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Published in: European Journal of Pediatrics 4/2009

01-04-2009 | Original Paper

Incidence of hepatotropic viruses in biliary atresia

Authors: Stefan Rauschenfels, Miriam Krassmann, Ahmed N. Al-Masri, Willem Verhagen, Johannes Leonhardt, Joachim F. Kuebler, Claus Petersen

Published in: European Journal of Pediatrics | Issue 4/2009

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Abstract

Biliary atresia (BA) is the most frequent indication for paediatric liver transplantation. We tested the hypothesis of a viral aetiology of this disease by screening liver samples of a large number of BA patients for the common human hepatotropic viruses. Moreover, we correlated our findings to the expression of Mx protein, which has been shown to be significantly up-regulated during viral infections. Seventy-four liver biopsies (taken during Kasai portoenterostomy) were tested by polymerase chain reaction (PCR) for DNA viruses (herpes simplex virus [HSV], Epstein-Barr virus [EBV], varicella zoster virus [VZV], cytomegalovirus [CMV], adenovirus, parvovirus B19 and polyoma BK) and RNA viruses (enteroviruses, rotavirus and reovirus 3). Mx protein expression was assessed by immunohistochemistry. Virus DNA/RNA was found in less than half of the biopsies (8/74 CMV, 1/74 adenovirus; 21/64 reovirus, 1/64 enterovirus). A limited number presented with double infection. Patients that had detectable viral RNA/DNA in their liver biopsies were significantly older than virus-free patients (P = 0.037). The majority (54/59) of the liver biopsies showed expression of Mx proteins in hepatocytes, bile ducts and epithelium. Our data suggest that the known hepatotropic viruses do not play a major role in the aetiology and progression of BA. Their incidence appears to be, rather, a secondary phenomenon. Nonetheless, the inflammatory response in the livers of BA patients mimics that observed during viral infections.
Literature
1.
go back to reference A-Kader HH, Nowicki MJ, Kuramoto KI, Baroudy B, Zeldis JB, Balistreri WF (1994) Evaluation of the role of hepatitis C virus in biliary atresia. Pediatr Infect Dis J 13:657–659PubMedCrossRef A-Kader HH, Nowicki MJ, Kuramoto KI, Baroudy B, Zeldis JB, Balistreri WF (1994) Evaluation of the role of hepatitis C virus in biliary atresia. Pediatr Infect Dis J 13:657–659PubMedCrossRef
2.
go back to reference Al-Masri AN, Werfel T, Jakschies D, von Wussow P (1997) Intracellular staining of Mx proteins in cells from peripheral blood, bone marrow and skin. Mol Pathol 50:9–14PubMedCrossRef Al-Masri AN, Werfel T, Jakschies D, von Wussow P (1997) Intracellular staining of Mx proteins in cells from peripheral blood, bone marrow and skin. Mol Pathol 50:9–14PubMedCrossRef
3.
go back to reference Al-Masri AN, Flemming P, Rodeck B, Melter M, Leonhardt J, Petersen C (2006) Expression of the interferon-induced Mx proteins in biliary atresia. J Pediatr Surg 41:1139–1143PubMedCrossRef Al-Masri AN, Flemming P, Rodeck B, Melter M, Leonhardt J, Petersen C (2006) Expression of the interferon-induced Mx proteins in biliary atresia. J Pediatr Surg 41:1139–1143PubMedCrossRef
4.
5.
go back to reference Batusic DS, Armbrust T, Saile B, Ramadori G (2004) Induction of Mx-2 in rat liver by toxic injury. J Hepatol 40:446–453PubMedCrossRef Batusic DS, Armbrust T, Saile B, Ramadori G (2004) Induction of Mx-2 in rat liver by toxic injury. J Hepatol 40:446–453PubMedCrossRef
6.
go back to reference Bezerra JA, Tiao G, Ryckman FC, Alonso M, Sabla GE, Shneider B, Sokol RJ, Aronow BJ (2002) Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet 360:1563–1659CrossRef Bezerra JA, Tiao G, Ryckman FC, Alonso M, Sabla GE, Shneider B, Sokol RJ, Aronow BJ (2002) Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet 360:1563–1659CrossRef
