1932

Abstract

Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathmechdis-031521-025623
2024-01-24
2024-06-12
Loading full text...

Full text loading...

/deliver/fulltext/pathol/19/1/annurev-pathmechdis-031521-025623.html?itemId=/content/journals/10.1146/annurev-pathmechdis-031521-025623&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Suchy FJ. 2004. Neonatal cholestasis. Pediatr. Rev. 25:38896
    [Google Scholar]
  2. 2.
    Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N et al. 2017. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 64:15468
    [Google Scholar]
  3. 3.
    Balistreri WF, Bezerra JA. 2006. Whatever happened to “neonatal hepatitis”?. Clin. Liver Dis. 10:2753
    [Google Scholar]
  4. 4.
    Elisofon SA, Magee JC, Ng VL, Horslen SP, Fioravanti V et al. 2020. Society of pediatric liver transplantation: current registry status 2011–2018. Pediatr. Transplant. 24:e13605
    [Google Scholar]
  5. 5.
    Baumann U, Karam V, Adam R, Fondevila C, Dhawan A et al. 2022. Prognosis of children undergoing liver transplantation: a 30-year European study. Pediatrics 150:e2022057424
    [Google Scholar]
  6. 6.
    Hoerning A, Raub S, Dechene A, Brosch MN, Kathemann S et al. 2014. Diversity of disorders causing neonatal cholestasis—the experience of a tertiary pediatric center in Germany. Front. Pediatr. 2:65
    [Google Scholar]
  7. 7.
    Karpen SJ, Kamath BM, Alexander JJ, Ichetovkin I, Rosenthal P et al. 2021. Use of a comprehensive 66-gene cholestasis sequencing panel in 2171 cholestatic infants, children, and young adults. J. Pediatr. Gastroenterol. Nutr. 72:65460
    [Google Scholar]
  8. 8.
    Pianese P, Salvia G, Campanozzi A, D'Apolito O, Dello Russo A et al. 2008. Sterol profiling in red blood cell membranes and plasma of newborns receiving total parenteral nutrition. J. Pediatr. Gastroenterol. Nutr. 47:64551
    [Google Scholar]
  9. 9.
    Strijbosch RA, van den Hoonaard TL, Olieman JF, Escher JC, Alwayn IP, Meijers-Ijsselstijn H. 2010. Fish oil in prolonged parenteral nutrition in children—omega-3-fatty acids have a beneficial effect on the liver. Ned. Tijdschr. Geneeskd. 154:A2003
    [Google Scholar]
  10. 10.
    Feldman AG, Sokol RJ. 2020. Recent developments in diagnostics and treatment of neonatal cholestasis. Semin. Pediatr. Surg. 29:150945
    [Google Scholar]
  11. 11.
    Tam PKH, Yiu RS, Lendahl U, Andersson ER. 2018. Cholangiopathies—towards a molecular understanding. EbioMedicine 35:38193
    [Google Scholar]
  12. 12.
    Vakili K, Pomfret EA. 2008. Biliary anatomy and embryology. Surg. Clin. North Am. 88:115974
    [Google Scholar]
  13. 13.
    Lemaigre FP. 2020. Development of the intrahepatic and extrahepatic biliary tract: a framework for understanding congenital diseases. Annu. Rev. Pathol. Mech. Dis. 15:122
    [Google Scholar]
  14. 14.
    Huppert SS, Iwafuchi-Doi M. 2019. Molecular regulation of mammalian hepatic architecture. Curr. Top. Dev. Biol. 132:91136
    [Google Scholar]
  15. 15.
    Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P et al. 2009. Notch signaling controls liver development by regulating biliary differentiation. Development 136:172739
    [Google Scholar]
  16. 16.
    Vestentoft PS, Jelnes P, Hopkinson BM, Vainer B, Mollgard K et al. 2011. Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver. BMC Dev. Biol 11:56
    [Google Scholar]
  17. 17.
    Van Eyken P, Sciot R, Callea F, Van der Steen K, Moerman P, Desmet VJ. 1988. The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Hepatology 8:158695
    [Google Scholar]
  18. 18.
    Stellaard F, Lutjohann D. 2021. Dynamics of the enterohepatic circulation of bile acids in healthy humans. Am. J. Physiol. Gastrointest. Liver Physiol. 321:G5566
    [Google Scholar]
  19. 19.
