Skip to main content
Log in

Liver fibrosis in biliary atresia

  • Review Article
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Background

Biliary atresia (BA) is the most common cause of obstructive jaundice in infants. Although the Kasai procedure has greatly improved the prognosis, most patients still need liver transplantation (LT) for long-term survival. The pathogenesis of BA has not been fully clarified, and liver fibrosis in BA is far beyond biliary obstructive cirrhosis.

Data sources

Literature reviews were underwent through PubMed. Persistent inflammation, immune response, biliary epithelial–mesenchymal transition, matrix deposition, decompensated angiogenesis, and unique biliary structure development all contribute to the fibrosis process. Observed evidences in such fields have been collected and form the backbone of this review.

Results

Interactions of the multiple pathways accelerate this process.

Conclusions

Understanding the mechanisms of the liver fibrosis in BA may pave the way to improved survival after the Kasai procedure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bates MD, Bucuvalas JC, Alonso MH, Ryckman FC. Biliary atresia: pathogenesis and treatment. Semin Liver Dis. 1998;18:281–93.

    Article  CAS  PubMed  Google Scholar 

  2. Bessho K. Complications and quality of life in long-term survivors of biliary atresia with their native livers. J Pediatr. 2015;167:1202–6.

    Article  PubMed  Google Scholar 

  3. Shneider BL, Mazariegos GV. Biliary atresia: a transplant perspective. Liver Transpl. 2007;13:1482–95.

    Article  PubMed  Google Scholar 

  4. Gibeli NE, Tanuri U, de Mello ES, Rodrigues CJ. Bile duct ligation in neonatal rats: is it a valid experimental model for biliary atresia studies? Pediatr Transplant. 2009;13:81–8.

    Article  Google Scholar 

  5. Mack CI, Tuker RM, Lu BR, Sokol RJ, Fontenot AP, Ueno Y, et al. Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia. Hepatology. 2006;44:1231–9.

    Article  CAS  PubMed  Google Scholar 

  6. Shimadera S, Iwai N, Deguchi E, Kimura O, Ono S, Fumino S, et al. Significance of ductal plate malformation in the postoperative clinical course of biliary atresia. J Pediatr Surg. 2008;43:304–7.

    Article  PubMed  Google Scholar 

  7. Safwan M, Ramachandran P, Vij M, Shanmugam N, Rela M. Impact of ductal plate malformation on survival with native liver in children with biliary atresia. Pediatr Surg Int. 2015;31:837–43.

    Article  PubMed  Google Scholar 

  8. Vijayan V, El Tan C. Computer-generated three-dimensional morphology of the hepatic hilar bile ducts in biliary atresia. J Pediatr Surg. 2000;35:1230–5.

    Article  CAS  PubMed  Google Scholar 

  9. Cocjin J, Rosenthal P, Buslon V, Luk L Jr, Barajas L, Geller SA, et al. Bile ductule formation in fetal, neonatal, and infant livers compared with extrahepatic biliary atresia. Hepatology. 1996;24:568–74.

    Article  CAS  PubMed  Google Scholar 

  10. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Desmet VJ. Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered. Virchows Arch. 2011;458:251–9.

    Article  PubMed  Google Scholar 

  12. Stamp LA, Braxton DR, Wu J, Akopian V, Hasegawa K, Chandrasoma PT, et al. The GCTM-5 epitope associated with the muciun-like glycoprotein FCGBP marks progenitor cells in tissues of endodermal origin. Stem Cells. 2012;30:1999–2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mavila N, James D, Shivakumar P, Nguyen MV, Utley S, Mak K, et al. Expansion of promnin-1-expressing cells in association with fibrosis of biliary atresia. Hepatology. 2014;60:941–53.

    Article  CAS  PubMed  Google Scholar 

  14. Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr. 2006;148:467–74.

    Article  PubMed  Google Scholar 

  15. Schwarz KB, Haber BH, Rosenthal P, Mack CL, Moore J, Bove K, et al. Extrahepatic anomalies in infants with biliary atresia: results of a large prospective North American multicenter study. Hepatology. 2013;58:1724–31.