7.
go back to reference Bobo L, Ojeh C, Chiu D, Machado A, Colombani P, Schwarz K (1997) Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia. Pediatr Res 41:229–234PubMedCrossRef Bobo L, Ojeh C, Chiu D, Machado A, Colombani P, Schwarz K (1997) Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia. Pediatr Res 41:229–234PubMedCrossRef
8.
go back to reference Brown WR, Sokol RJ, Levin MJ, Silverman A, Tamaru T, Lilly JR, Hall RJ, Cheney M (1988) Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis. J Pediatr 113:670–676PubMedCrossRef Brown WR, Sokol RJ, Levin MJ, Silverman A, Tamaru T, Lilly JR, Hall RJ, Cheney M (1988) Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis. J Pediatr 113:670–676PubMedCrossRef
9.
go back to reference Chang MH, Huang HH, Huang ES, Kao CL, Hsu HY, Lee CY (1992) Polymerase chain reaction to detect human cytomegalovirus in livers of infants with neonatal hepatitis. Gastroenterology 103:1022–1025PubMed Chang MH, Huang HH, Huang ES, Kao CL, Hsu HY, Lee CY (1992) Polymerase chain reaction to detect human cytomegalovirus in livers of infants with neonatal hepatitis. Gastroenterology 103:1022–1025PubMed
10.
go back to reference Chieux V, Hober D, Harvey J, Lion G, Lucidarme D, Forzy G, Duhamel M, Cousin J, Ducoulombier H, Wattré P (1998) The MxA protein levels in whole blood lysates of patients with various viral infections. J Virol Methods 70(2):183–191PubMedCrossRef Chieux V, Hober D, Harvey J, Lion G, Lucidarme D, Forzy G, Duhamel M, Cousin J, Ducoulombier H, Wattré P (1998) The MxA protein levels in whole blood lysates of patients with various viral infections. J Virol Methods 70(2):183–191PubMedCrossRef
11.
go back to reference Davenport M, Gonde C, Redkar R, Koukoulis G, Tredger M, Mieli-Vergani G, Portmann B, Howard ER (2001) Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia. J Pediatr Surg 36:1017–1025PubMedCrossRef Davenport M, Gonde C, Redkar R, Koukoulis G, Tredger M, Mieli-Vergani G, Portmann B, Howard ER (2001) Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia. J Pediatr Surg 36:1017–1025PubMedCrossRef
12.
go back to reference De Tommaso AM, Andrade PD, Costa SC, Escanhoela CA, Hessel G (2005) High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis. BMC Infect Dis 5:108PubMedCrossRef De Tommaso AM, Andrade PD, Costa SC, Escanhoela CA, Hessel G (2005) High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis. BMC Infect Dis 5:108PubMedCrossRef
13.
go back to reference Domiati-Saad R, Dawson DB, Margraf LR, Finegold MJ, Weinberg AG, Rogers BB (2000) Cytomegalovirus and human herpesvirus 6, but not human papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic biliary atresia. Pediatric Dev Pathol 3:367–373CrossRef Domiati-Saad R, Dawson DB, Margraf LR, Finegold MJ, Weinberg AG, Rogers BB (2000) Cytomegalovirus and human herpesvirus 6, but not human papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic biliary atresia. Pediatric Dev Pathol 3:367–373CrossRef
14.
go back to reference Drut R, Drut RM, Gómez MA, Cueto Rúa E, Lojo MM (1998) Presence of human papillomavirus in extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 27:530–535PubMedCrossRef Drut R, Drut RM, Gómez MA, Cueto Rúa E, Lojo MM (1998) Presence of human papillomavirus in extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 27:530–535PubMedCrossRef
15.
