliary atresia and congenital dilatation of the bile duct.  J Hepatol. 2004;  40 203-211
  • 35 Papadimitriou J M. The biliary tract in acute murine reovirus 3 infection.  Am J Pathol. 1968;  52 595-611
  • 36 Bangaru B, Morecki R, Glaser J H, Gartner L M, Horwitz M S. Comparative studies of biliary atresia in the human newborn and reovirus-induced cholangitis in weanling mice.  Lab Invest. 1980;  43 456-462
  • 37 Parashar K, Tarlow M J, McCrae M A. Experimental reovirus type 3-induced murine biliary tract disease.  J Pediatr Surg. 1992;  27 843-847
  • 38 Wilson G A, Morrison L A, Fields B N. Association of the reovirus S1 gene with serotype 3-induced biliary atresia in mice.  J Virol. 1994;  68 6458-6465
  • 39 Barton E S, Youree B E, Ebert D H et al.. Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease.  J Clin Invest. 2003;  111 1823-1833
  • 40 Rosenberg D P, Morecki R, Lollini L O, Glaser J, Cornelius C E. Extrahepatic biliary atresia in a rhesus monkey (Macaca mulatta).  Hepatology. 1983;  3 577-580
  • 41 Gilger M A, Matson D O, Conner M E et al.. Extraintestinal rotavirus infections in children with immunodeficiency.  J Pediatr. 1992;  120 912-917
  • 42 Qiao H, Zhaori G, Jiang Z et al.. Detection of group C rotavirus antigen in bile duct and liver tissues of an infant with extrahepatic biliary atresia.  Chin Med J (Engl). 1999;  112 93-95
  • 43 Bobo L, Ojeh C, Chiu D et al.. Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia.  Pediatr Res. 1997;  41 229-234
  • 44 Riepenhoff-Talty M, Schaekel K, Clark H F et al.. Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice.  Pediatr Res. 1993;  33 394-399
  • 45 Petersen C, Biermanns D, Kuske M et al.. New aspects in a murine model for extrahepatic biliary atresia.  J Pediatr Surg. 1997;  32 1190-1195
  • 46 Petersen C, Grassholl S, Luciano L. Diverse morphology of biliary atresia in an animal model.  J Hepatol. 1998;  28 603-607
  • 47 Czech-Schmidt G, Verhagen W, Szavay P et al.. Immunological gap in the infectious animal model for biliary atresia.  J Surg Res. 2001;  101 62-67
  • 48 Mack C L, Tucker R M, Sokol R J, Kotzin B L. Armed CD4+ effector cells and activated macrophages participate in bile duct injury in murine biliary atresia.  Clin Immunol. 2005;  115 200-209
  • 49 Allen S R, Jafri M, Donnelly B et al.. Effect of rotavirus strain on the murine model of biliary atresia.  J Virol. 2007;  81 1671-1679
  • 50 Ko H M, Kim K S, Park J W et al.. Congenital cytomegalovirus infection: three autopsy case reports.  J Korean Med Sci. 2000;  15 337-432
  • 51 Martelius T, Krogerus L, Hockerstedt K, Bruggeman C, Lautenschlager I. Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts.  Hepatology. 1998;  27 996-1002
  • 52 Evans P C, Coleman N, Wreghitt T G, Wight D G, Alexandder G J. Cytomegalovirus infection of bile duct epithelial cells, hepatic artery and portal venous endothelium in relation to chronic rejection of liver grafts.  J Hepatol. 1999;  31 913-920
  • 53 De Tommaso A M, Andrade P D, Costa S, Escanhoela C, Hessel G. High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis.  BMC Infect Dis. 2005;  5 108
  • 54 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 57-64
  • 55 Dillon P W, Belchis D, Minnick K, Tracy T. Differential expression of the major histocompatibility antigens and ICAM-1 on bile duct epithelial cells in biliary atresia.  Tohoku J Exp Med. 1997;  181 33-40
  • 56 Broome U, Nemeth A, Hultcrantz R, Scheynius A. Different expression of HLA-DR and ICAM-1 in livers from patients with biliary atresia and Byler's disease.  J Hepatol. 1997;  26 857-862
  • 57 Davenport M, Gonde C, Redkar R et al.. Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia.  J Pediatr Surg. 2001;  36 1017-1025
  • 58 Ahmed A F, Ohtani H, Nio M et al.. CD8+ T cells infiltrating into bile ducts in biliary atresia do not appear to function as cytotoxic T cells: a clinicopathological analysis.  J Pathol. 2001;  193 383-389
  • 59 Mack C L, Tucker R M, Sokol R J et al.. Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation.  Pediatr Res. 2004;  56 79-87
  • 60 Ohya T, Fujimoto T, Shimomura H, Miyano T. Degeneration of intrahepatic bile duct with lymphocyte infiltration into biliary epithelial cells in biliary atresia.  J Pediatr Surg. 1995;  30 515-518
  • 61 Mack C L, Falta M T, Sullivan A K et al. Oligoclonal expansions of CD4+ and CD8+ T cells in the target organ of patients with biliary atresia.  Gastroenterology. 2007;  , doi: 10.1053/j.gastro.2007.04.032