    Li T, Apte U. 2015. Bile acid metabolism and signaling in cholestasis, inflammation, and cancer. Adv. Pharmacol. 74:263302
    [Google Scholar]
  20. 20.
    Boyer JL. 2013. Bile formation and secretion. Compr. Physiol. 3:103578
    [Google Scholar]
  21. 21.
    Fickert P, Wagner M. 2017. Biliary bile acids in hepatobiliary injury—What is the link?. J. Hepatol. 67:61931
    [Google Scholar]
  22. 22.
    Dawson PA, Karpen SJ. 2015. Intestinal transport and metabolism of bile acids. J. Lipid Res. 56:108599
    [Google Scholar]
  23. 23.
    Jones H, Alpini G, Francis H. 2015. Bile acid signaling and biliary functions. Acta Pharm. Sin. B 5:12328
    [Google Scholar]
  24. 24.
    Fuchs CD, Trauner M. 2022. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat. Rev. Gastroenterol. Hepatol. 19:43250
    [Google Scholar]
  25. 25.
    Zou TT, Zhu Y, Wan CM, Liao Q. 2021. Clinical features of sodium-taurocholate cotransporting polypeptide deficiency in pediatric patients: case series and literature review. Transl. Pediatr. 10:104554
    [Google Scholar]
  26. 26.
    Bull LN, Thompson RJ. 2018. Progressive familial intrahepatic cholestasis. Clin. Liver Dis. 22:65769
    [Google Scholar]
  27. 27.
    Cai SY, Ouyang X, Chen Y, Soroka CJ, Wang J et al. 2017. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2:e90780
    [Google Scholar]
  28. 28.
    Allen K, Jaeschke H, Copple BL. 2011. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am. J. Pathol. 178:17586
    [Google Scholar]
  29. 29.
    Kim ND, Moon JO, Slitt AL, Copple BL. 2006. Early growth response factor-1 is critical for cholestatic liver injury. Toxicol. Sci. 90:58695
    [Google Scholar]
  30. 30.
    Allen K, Kim ND, Moon JO, Copple BL. 2010. Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling. Toxicol. Appl. Pharmacol. 243:6367
    [Google Scholar]
  31. 31.
    Gan C, Cai Q, Tang C, Gao J. 2022. Inflammasomes and pyroptosis of liver cells in liver fibrosis. Front. Immunol. 13:896473
    [Google Scholar]
  32. 32.
    Che Y, Xu W, Ding C, He T, Xu X et al. 2023. Bile acids target mitofusin 2 to differentially regulate innate immunity in physiological versus cholestatic conditions. Cell Rep. 42:112011
    [Google Scholar]
  33. 33.
    Wei S, Ma X, Zhao Y. 2020. Mechanism of hydrophobic bile acid-induced hepatocyte injury and drug discovery. Front. Pharmacol. 11:1084
    [Google Scholar]
  34. 34.
    Xu W, Che Y, Zhang Q, Huang H, Ding C et al. 2021. Apaf-1 pyroptosome senses mitochondrial permeability transition. Cell Metab. 33:42436.e10
    [Google Scholar]
  35. 35.
    Szabo G, Petrasek J. 2015. Inflammasome activation and function in liver disease. Nat. Rev. Gastroenterol. Hepatol. 12:387400
    [Google Scholar]
  36. 36.
    Dommergues JP. 1972. Intra-hepatic biliary tract atresia with permeable extra-hepatic biliary tract in children. Apropos of 23 cases. Ann. Med. Interne 123:87173
    [Google Scholar]
  37. 37.
    Li L, Krantz ID, Deng Y, Genin A, Banta AB et al. 1997. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet. 16:24351
    [Google Scholar]
  38. 38.
    Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, Chao G et al. 2019. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum. Mutat. 40:2197220
    [Google Scholar]
  39. 39.
    Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. 2010. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 51:1391400
    [Google Scholar]
  40. 40.
    Kopan R, Ilagan MX. 2009. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:21633
    [Google Scholar]
  41. 41.
    del Alamo D, Rouault H, Schweisguth F. 2011. Mechanism and significance of cis-inhibition in Notch signalling. Curr. Biol. 21:R4047
    [Google Scholar]
  42. 42.