go back to reference Fischler B, Ehrnst A, Forsgren M, Örvell C, Nemeth A (1998) The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 27:57–64PubMedCrossRef Fischler B, Ehrnst A, Forsgren M, Örvell C, Nemeth A (1998) The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 27:57–64PubMedCrossRef
16.
go back to reference Fjær RB, Bruu A-L, Nordbø SA (2005) Extrahepatic bile duct atresia and viral involvement. Pediatr Transplant 9:68–73PubMedCrossRef Fjær RB, Bruu A-L, Nordbø SA (2005) Extrahepatic bile duct atresia and viral involvement. Pediatr Transplant 9:68–73PubMedCrossRef
17.
go back to reference Floege J, Burg M, Al Masri AN, Gröne HJ, von Wussow P (1999) Expression of interferon-inducible Mx-proteins in patients with IgA nephropathy or Henoch-Schönlein purpura. Am J Kidney Dis 33:434–440PubMedCrossRef Floege J, Burg M, Al Masri AN, Gröne HJ, von Wussow P (1999) Expression of interferon-inducible Mx-proteins in patients with IgA nephropathy or Henoch-Schönlein purpura. Am J Kidney Dis 33:434–440PubMedCrossRef
18.
go back to reference Frese M, Kochs G, Feldmann H, Hertkorn C, Haller O (1996) Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein. J Virol 70(2):915–923PubMed Frese M, Kochs G, Feldmann H, Hertkorn C, Haller O (1996) Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein. J Virol 70(2):915–923PubMed
19.
go back to reference Heim A, Ebnet C, Harste G, Pring-Akerblom P (2003) Rapid and quantitative detection of human adenovirus DNA by real-time PCR. J Med Virol 70:228–239PubMedCrossRef Heim A, Ebnet C, Harste G, Pring-Akerblom P (2003) Rapid and quantitative detection of human adenovirus DNA by real-time PCR. J Med Virol 70:228–239PubMedCrossRef
20.
go back to reference Huang YH, Chou MH, Du YY, Huang CC, Wu CL, Chen CL, Chuang JH (2007) Expression of toll-like receptors and type 1 interferon specific protein MxA in biliary atresia. Lab Invest 87(1):66–74PubMedCrossRef Huang YH, Chou MH, Du YY, Huang CC, Wu CL, Chen CL, Chuang JH (2007) Expression of toll-like receptors and type 1 interferon specific protein MxA in biliary atresia. Lab Invest 87(1):66–74PubMedCrossRef
21.
go back to reference Jevon GP, Dimmik JE (1999) Biliary atresia and cytomegalovirus infection: a DNA study. Pediatr Dev Pathol 2:11–14PubMedCrossRef Jevon GP, Dimmik JE (1999) Biliary atresia and cytomegalovirus infection: a DNA study. Pediatr Dev Pathol 2:11–14PubMedCrossRef
22.
go back to reference Landing BH (1974) Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst—the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 6:113–139PubMed Landing BH (1974) Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst—the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 6:113–139PubMed
23.
go back to reference Leonhardt J, Stanulla M, von Wasielewski R, Skokowa J, Kübler J, Ure BM, Petersen C (2006) Gene expression profile of the infective murine model for biliary atresia. Pediatr Surg Int 22(1):84–89PubMedCrossRef Leonhardt J, Stanulla M, von Wasielewski R, Skokowa J, Kübler J, Ure BM, Petersen C (2006) Gene expression profile of the infective murine model for biliary atresia. Pediatr Surg Int 22(1):84–89PubMedCrossRef
24.
go back to reference Morecki R, Glaser JH, Cho S, Balistreri WF, Horwitz MS (1982) Biliary atresia and reovirus type 3 infection. N Engl J Med 307:481–484PubMed Morecki R, Glaser JH, Cho S, Balistreri WF, Horwitz MS (1982) Biliary atresia and reovirus type 3 infection. N Engl J Med 307:481–484PubMed
25.
go back to reference Pavlovic J, Zürcher T, Haller O, Staeheli P (1990) Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 64(7):3370−3375PubMed Pavlovic J, Zürcher T, Haller O, Staeheli P (1990) Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 64(7):3370−3375PubMed
26.
