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Biliary atresia: the development, pathological features, and classification of the bile duct

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Abstract

Biliary atresia is an occlusive biliary disease involving intrahepatic and extrahepatic bile ducts. Its etiology and pathogenesis are unclear. There are many manifestations of bile duct involvement in biliary atresia, but little is known about its occurrence and development. In addition, different classification methods have been proposed in different periods of biliary atresia, each with its advantages and disadvantages. The combined application of biliary atresia classification will help to improve the survival rate of patients with native liver. Therefore, this article reviews the development, pathological features, and classification of intrahepatic and extrahepatic bile ducts in biliary atresia, to provide a reference for the study of the pathogenesis and the choice of treatment methods.

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References

  1. Bezerra JA, Wells RG, Mack CL et al (2018) Biliary atresia: clinical and research challenges for the twenty-first century. Hepatology 68(3):1163–1173. https://doi.org/10.1002/hep.29905

    Article  PubMed  Google Scholar 

  2. Boster JM, Feldman AG, Mack CL, Sokol RJ, Sundaram SS (2022) Malnutrition in biliary atresia: assessment, management, and outcomes. Liver Transpl 28(3):483–492. https://doi.org/10.1002/lt.26339

    Article  PubMed  Google Scholar 

  3. Kwong AJ, Ebel NH, Kim WR et al (2022) OPTN/SRTR 2020 Annual Data Report: Liver. Am J Transplant 22(Suppl 2):204–309. https://doi.org/10.1111/ajt.16978

    Article  PubMed  Google Scholar 

  4. Tomita H, Hara A (2022) Development of extrahepatic bile ducts and mechanisms of tumorigenesis: lessons from mouse models. Pathol Int. https://doi.org/10.1111/pin.13287

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lemaigre FP (2009) Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology 137(1):62–79. https://doi.org/10.1053/j.gastro.2009.03.035

    Article  CAS  PubMed  Google Scholar 

  6. Roskams T, Desmet V (2008) Embryology of extra- and intrahepatic bile ducts, the ductal plate. Anat Rec (Hoboken) 291(6):628–635. https://doi.org/10.1002/ar.20710

    Article  CAS  PubMed  Google Scholar 

  7. Tan CE, Moscoso GJ (1994) The develo** human biliary system at the porta hepatis level between 29 days and 8 weeks of gestation: a way to understanding biliary atresia. Part 1. Pathol Int 44(8):587–599. https://doi.org/10.1111/j.1440-1827.1994.tb01719.x

    Article  CAS  PubMed  Google Scholar 

  8. Terada T (2014) Development of extrahepatic bile duct excluding gall bladder in human fetuses: histological, histochemical, and immunohistochemical analysis. Microsc Res Tech 77(10):832–840. https://doi.org/10.1002/jemt.22406

    Article  CAS  PubMed  Google Scholar 

  9. Hunter MP, Wilson CM, Jiang X et al (2007) The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev Biol 308(2):355–367. https://doi.org/10.1016/j.ydbio.2007.05.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Muntean A, Davenport M (2022) Biliary atresia & choledochal malformation–Embryological and anatomical considerations. Semin Pediatr Surg 31(6):151235. https://doi.org/10.1016/j.sempedsurg.2022.151235

    Article  PubMed  Google Scholar 

  11. Spence JR, Lange AW, Lin SCJ et al (2009) Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev Cell 17(1):62–74. https://doi.org/10.1016/j.devcel.2009.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Coffinier C, Gresh L, Fiette L et al (2002) Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. Development 129(8):1829–1838. https://doi.org/10.1242/dev.129.8.1829

    Article  CAS  PubMed  Google Scholar 

  13. Sumazaki R, Shiojiri N, Isoyama S et al (2004) Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 36(1):83–87. https://doi.org/10.1038/ng1273

    Article  CAS  PubMed  Google Scholar 

  14. Ober EA, Lemaigre FP (2018) Development of the liver: insights into organ and tissue morphogenesis. J Hepatol 68(5):1049–1062. https://doi.org/10.1016/j.jhep.2018.01.005

    Article  CAS  PubMed  Google Scholar 

  15. Antoniou A, Raynaud P, Cordi S et al (2009) Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136(7):2325–2333. https://doi.org/10.1053/j.gastro.2009.02.051

    Article  CAS  PubMed  Google Scholar 

  16. Bai MR, Pei HY, Zhou Y et al (2023) Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia. Front Genet 14:1186882. https://doi.org/10.3389/fgene.2023.1186882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Adams JM, Huppert KA, Castro EC et al (2020) Sox9 is a modifier of the liver disease severity in a mouse model of Alagille syndrome. Hepatology 71(4):1331–1349. https://doi.org/10.1002/hep.30912