    Russell JO, Camargo FD. 2022. Hippo signalling in the liver: role in development, regeneration and disease. Nat. Rev. Gastroenterol. Hepatol. 19:297312
    [Google Scholar]
  43. 43.
    Driskill JH, Pan D. 2021. The Hippo pathway in liver homeostasis and pathophysiology. Annu. Rev. Pathol. Mech. Dis. 16:299322
    [Google Scholar]
  44. 44.
    Schaub JR, Huppert KA, Kurial SNT, Hsu BY, Cast AE et al. 2018. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 557:24751
    [Google Scholar]
  45. 45.
    Molina LM, Zhu J, Li Q, Pradhan-Sundd T, Krutsenko Y et al. 2021. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell Rep. 36:109310
    [Google Scholar]
  46. 46.
    Lemaigre FP. 2009. Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology 137:6279
    [Google Scholar]
  47. 47.
    Pepe-Mooney BJ, Dill MT, Alemany A, Ordovas-Montanes J, Matsushita Y et al. 2019. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell 25:2338.e8
    [Google Scholar]
  48. 48.
    Saleh M, Kamath BM, Chitayat D. 2016. Alagille syndrome: clinical perspectives. Appl. Clin. Genet. 9:7582
    [Google Scholar]
  49. 49.
    Vandriel SM, Li LT, She H, Wang JS, Gilbert MA et al. 2023. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from the GALA study. Hepatology 77:51229
    [Google Scholar]
  50. 50.
    Kamath BM, Ye W, Goodrich NP, Loomes KM, Romero R et al. 2020. Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatol. Commun. 4:38798
    [Google Scholar]
  51. 51.
    Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. 1999. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29:82229
    [Google Scholar]
  52. 52.
    Bhadri VA, Stormon MO, Arbuckle S, Lam AH, Gaskin KJ, Shun A. 2005. Hepatocellular carcinoma in children with Alagille syndrome. J. Pediatr. Gastroenterol. Nutr. 41:67678
    [Google Scholar]
  53. 53.
    Ayoub MD, Kamath BM. 2020. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics 10:907
    [Google Scholar]
  54. 54.
    Lam WY, Tang CS, So MT, Yue H, Hsu JS 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
    [Google Scholar]
  55. 55.
    Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, Meunier-Rotival M. 2001. Jagged1 mutations in Alagille syndrome. Hum. Mutat. 17:1833
    [Google Scholar]
  56. 56.
    Kamath BM, Thiel BD, Gai X, Conlin LK, Munoz PS et al. 2009. SNP array mapping of chromosome 20p deletions: genotypes, phenotypes, and copy number variation. Hum. Mutat. 30:37178
    [Google Scholar]
  57. 57.
    Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J et al. 2012. NOTCH2 mutations in Alagille syndrome. J. Med. Genet. 49:13844
    [Google Scholar]
  58. 58.
    McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A et al. 2006. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am. J. Hum. Genet. 79:16973
    [Google Scholar]
  59. 59.
    Izumi K, Hayashi D, Grochowski CM, Kubota N, Nishi E et al. 2016. Discordant clinical phenotype in monozygotic twins with Alagille syndrome: possible influence of non-genetic factors. Am. J. Med. Genet. A 170A:47175
    [Google Scholar]
  60. 60.
    Ryan MJ, Bales C, Nelson A, Gonzalez DM, Underkoffler L et al. 2008. Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype. Hepatology 48:198997
    [Google Scholar]
  61. 61.
    Thakurdas SM, Lopez MF, Kakuda S, Fernandez-Valdivia R, Zarrin-Khameh N et al. 2016. Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology 63:55065
    [Google Scholar]
  62. 62.
    Tsai EA, Gilbert MA, Grochowski CM, Underkoffler LA, Meng H et al. 2016. THBS2 is a candidate modifier of liver disease severity in Alagille syndrome. Cell. Mol. Gastroenterol. Hepatol. 2:66375.e2
    [Google Scholar]
  63. 63.
    Alam S, Lal BB. 2022. Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: outcome and therapeutic strategies. World J. Hepatol. 14:98118
    [Google Scholar]
  64. 64.
    Sambrotta M, Strautnieks S, Papouli E, Rushton P, Clark BE et al. 2014. Mutations in TJP2 cause progressive cholestatic liver disease. Nat. Genet. 46:32628
    [Google Scholar]
  65. 65.
    Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS et al. 2016. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat. Commun. 7:10713
    [Google Scholar]
  66. 66.
    Girard M, Lacaille F, Verkarre V, Mategot R, Feldmann G et al. 2014. MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease. Hepatology 60:30110
    [Google Scholar]
  67. 67.
    Boyer JL, Soroka CJ. 2021. Bile formation and secretion: an update. J. Hepatol. 75:190201
    [Google Scholar]
  68. 68.
    Kunst RF, Verkade HJ, Oude Elferink RPJ, van de Graaf SFJ 2021. Targeting the four pillars of enterohepatic bile salt cycling; lessons from genetics and pharmacology. Hepatology 73:257785
    [Google Scholar]
  69. 69.
    Vartak N, Drasdo D, Geisler F, Itoh T, Oude Elferink RPJ et al. 2021. On the mechanisms of biliary flux. Hepatology 74:3497512
    [Google Scholar]
  70. 70.
    Kriegermeier A, Green R. 2020. Pediatric cholestatic liver disease: review of bile acid metabolism and discussion of current and emerging therapies. Front. Med. 7:149
    [Google Scholar]
  71. 71.
    Sundaram SS, Bove KE, Lovell MA, Sokol RJ. 2008. Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin. Pract. Gastroenterol. Hepatol. 5:45668
    [Google Scholar]
  72. 72.
    Orntoft NW, Munk OL, Frisch K, Ott P, Keiding S, Sorensen M. 2017. Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-Csar quantified in healthy humans and patients by positron emission tomography. J. Hepatol. 67:32127
    [Google Scholar]
  73. 73.
    Bull LN, Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P et al. 2018. Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. Hepatol. Commun. 2:51528
    [Google Scholar]
  74. 74.
    Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E et al. 2010. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology 51:164555
    [Google Scholar]
  75. 75.
    Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ. 2019. Systematic review of progressive familial intrahepatic cholestasis. Clin. Res. Hepatol. Gastroenterol. 43:2036
    [Google Scholar]
  76. 76.
    van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Shneider BL et al. 2021. Impact of genotype, serum bile acids, and surgical biliary diversion on native liver survival in FIC1 deficiency. Hepatology 74:892906
    [Google Scholar]
  77. 77.
    van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Sokal E et al. 2020. Genotype correlates with the natural history of severe bile salt export pump deficiency. J. Hepatol. 73:8493
    [Google Scholar]
  78. 78.
    Siebold L, Dick AA, Thompson R, Maggiore G, Jacquemin E et al. 2010. Recurrent low gamma-glutamyl transpeptidase cholestasis following liver transplantation for bile salt export pump (BSEP) disease (posttransplant recurrent BSEP disease). Liver Transpl. 16:85663
    [Google Scholar]
  79. 79.
    Stindt J, Kluge S, Droge C, Keitel V, Stross C et al. 2016. Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency. Hepatology 63:52437
    [Google Scholar]
  80. 80.
    Wang L, Soroka CJ, Boyer JL. 2002. The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J. Clin. Investig. 110:96572
    [Google Scholar]
  81. 81.
    Balistreri WF, Bezerra JA, Jansen P, Karpen SJ, Shneider BL, Suchy FJ. 2005. Intrahepatic cholestasis: summary of an American Association for the Study of Liver Diseases single-topic conference. Hepatology 42:22235
    [Google Scholar]
  82. 82.
    Reichert MC, Lammert F. 2018. ABCB4 gene aberrations in human liver disease: an evolving spectrum. Semin. Liver Dis. 38:299307
    [Google Scholar]
  83. 83.
    Nayagam JS, Foskett P, Strautnieks S, Agarwal K, Miquel R et al. 2022. Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1. Hepatol. Commun. 6:265464
    [Google Scholar]
  84. 84.
    Gonzales E, Taylor SA, Davit-Spraul A, Thebaut A, Thomassin N et al. 2017. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology 65:16473
    [Google Scholar]
  85. 85.
    Pradhan-Sundd T, Monga SP. 2019. Blood-bile barrier: morphology, regulation, and pathophysiology. Gene Expr. 19:6987
    [Google Scholar]
  86. 86.
    Vinayagamoorthy V, Srivastava A, Sarma MS. 2021. Newer variants of progressive familial intrahepatic cholestasis. World J. Hepatol. 13:202438
    [Google Scholar]
  87. 87.