  • 62 Bezerra J A, Tiao G, Ryckman F C et al.. Genetic induction of proinflammatory immunity in children with biliary atresia.  Lancet. 2002;  360 1653-1659
  • 63 Leonhardt J, Stanulla M, von Wasielewski R et al.. Gene expression profile of the infective murine model for biliary atresia.  Pediatr Surg Int. 2006;  22 84-89
  • 64 Carvalho E, Liu C, Shivakumar P et al.. Analysis of the biliary transcriptome in experimental biliary atresia.  Gastroenterology. 2005;  129 713-717
  • 65 Shivakumar P, Campbell K M, Sabla G E et al.. Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia.  J Clin Invest. 2004;  114 322-329
  • 66 Mohanty S K, Shivakumar P, Sabla G, Bezerra J A. Loss of IL-12 modifies the pro-inflammatory response but does not prevent duct obstruction in experimental biliary atresia.  BMC Gastroenterol. 2006;  6 14
  • 67 Tucker R M, Hendrickson R, Mukaida N, Gill R G, Mack C L. Progressive biliary destruction is independent of a functional TNF-α pathway in a rhesus rotavirus-induced murine model of biliary atresia.  Viral Immunol. 2007;  20 34-43
  • 68 Hadchouel M, Hugon R N, Odievre M. Immunoglobulin deposits in the biliary remnants of extrahepatic biliary atresia: a study by immunoperoxidase staining in 128 infants.  Histopathology. 1981;  5 217-221
  • 69 Vasiliauskas E, Targan S, Cobb L, Vidrich A, Rosenthal P. Biliary atresia: an autoimmune disorder?.  Hepatology. 1995;  22 87 (Abstract)
  • 70 Burch J M, Sokol R J, Narkewicz M R et al.. Autoantibodies in mothers of children with neonatal liver disease.  J Pediatr Gastroenterol Nutr. 2003;  37 262-267
  • 71 Mack C L, Tucker R M, Lu B R et al.. Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia.  Hepatology. 2006;  44 1231-1239
  • 72 Witebsky E, Rose N R, Terplan K, Paine J R, Egan R W. Chronic thyroiditis and autoimmunization.  J Am Med Assoc. 1957;  164 1439-1447
  • 73 Rose N R, Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited).  Immunol Today. 1993;  14 426-430
  • 74 Kerkar N, Hadzic N, Davies E et al.. De-novo autoimmune hepatitis after liver transplantation.  Lancet. 1998;  351 409-413
  • 75 Gupta P, Hart J, Millis J M, Cronin D, Brady L. De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation.  Transplantation. 2001;  71 664-668
  • 76 Broome U, Nemeth A, Hultcrantz R et al.. Different expression of HLA-DR and ICAM-1 in livers from patients with biliary atresia and Byler's disease.  J Hepatol. 1997;  26 857-862
  • 77 Feng J, Li M, Hu W, Tang H, Yu S. The aberrant expression of HLA-DR in intrahepatic bile ducts in patients with biliary atresia: an immunohistochemistry and immune electron microscopy study.  J Pediatr Surg. 2004;  39 1658-1662
  • 78 Donaldson P T, Clare M, Constantini P K et al.. HLA and cytokine gene polymorphisms in biliary atresia.  Liver. 2002;  22 213-219
  • 79 Yuasa T, Tsuji H, Kimura S et al.. Human leukocyte antigens in Japanese patients with biliary atresia: retrospective analysis of patients who underwent living donor liver transplantation.  Hum Immunol. 2005;  66 295-300
  • 80 A-Kader H H, El-Ayyouti M, Hawas S et al.. HLA in Egyptian children with biliary atresia.  J Pediatr. 2002;  141 432-433
  • 81 Dillon P W, Owings E, Cilley R et al.. Immunosuppression as adjuvant therapy for biliary atresia.  J Pediatr Surg. 2001;  36 80-85
  • 82 Meyers R L, Book L S, O'Gorman M A et al.. High-dose steroids, ursodeoxycholic acid and chronic intravenous antibiotics improve bile flow after Kasai procedure in infants with biliary atresia.  J Pediatr Surg. 2003;  38 406-411
  • 83 Muraji T, Nio M, Ohhama Y et al.. Postoperative corticosteroid therapy for bile drainage in biliary atresia: a nationwide study.  J Pediatr Surg. 2004;  39 1803-1805
  • 84 Kobayashi H, Yamataka A, Koga H et al.. Optimum prednisolone useage in patients with biliary atresia post-portoenterostomy.  J Pediatr Surg. 2005;  40 327-330
  • 85 Escobar M A, Jay C L, Brooks R M et al.. Effect of corticosteroid therapy on outcomes in biliary atresia after Kasai portoenterostomy.  J Pediatr Surg. 2006;  41 99-103
  • 86 Sokol R J. New North American research network focuses on biliary atresia and neonatal liver disease.  J Pediatr Gastroenterol Nutr. 2003;  36 1

Cara L MackM.D. 

Assistant Professor of Pediatrics, Pediatric Liver Center and Liver Transplant Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital, University of Colorado at Denver-Health Sciences Center

1056 E. 19th Avenue, Box B290, Denver, CO 80218

    >