    Article  CAS  PubMed  Google Scholar 

  18. Wang W, Feng Y, Aimaiti Y, ** X, Mao X, Li D (2018) TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1-Notch-Sox9 signaling axis. J Cell Physiol 233(8):5780–5791. https://doi.org/10.1002/jcp.26304

    Article  CAS  PubMed  Google Scholar 

  19. Wu N, Nguyen Q, Wan Y et al (2017) The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. Lab Investig 97(7):843–853. https://doi.org/10.1038/labinvest.2017.29

    Article  CAS  PubMed  Google Scholar 

  20. Clotman F, Lannoy VJ, Reber M et al (2002) The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129(8):1819–1828. https://doi.org/10.1242/dev.129.8.1819

    Article  CAS  PubMed  Google Scholar 

  21. Vanderpool C, Sparks EE, Huppert KA, Gannon M, Means AL, Huppert SS (2012) Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo. Hepatology 55(1):233–243. https://doi.org/10.1002/hep.24631

    Article  CAS  PubMed  Google Scholar 

  22. Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G (2019) Ductular reaction in liver diseases: pathological mechanisms and translational significances. Hepatology 69(1):420. https://doi.org/10.1002/hep.30150

    Article  PubMed  Google Scholar 

  23. Zagory JA, Nguyen MV, Wang KS (2015) Recent advances in the pathogenesis and management of biliary atresia. Curr Opin Pediatr 27(3):389–394. https://doi.org/10.1097/MOP.0000000000000214

    Article  PubMed  PubMed Central  Google Scholar 

  24. Qi BN, Lv WJ, Jian JB et al (2023) Insight into microvascular adaptive alterations in the Glisson system of biliary atresia after Kasai portoenterostomy using X-ray phase-contrast CT. Eur Radiol 33(6):4082–4093. https://doi.org/10.1007/s00330-022-09364-4

    Article  PubMed  Google Scholar 

  25. Dc Y, Fr P (2011) Morphometrical and immunohistochemical study of intrahepatic bile ducts in biliary atresia. Eur J Gastroenterol Hepatol 23(9):759–765. https://doi.org/10.1097/MEG.0b013e32832e9df0

    Article  CAS  Google Scholar 

  26. Fabris L, Spirli C, Cadamuro M, Fiorotto R, Strazzabosco M (2017) Emerging concepts in biliary repair and fibrosis. Am J Physiol Gastrointest Liver Physiol 313(2):G102–G116. https://doi.org/10.1152/ajpgi.00452.2016

    Article  PubMed  PubMed Central  Google Scholar 

  27. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ (2019) Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol 16(5):269–281. https://doi.org/10.1038/s41575-019-0125-y

    Article  PubMed  PubMed Central  Google Scholar 

  28. Coc** J, Rosenthal P, Buslon V et al (1996) Bile ductule formation in fetal, neonatal, and infant livers compared with extrahepatic biliary atresia. Hepatology 24(3):568–574. https://doi.org/10.1002/hep.510240318

    Article  CAS  PubMed  Google Scholar 

  29. Arii R, Koga H, Arakawa A et al (2011) How valuable is ductal plate malformation as a predictor of clinical course in postoperative biliary atresia patients? Pediatr Surg Int 27(3):275–277. https://doi.org/10.1007/s00383-010-2793-0

    Article  PubMed  Google Scholar 

  30. Nguyen AHP, Pham YHT, Vu GH, Nguyen MH, Hoang TN, Holterman A (2021) Biliary atresia liver histopathological determinants of early post-Kasai outcome. J Pediatr Surg 56(7):1169–1173. https://doi.org/10.1016/j.jpedsurg.2021.03.039

    Article  PubMed  Google Scholar 

  31. Safwan M, Ramachandran P, Vij M, Shanmugam N, Rela M (2015) Impact of ductal plate malformation on survival with native liver in children with biliary atresia. Pediatr Surg Int 31(9):837–843. https://doi.org/10.1007/s00383-015-3728-6

    Article  PubMed  Google Scholar 

  32. Chusilp S, Balsamo F, Li B, Vejchapipat P, Pierro A (2023) Development of liver inflammatory injury in biliary atresia: from basic to clinical research. Pediatr Surg Int 39(1):207. https://doi.org/10.1007/s00383-023-05489-9

    Article  PubMed  Google Scholar 

  33. Desmet VJ (1992) Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation.” Hepatology 16(4):1069–1083. https://doi.org/10.1002/hep.1840160434