    Aldrian D, Vogel GF, Frey TK, Ayyildiz Civan H, Aksu AU et al. 2021. Congenital diarrhea and cholestatic liver disease: phenotypic spectrum associated with MYO5B mutations. J. Clin. Med. 10:481
    [Google Scholar]
  88. 88.
    Maddirevula S, Alhebbi H, Alqahtani A, Algoufi T, Alsaif HS et al. 2019. Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. Genet. Med. 21:116472
    [Google Scholar]
  89. 89.
    van Ooteghem NA, Klomp LW, van Berge-Henegouwen GP, Houwen RH. 2002. Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J. Hepatol. 36:43943
    [Google Scholar]
  90. 90.
    Poupon R, Rosmorduc O, Boelle PY, Chretien Y, Corpechot C et al. 2013. Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. Hepatology 58:110510
    [Google Scholar]
  91. 91.
    Ortiz-Perez A, Donnelly B, Temple H, Tiao G, Bansal R, Mohanty SK. 2020. Innate immunity and pathogenesis of biliary atresia. Front. Immunol. 11:329
    [Google Scholar]
  92. 92.
    Pinto C, Giordano DM, Maroni L, Marzioni M. 2018. Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology. Biochim. Biophys. Acta Mol. Basis Dis. 1864:127078
    [Google Scholar]
  93. 93.
    Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. 2019. Cholangiocyte pathobiology. Nat. Rev. Gastroenterol. Hepatol. 16:26981
    [Google Scholar]
  94. 94.
    Hartley JL, Davenport M, Kelly DA. 2009. Biliary atresia. Lancet 374:170413
    [Google Scholar]
  95. 95.
    Thomson J. 1892. On congenital obliteration of the bile-ducts. Trans. Edinb. Obstet. Soc. 17:1749
    [Google Scholar]
  96. 96.
    Davenport M, Muntean A, Hadzic N. 2021. Biliary atresia: clinical phenotypes and aetiological heterogeneity. J. Clin. Med. 10:5675
    [Google Scholar]
  97. 97.
    Asai A, Miethke A, Bezerra JA. 2015. Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes. Nat. Rev. Gastroenterol. Hepatol. 12:34252
    [Google Scholar]
  98. 98.
    Harpavat S, Finegold MJ, Karpen SJ. 2011. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics 128:e142833
    [Google Scholar]
  99. 99.
    Harpavat S, Garcia-Prats JA, Shneider BL. 2016. Newborn bilirubin screening for biliary atresia. N. Engl. J. Med. 375:6056
    [Google Scholar]
  100. 100.
    Mysore KR, Shneider BL, Harpavat S. 2019. Biliary atresia as a disease starting in utero: implications for treatment, diagnosis, and pathogenesis. J. Pediatr. Gastroenterol. Nutr. 69:396403
    [Google Scholar]
  101. 101.
    Rabbani T, Guthery SL, Himes R, Shneider BL, Harpavat S. 2021. Newborn screening for biliary atresia: a review of current methods. Curr. Gastroenterol. Rep. 23:28
    [Google Scholar]
  102. 102.
    Davenport M, Tizzard SA, Underhill J, Mieli-Vergani G, Portmann B, Hadzic N. 2006. The biliary atresia splenic malformation syndrome: a 28-year single-center retrospective study. J. Pediatr. 149:393400
    [Google Scholar]
  103. 103.
    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. 40:42933
    [Google Scholar]
  104. 104.
    Xu X, Dou R, Zhao S, Zhao J, Gou Q 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:e000346
    [Google Scholar]
  105. 105.
    Fischler B, Ehrnst A, Forsgren M, Orvell 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. 27:5764
    [Google Scholar]
  106. 106.
    Xu Y, Yu J, Zhang R, Yin Y, Ye J et al. 2012. The perinatal infection of cytomegalovirus is an important etiology for biliary atresia in China. Clin. Pediatr. 51:10913
    [Google Scholar]
  107. 107.
    Fischler B, Czubkowski P, Dezsofi A, Liliemark U, Socha P et al. 2022. Incidence, impact and treatment of ongoing CMV infection in patients with biliary atresia in four European centres. J. Clin. Med. 11:945
    [Google Scholar]
  108. 108.