    Article  PubMed  Google Scholar 

  16. Davit-Spraul A, Baussan C, Hermeziu B, Bernard O, Jacquemin E. CFC1 gene involvement in biliary atresia with polysplenia syndrome. J Pediatr Gastroenterol Nutr. 2008;46:111–2.

    Article  CAS  PubMed  Google Scholar 

  17. Guttman OR, Roberts EA, Schreiber RA, Barker CC, Ng VL. Canadian pediatric hepatology research group. Biliary atresia with associated structural malformations in Canadian infants. Liver Int. 2011;31:1485–93.

    Article  PubMed  Google Scholar 

  18. Wells ML, Fenstad ER, Poterucha JT, Hough DM, Young PM, Araoz PA, et al. Imaging findings of congestive hepatopathy. Radioqraphics. 2016;36:1024–37.

    Google Scholar 

  19. Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol. 2015;62:934–45.

    Article  CAS  PubMed  Google Scholar 

  20. Harada K, Nakanuma Y. Biliary innate immunity: function and modulation. Mediators Inflamm. 2010;2010:373878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zani A, Quaglia A, Hadzić N, Zuckerman M, Davenport M. Cytomegalovirus-associated biliary atresia: an aetiological and prognostic subgroup. J Pediatr Surg. 2015;50:1739–45.

    Article  PubMed  Google Scholar 

  22. Mack CL. The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis. 2007;27:233–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rauschenfels S, Krassmann M, Al-Masri AN, Verhagen W, Leonhardt J, Kuebler JF, et al. Incidence of hepatotropic viruses in biliary atresia. Eur J Pediatr. 2009;168:469–76.

    Article  PubMed  Google Scholar 

  24. Kobayashi A, Kawai S, Ohbe Y, Benno Y. Fecal flora of infants with biliary atresia: effects of the absence of bile on fecal flora. Am J Clin Nutr. 1988;48:1211–3.

    Article  CAS  PubMed  Google Scholar 

  25. Lee JY, Lim LT, Quak SH, Prabhakaran K, Aw M. Cholangitis in children with biliary atresia: health-care resource utilisation. J Paediatr Child Health. 2014;50:196–201.

    Article  PubMed  Google Scholar 

  26. Lien TH, Bu LN, Wu JF, Chen HL, Chen AC, Lai MW, et al. Use of Lactobacillus casei rhamnosus to prevent cholangitis in biliary atresia after Kasai pperation. J Pediatr Gastroenterol Nutr. 2015;60:654–8.

    Article  PubMed  Google Scholar 

  27. Bu LN, Chen HL, Chang CJ, Ni YH, Hsu HY, Lai HS, et al. Prophylactic oral antibiotics in prevention of recurrent cholangitis after the Kasai portoenterostomy. J Pediatr Surg. 2003;38:590–3.

    Article  PubMed  Google Scholar 

  28. Zani A, Quaqlia A, Hadzić N, Zuckerman M, Davenport M. Cytomegalovirus-associated biliary atresia: an aetiological and prognostic subgroup. J Pediatr Surg. 2015;50:1739–45.

    Article  PubMed  Google Scholar 

  29. Kotb MA, El Henawy A, Talaat S, Aziz M, El Tagy GH, El Barbary MM, et al. Immune-mediated liver injury: prognostic value of CD4 + , CD8 + , and CD68 + in infants with extrahepatic biliary atresia. J Pediatr Surg. 2005;40:1252–7.

    Article  PubMed  Google Scholar 

  30. Feldman AG, Mack CL. Biliary atresia: cellular dynamics and immune dysregulation. Semin Pediatr Surg. 2012;21:192–200.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Vejchapipat P, Poomsawat S, Chongsrisawat V, Honsawek S, Poovorawan Y. Elevated serum IL-18 and interferon-gamma in medium-term survivors of biliary atresia. Eur J Pediatr Surg. 2012;22:29–33.

    Article  CAS  PubMed  Google Scholar 

  32. Lu BR, Brindley SM, Tucker RM, Lambert CL, Mack CL. α-enolase autoantibodies cross-reactive to viral proteins in a mouse model of biliary atresia. Gastroenterology. 2010;139:1753–61.