    Article  CAS  PubMed  Google Scholar 

  34. Low Y, Vijayan V, Tan CE (2001) The prognostic value of ductal plate malformation and other histologic parameters in biliary atresia: an immunohistochemical study. J Pediatr 139(2):320–322. https://doi.org/10.1067/mpd.2001.117003

    Article  CAS  PubMed  Google Scholar 

  35. Russo P, Magee JC, Anders RA et al (2016) Key histopathologic features of liver biopsies that distinguish biliary atresia from other causes of infantile cholestasis and their correlation with outcome: a multicenter study. Am J Surg Pathol 40(12):1601–1615. https://doi.org/10.1097/PAS.0000000000000755

    Article  PubMed  PubMed Central  Google Scholar 

  36. Takeda M, Sakamoto S, Uchida H et al (2021) The morphological and histopathological assessment of Alagille syndrome with extrahepatic bile duct obstruction: the importance of the differential diagnosis with subgroup “o” biliary atresia. Pediatr Surg Int 37(9):1167–1174. https://doi.org/10.1007/s00383-021-04932-z

    Article  PubMed  Google Scholar 

  37. Amarachintha SP, Mourya R, Ayabe H et al (2022) Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia. Hepatology 75(1):89–103. https://doi.org/10.1002/hep.32107

    Article  CAS  PubMed  Google Scholar 

  38. Frassetto R, Parolini F, Marceddu S et al (2018) Intrahepatic bile duct primary cilia in biliary atresia. Hepatol Res 48(8):664–674. https://doi.org/10.1111/hepr.13060

    Article  PubMed  Google Scholar 

  39. Lam WY, Tang CSM, So MT et al (2021) Identification of a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia patients implicates ciliary dysfunction as a novel disease mechanism. EBioMedicine 71:103530. https://doi.org/10.1016/j.ebiom.2021.103530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chiba T, Kasai M, Sasano N (1975) Reconstruction of intrahepatic bile ducts in congenital biliary atresia. Tohoku J Exp Med 115(2):99–110. https://doi.org/10.1620/tjem.115.99

    Article  CAS  PubMed  Google Scholar 

  41. Nio M, Ohi R, Miyano T et al (2003) Five- and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry. J Pediatr Surg 38(7):997–1000. https://doi.org/10.1016/s0022-3468(03)00178-7

    Article  PubMed  Google Scholar 

  42. Zhan J, Feng J, Chen Y, Liu J, Wang B (2017) Incidence of biliary atresia associated congenital malformations: a retrospective multicenter study in China. Asian J Surg 40(6):429–433. https://doi.org/10.1016/j.asjsur.2016.04.003

    Article  PubMed  Google Scholar 

  43. Kasai M, Sawaguchi M, Akiyama T et al (1976) A proposal for a new classification of biliary atresia. JJSPS 12:327–331

    Google Scholar 

  44. Superina R, Magee JC, Brandt ML et al (2011) The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival. Ann Surg 254(4):577–585. https://doi.org/10.1097/SLA.0b013e3182300950

    Article  PubMed  Google Scholar 

  45. Sasaki H, Nio M, Ando H et al (2021) Anatomical patterns of biliary atresia including hepatic radicles at the porta hepatis influence short- and long-term prognoses. J Hepatobiliary Pancreat Sci 28(11):931–941. https://doi.org/10.1002/jhbp.989

    Article  PubMed  Google Scholar 

  46. Muise AM, Turner D, Wine E, Kim P, Marcon M, Ling SC (2006) Biliary atresia with choledochal cyst: implications for classification. Clin Gastroenterol Hepatol 4(11):1411–1414. https://doi.org/10.1016/j.cgh.2006.07.005

    Article  PubMed  Google Scholar 

  47. Qipeng Z, Fang Y, Yilin Z et al (2022) The favorable prognosis of cystic biliary atresia may be related to early surgery and mild liver pathological changes. Pediatr Surg Int 38(2):217–224. https://doi.org/10.1007/s00383-021-05030-w

    Article  PubMed  Google Scholar 

  48. Chardot C, Buet C, Serinet MO et al (2013) Improving outcomes of biliary atresia: French National Series 1986–2009. J Hepatol 58(6):1209–1217. https://doi.org/10.1016/j.jhep.2013.01.040

    Article  PubMed  Google Scholar 

  49. Davenport M (2012) Biliary atresia: clinical aspects. Semin Pediatr Surg 21(3):175–184. https://doi.org/10.1053/j.sempedsurg.2012.05.010

    Article  PubMed  Google Scholar 

  50. He L, Chung PHY, Lui VCH, Tang CSM, Tam PKH (2022) Current understanding in the clinical characteristics and molecular mechanisms in different subtypes of biliary atresia. Int J Mol Sci 23(9):4841. https://doi.org/10.3390/ijms23094841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kerola A, Lampela H, Lohi J et al (2017) Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy. Surgery 162(3):548–556. https://doi.org/10.1016/j.surg.2017.04.013