    Kaye AJ, Rand EB, Munoz PS, Spinner NB, Flake AW, Kamath BM. 2010. Effect of Kasai procedure on hepatic outcome in Alagille syndrome. J. Pediatr. Gastroenterol. Nutr. 51:31921
    [Google Scholar]
  109. 109.
    Hopkins PC, Yazigi N, Nylund CM. 2017. Incidence of biliary atresia and timing of hepatoportoenterostomy in the United States. J. Pediatr. 187:25357
    [Google Scholar]
  110. 110.
    Schreiber RA, Barker CC, Roberts EA, Martin SR, Alvarez F et al. 2007. Biliary atresia: the Canadian experience. J. Pediatr. 151:65965.e1
    [Google Scholar]
  111. 111.
    Serinet MO, Broue P, Jacquemin E, Lachaux A, Sarles J et al. 2006. Management of patients with biliary atresia in France: results of a decentralized policy 1986–2002. Hepatology 44:7584
    [Google Scholar]
  112. 112.
    Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K et al. 2006. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J. Pediatr. 148:46774
    [Google Scholar]
  113. 113.
    Chardot C, Buet C, Serinet MO, Golmard JL, Lachaux A et al. 2013. Improving outcomes of biliary atresia: French national series 1986–2009. J. Hepatol. 58:120917
    [Google Scholar]
  114. 114.
    Amarachintha SP, Mourya R, Ayabe H, Yang L, Luo Z et al. 2022. Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia. Hepatology 75:89103
    [Google Scholar]
  115. 115.
    Mack CL, Tucker RM, Sokol RJ, Kotzin BL. 2005. Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia. Clin. Immunol. 115:2009
    [Google Scholar]
  116. 116.
    Kilgore A, Mack CL. 2017. Update on investigations pertaining to the pathogenesis of biliary atresia. Pediatr. Surg. Int. 33:123341
    [Google Scholar]
  117. 117.
    Bezerra JA, Spino C, Magee JC, Shneider BL, Rosenthal P et al. 2014. Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA 311:175059
    [Google Scholar]
  118. 118.
    Lages CS, Simmons J, Maddox A, Jones K, Karns R et al. 2017. The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia. Hepatology 65:17488
    [Google Scholar]
  119. 119.
    McHedlidze T, Waldner M, Zopf S, Walker J, Rankin AL et al. 2013. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39:35771
    [Google Scholar]
  120. 120.
    Russo P, Magee JC, Boitnott J, Bove KE, Raghunathan T et al. 2011. Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy. Clin. Gastroenterol. Hepatol. 9:35762.e2
    [Google Scholar]
  121. 121.
    Azar G, Beneck D, Lane B, Markowitz J, Daum F, Kahn E. 2002. Atypical morphologic presentation of biliary atresia and value of serial liver biopsies. J. Pediatr. Gastroenterol. Nutr. 34:21215
    [Google Scholar]
  122. 122.
    Parra DA, Peters SE, Kohli R, Chamlati R, Connolly BL et al. 2023. Findings in percutaneous trans-hepatic cholecysto-cholangiography in neonates and infants presenting with conjugated hyperbilirubinemia: emphasis on differential diagnosis and cholangiographic patterns. BMC Pediatr. 23:22
    [Google Scholar]
  123. 123.
    Karjoo S, Hand NJ, Loarca L, Russo PA, Friedman JR, Wells RG. 2013. Extrahepatic cholangiocyte cilia are abnormal in biliary atresia. J. Pediatr. Gastroenterol. Nutr. 57:96101
    [Google Scholar]
  124. 124.
    Chu AS, Russo PA, Wells RG. 2012. Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Mod. Pathol. 25:75157
    [Google Scholar]
  125. 125.
    Berauer JP, Mezina AI, Okou DT, Sabo A, Muzny DM et al. 2019. Identification of polycystic kidney disease 1 like 1 gene variants in children with biliary atresia splenic malformation syndrome. Hepatology 70:899910
    [Google Scholar]
  126. 126.
    Cotter JM, Mack CL. 2017. Primary sclerosing cholangitis: unique aspects of disease in children. Clin. Liver Dis. 10:12023
    [Google Scholar]
  127. 127.