go back to reference Petersen C (2006) Pathogenesis and treatment opportunities for biliary atresia. Clin Liver Dis 10:73−88PubMedCrossRef Petersen C (2006) Pathogenesis and treatment opportunities for biliary atresia. Clin Liver Dis 10:73−88PubMedCrossRef
27.
go back to reference Riepenhoff-Talty M, Schaekel K, Clark HF, Mueller W, Uhnoo I, Rossi T, Fisher J, Ogra PL (1993) Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr Res 33:394–399PubMedCrossRef Riepenhoff-Talty M, Schaekel K, Clark HF, Mueller W, Uhnoo I, Rossi T, Fisher J, Ogra PL (1993) Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr Res 33:394–399PubMedCrossRef
28.
go back to reference Riepenhoff-Talty M, Gouvea V, Evans MJ, Svensson L, Hoffenberg E, Sokol RJ, Uhnoo I, Greenberg SJ, Schäkel K, Zhaori G, Fitzgerald J, Chong S, el-Yousef M, Nemeth A, Brown M, Piccoli D, Hyams J, Ruffin D, Rossi T (1996) Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 174:8–15PubMed Riepenhoff-Talty M, Gouvea V, Evans MJ, Svensson L, Hoffenberg E, Sokol RJ, Uhnoo I, Greenberg SJ, Schäkel K, Zhaori G, Fitzgerald J, Chong S, el-Yousef M, Nemeth A, Brown M, Piccoli D, Hyams J, Ruffin D, Rossi T (1996) Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 174:8–15PubMed
29.
go back to reference Saito T, Shinozaki K, Matsunaga T, Ogawa T, Etoh T, Muramatsu T, Kawamura K, Yoshida H, Ohnuma N, Shirasawa H (2004) Lack of evidence for reovirus infection in tissues from patients with biliary atresia and congenital dilatation of the bile duct. J Hepatol 40:203–211PubMedCrossRef Saito T, Shinozaki K, Matsunaga T, Ogawa T, Etoh T, Muramatsu T, Kawamura K, Yoshida H, Ohnuma N, Shirasawa H (2004) Lack of evidence for reovirus infection in tissues from patients with biliary atresia and congenital dilatation of the bile duct. J Hepatol 40:203–211PubMedCrossRef
31.
go back to reference Schreiber RA, Kleinman RE (1993) Genetics, immunology, and biliary atresia: an opening or a diversion? J Pediatr Gastroenterol Nutr 16:111–113PubMedCrossRef Schreiber RA, Kleinman RE (1993) Genetics, immunology, and biliary atresia: an opening or a diversion? J Pediatr Gastroenterol Nutr 16:111–113PubMedCrossRef
32.
33.
go back to reference Sokol RJ, Mack C, Narkewicz MR, Karrer FM (2003) Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 37:4–21PubMedCrossRef Sokol RJ, Mack C, Narkewicz MR, Karrer FM (2003) Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 37:4–21PubMedCrossRef
34.
go back to reference Steel MI, Marshall CM, Lloyd RE, Randolph VE (1995) Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease. Hepatology 21:697–702 Steel MI, Marshall CM, Lloyd RE, Randolph VE (1995) Reovirus 3 not detected by reverse transcriptase-mediated polymerase chain reaction analysis of preserved tissue from infants with cholestatic liver disease. Hepatology 21:697–702
35.
go back to reference Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM, Narkewicz MR, Tyson RW, Murphy JR, Low R, Brown WR (1998) Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 27:1475–1482PubMedCrossRef Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM, Narkewicz MR, Tyson RW, Murphy JR, Low R, Brown WR (1998) Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 27:1475–1482PubMedCrossRef
Metadata
Title
Incidence of hepatotropic viruses in biliary atresia
Authors
Stefan Rauschenfels
Miriam Krassmann
Ahmed N. Al-Masri
Willem Verhagen
Johannes Leonhardt
Joachim F. Kuebler
Claus Petersen
Publication date
01-04-2009
Publisher
Springer-Verlag
Published in
European Journal of Pediatrics / Issue 4/2009
Print ISSN: 0340-6199
Electronic ISSN: 1432-1076
DOI
https://doi.org/10.1007/s00431-008-0774-2

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