    Article  PubMed  Google Scholar 

  52. Wong ZH, Davenport M (2019) What happens after kasai for biliary atresia? A European Multicenter Survey. Eur J Pediatr Surg 29(1):1–6. https://doi.org/10.1055/s-0038-1668146

    Article  PubMed  Google Scholar 

  53. Zani A, Quaglia A, Hadzić N, Zuckerman M, Davenport M (2015) Cytomegalovirus-associated biliary atresia: an aetiological and prognostic subgroup. J Pediatr Surg 50(10):1739–1745. https://doi.org/10.1016/j.jpedsurg.2015.03.001

    Article  PubMed  Google Scholar 

  54. Zhao Y, Xu X, Liu G, Yang F, Zhan J (2021) Prognosis of biliary atresia associated with cytomegalovirus: a meta-analysis. Front Pediatr 9:710450. https://doi.org/10.3389/fped.2021.710450

    Article  PubMed  PubMed Central  Google Scholar 

  55. Parolini F, Hadzic N, Davenport M (2019) Adjuvant therapy of cytomegalovirus IgM + ve associated biliary atresia: Prima facie evidence of effect. J Pediatr Surg 54(9):1941–1945. https://doi.org/10.1016/j.jpedsurg.2018.12.014

    Article  PubMed  Google Scholar 

  56. Lal R, Prasad DKV, Krishna P et al (2007) Biliary atresia with a “cyst at porta”: management and outcome as per the cholangiographic anatomy. Pediatr Surg Int 23(8):773–778. https://doi.org/10.1007/s00383-007-1948-0

    Article  PubMed  Google Scholar 

  57. Nio M, Wada M, Sasaki H, Tanaka H (2015) Does hepatic hilum morphology influence long-term prognosis in type I/I cyst biliary atresia? Pediatr Surg Int 31(10):931–936. https://doi.org/10.1007/s00383-015-3771-3

    Article  PubMed  Google Scholar 

  58. Chu AS, Russo PA, Wells RG (2012) Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Mod Pathol 25(5):751–757. https://doi.org/10.1038/modpathol.2011.212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xu X, Dou R, Zhao S et al (2022) Outcomes of biliary atresia splenic malformation (BASM) syndrome following Kasai operation: a systematic review and meta-analysis. World J Pediatr Surg 5(3):e000346. https://doi.org/10.1136/wjps-2021-000346

    Article  PubMed  PubMed Central  Google Scholar 

  60. Berauer JP, Mezina AI, Okou DT et al (2019) Identification of polycystic kidney disease 1 like 1 gene variants in children with biliary atresia splenic malformation syndrome. Hepatology 70(3):899–910. https://doi.org/10.1002/hep.30515

    Article  CAS  PubMed  Google Scholar 

  61. Gonzales E, Davit-Spraul A, Jacquemin E (2020) A novel CFC1 mutation in a family with heterotaxy and biliary atresia splenic malformation syndromes. J Pediatr Gastroenterol Nutr 70(1):e24–e25. https://doi.org/10.1097/MPG.0000000000002531

    Article  PubMed  Google Scholar 

  62. Aldeiri B, Giamouris V, Pushparajah K, Miller O, Baker A, Davenport M (2021) Cardiac-associated biliary atresia (CABA): a prognostic subgroup. Arch Dis Child 106(1):68–72. https://doi.org/10.1136/archdischild-2020-319122

    Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the Tian** Science and Technology Program (No. 21ZXGWSY00070), the Tian** Applied Basic Research Project (No. 22JCZDJC00290), and Tian** University Children’s Hospital Projects (Grant No. Y2020002) for the support of the research.

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  1. Clinical School of Paediatrics, Tian** Medical University, Tian**, China

    Shaowen Liu, Tengfei Li, Qianhui Yang & **ngyuan Ke

  2. Department of General Surgery, Tian** Children’s Hospital, Tian**, China

    Shaowen Liu, Tengfei Li, Qianhui Yang, **ngyuan Ke & Jianghua Zhan

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SWL conceived and designed the study. SWL, QHY, and XYK performed the literature collection and the writing of the review. SWL and TFL drew the images and revised the article. JHZ revised and approved the final manuscript. All authors contributed to the manuscript and approved the version as submitted.

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Correspondence to Jianghua Zhan.

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Liu, S., Li, T., Yang, Q. et al. Biliary atresia: the development, pathological features, and classification of the bile duct. Pediatr Surg Int 40, 42 (2024). https://doi.org/10.1007/s00383-023-05627-3

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