    Article  CAS  PubMed  Google Scholar 

  33. Hertel PM, Crawford SE, Bessard BA, Estes MK. Prevention of cholestasis in the murine rotavirus-induced biliary atresia model using passive immunization and nonreplicating virus-like particles. Vaccine. 2013;31:5778–84.

    Article  CAS  PubMed  Google Scholar 

  34. Mohanty SK, Donnelly B, Lobeck I, Walther A, Dupree P, Coots A, et al. The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia. Hepatology. 2017;65:1278–92.

    Article  CAS  PubMed  Google Scholar 

  35. Matthews RP, Eauclaire SF, Mugnier M, Lorent K, Cui S, Ross MM, et al. DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia. Hepatology. 2011;53:905–14.

    Article  CAS  PubMed  Google Scholar 

  36. Chou MH, Chuang JH, Eng HL, Chen CM, Wang CH, Chen CL, et al. Endotoxin and CD14 in the progression of biliary atresia. J Transl Med. 2010;21(8):138.

    Article  CAS  Google Scholar 

  37. Shivakumar P, Sabla G, Mohanty S, McNeal M, Ward R, Stringer K, et al. Effector role of neonatal hepatic CD8 + lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia. Gastroenterology. 2007;133:268–77.

    Article  CAS  PubMed  Google Scholar 

  38. Li J, Rzaumilava N, Gores GJ, Walters S, Mizuochi T, Mourya R, et al. Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. J Clin Invest. 2014;124:3241–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Marvie P, Lisbonne M, L’helgoualc’h A, Rauch M, Turlin B, Preisser L, et al. Interlecukin-33 overexpression is associated with liver fibrosis in mice and humans. J Cell Mol Med. 2010;14:1726–39.

    Article  CAS  PubMed  Google Scholar 

  40. Tucker RM, Feldman AG, Fenner EK, Mack CL. Regulatory T cells inhibit Th1 cell-mediated bile duct injury in murine biliary atresia. J Hepatol. 2013;59:790–6.

    Article  CAS  PubMed  Google Scholar 

  41. Brindley SM, Lanham AM, Karrer FM, Tucker RM, Fontenot AP, Mack CL. Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells. Hepatology. 2012;55:1130–8.

    Article  CAS  PubMed  Google Scholar 

  42. Hill R, Quaqlia A, Hussain M, Hadzic N, Mieli-Vergani G, Vergani D, et al. Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome. J Pediatr Surg. 2015;50:1297–303.

    Article  PubMed  Google Scholar 

  43. Yang Y, Liu YJ, Tang ST, Yang L, Yang J, Cao GQ, et al. Elevated Th17 cells accompanied by decreased regulatory T cells and cytokine environment in infants with biliary atresia. Pediatr Surg Int. 2013;29:1249–60.

    Article  PubMed  Google Scholar 

  44. Schulze F, Schardt K, Wedemeyer I, Konze E, Wendland K, Dirsch O, et al. Epithelial–mesenchyal transition of biliary epithelial cells in advanced liver fibrosis. Verh Dtsch Ges Pathol. 2007;91:250–6 (in German).

    CAS  PubMed  Google Scholar 

  45. Ogawa T, Lizuka M, Sekiya Y, Yoshizato K, Ikeda K, Kawada N. Suppression of type I collagen production by microRNA-29b in cultured human stellate cells. Biochem Biophys Res Commun. 2010;39:316–21.

    Article  CAS  Google Scholar 

  46. Amara S, Lopez K, Banan B, Brown SK, Whalen M, Myles E, et al. Synergistic effect of pro-inflammatory TNFα and IL-17 in periostin mediated collagen deposition: potential role in liver fibrosis. Mol Immunol. 2015;64:26–35.

    Article  CAS  PubMed  Google Scholar 

  47. Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A. Transforming growth factor-betal induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem. 2007;282:22089–101.

    Article  CAS  PubMed  Google Scholar 

  48. Whitby T, Schroeder D, Kim HS, Petersen C, Dirsch O, Baumann U, et al. Modifications in integrin expression and extracellular matrix composition in children with biliary atresia. Klin Padiatr. 2015;227:15–22.

    Article  CAS  PubMed  Google Scholar 

  49. Huang CC, Chuang JH, Chou MH, Wu CL, Chen CM, Wang CC, et al. Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis. Mod Pathol. 2005;18:941–50.

    Article  CAS  PubMed  Google Scholar 

  50. Kerola A, Lampela H, Lohi J, Heikkilä P, Mutanen A, Hagström J, et al. Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia. J Pathol Clin Res. 2016;2:187–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Deng YH, Pu CL, Li YC, Zhu J, Xiang C, Zhang MM, et al. Analysis of biliary epithelial–mesenchymal transition in portal tract fibrogenesis in biliary atresia. Dig Dis Sci. 2011;56:731–40.

    Article  CAS  PubMed  Google Scholar 

  52. Li FB, Zhao H, Peng KR, Gao ZG, Huang SJ, Tou JF, et al. Expression of transforming growth factor-β1 and connective tissue growth factor in congenital biliary atresia and neonatal hepatitis liver tissue. Genet Mol Res. 2016. https://doi.org/10.4238/gmr.15017217.

    Article  PubMed  Google Scholar 

  53. Xiao Y, Zhou Y, Chen Y, Zhou K, Wen J, Wang Y, et al. The expression of epithelial–mesenchymal transition-related proteins in biliary epithelial cells is associated with liver fibrosis in biliary atresia. Pediatr Res. 2015;77:310–5.

    Article  CAS  PubMed  Google Scholar 

  54. Miao CG, Yang YY, He X, Huang C, Huang Y, Zhang L, et al. Wnt signaling in liver fibrosis: progress, challenges and potential directions. Biochimie. 2013;95:2326–35.

    Article  CAS  PubMed  Google Scholar 

  55. Kurioka K, Wato M, Iseki T, Tanaka A, Morita S. Differential expression of the epithelial mesenchymal transition factors Snail, Slug, Twist, TGF-β, and E-cadherin in ameloblastoma. Med Mol Morphol. 2017;50:68–75.

    Article  CAS  PubMed  Google Scholar 

  56. Paternostro C, David E, Novo E, Parola M. Hypoxia, angiogenesis and liver fibrogenesis in the progression of chronic liver diseases. World J Gastroenterol. 2010;16:281–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology. 2002;35:1010–21.

    Article  CAS  PubMed  Google Scholar 

  58. Lee HC, Chang TY, Yeung CY, Chan WT, Jiang CB, Chen WF, et al. Genetic variation in the vascular endothelial growth factor gene is associated with biliary atresia. J Clin Gastroenterol. 2010;44:135–9.

    Article  CAS  PubMed  Google Scholar 

  59. Yang L, Kwon J, Popv Y, Gajdos GB, Ordog T, Brekken RA, et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology. 2014;146:1339–50.

    Article  CAS  PubMed  Google Scholar 

  60. DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology. 2015;61:1740–6.

    Article  CAS  PubMed  Google Scholar 

  61. Liu Y, Wang Z, Wang J, Lam W, Kwong S, Li F, et al. A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signaling. Liver Int. 2013;33:504–15.

    Article  CAS  PubMed  Google Scholar 

  62. Yu ZY, Bai YN, Luo LX, Wu H, Zeng Y. Expression of microRNA-150 targeting vascular endothelial growth factor-A is downregulated under hypoxia during liver regeneration. Mol Med Rep. 2013;8:287–93.

    Article  CAS  PubMed  Google Scholar 

  63. Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol. 2010;53:976–80.

    Article  PubMed  Google Scholar 

  64. Nakamura l, Zakharia K, Banini BA, Mikhail DS, Kim TH, Yang JD, et al. Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling. PLoS One. 2014;9:e92273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of China (No. 81400576).

Author information

Authors and Affiliations

Authors

Contributions

WJS and MW reviewed and wrote the draft, and SZ and GC directed and edited this scientific work. All the authors approved the final version of the manuscript.

Corresponding author

Correspondence to Shan Zheng.

Ethics declarations

Ethical approval

This work had the permit from IRB of the Children’s Hospital of Fudan University.

Conflict of interest

The authors have no conflicts of interest or ties to disclose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, WJ., Chen, G., Wang, M. et al. Liver fibrosis in biliary atresia. World J Pediatr 15, 117–123 (2019). https://doi.org/10.1007/s12519-018-0203-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-018-0203-1

Keywords

Navigation