    Deneau MR, El-Matary W, Valentino PL, Abdou R, Alqoaer K et al. 2017. The natural history of primary sclerosing cholangitis in 781 children: a multicenter, international collaboration. Hepatology 66:51827
    [Google Scholar]
  128. 128.
    Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. 2017. Primary sclerosing cholangitis—a comprehensive review. J. Hepatol. 67:1298323
    [Google Scholar]
  129. 129.
    Ricciuto A, Kamath BM, Griffiths AM. 2018. The IBD and PSC phenotypes of PSC-IBD. Curr. Gastroenterol. Rep. 20:16
    [Google Scholar]
  130. 130.
    Martinez M, Perito ER, Valentino P, Mack CL, Aumar M et al. 2021. Recurrence of primary sclerosing cholangitis after liver transplant in children: an international observational study. Hepatology 74:204757
    [Google Scholar]
  131. 131.
    Bjornsson E, Olsson R, Bergquist A, Lindgren S, Braden B et al. 2008. The natural history of small-duct primary sclerosing cholangitis. Gastroenterology 134:97580
    [Google Scholar]
  132. 132.
    Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT et al. 2001. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 33:54453
    [Google Scholar]
  133. 133.
    Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP et al. 2011. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J. Hepatol. 54:37485
    [Google Scholar]
  134. 134.
    Ricciuto A, Kamath BM, Hirschfield GM, Trivedi PJ. 2023. Primary sclerosing cholangitis and overlap features of autoimmune hepatitis: a coming of age or an age-ist problem?. J. Hepatol. 79:256775
    [Google Scholar]
  135. 135.
    Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P. 2003. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology 38:21017
    [Google Scholar]
  136. 136.
    Little R, Wine E, Kamath BM, Griffiths AM, Ricciuto A. 2020. Gut microbiome in primary sclerosing cholangitis: a review. World J. Gastroenterol. 26:276880
    [Google Scholar]
  137. 137.
    Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF et al. 2004. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J. Exp. Med. 200:151117
    [Google Scholar]
  138. 138.
    Grant AJ, Lalor PF, Salmi M, Jalkanen S, Adams DH. 2002. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet 359:15057
    [Google Scholar]
  139. 139.
    Buchholz BM, Lykoudis PM, Ravikumar R, Pollok JM, Fusai GK. 2018. Role of colectomy in preventing recurrent primary sclerosing cholangitis in liver transplant recipients. World J. Gastroenterol. 24:317180
    [Google Scholar]
  140. 140.
    Lindstrom L, Jorgensen KK, Boberg KM, Castedal M, Rasmussen A et al. 2018. Risk factors and prognosis for recurrent primary sclerosing cholangitis after liver transplantation: a Nordic multicentre study. Scand. J. Gastroenterol. 53:297304
    [Google Scholar]
  141. 141.
    Cangemi JR, Wiesner RH, Beaver SJ, Ludwig J, MacCarty RL et al. 1989. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology 96:79094
    [Google Scholar]
  142. 142.
    Grammatikopoulos T, Sambrotta M, Strautnieks S, Foskett P, Knisely AS et al. 2016. Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis. J. Hepatol. 65:117987
    [Google Scholar]
  143. 143.
    Syryn H, Hoorens A, Grammatikopoulos T, Deheragoda M, Symoens S et al. 2021. Two cases of DCDC2-related neonatal sclerosing cholangitis with developmental delay and literature review. Clin. Genet. 100:44752
    [Google Scholar]
  144. 144.
    Girard M, Bizet AA, Lachaux A, Gonzales E, Filhol E et al. 2016. DCDC2 mutations cause neonatal sclerosing cholangitis. Hum. Mutat. 37:102529
    [Google Scholar]
  145. 145.
    Riepenhoff-Talty M, Schaekel K, Clark HF, Mueller W, Uhnoo I et al. 1993. Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr. Res. 33:39499
    [Google Scholar]
  146. 146.
    Hellen DJ, Bennett A, Malla S, Klindt C, Rao A et al. 2023. Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy. Hepatology 77:127486
    [Google Scholar]
  147. 147.
    Waisbourd-Zinman O, Koh H, Tsai S, Lavrut PM, Dang C et al. 2016. The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17. Hepatology 64:88093
    [Google Scholar]
  148. 148.
    Mauad TH, van Nieuwkerk CM, Dingemans KP, Smit JJ, Schinkel AH et al. 1994. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am. J. Pathol. 145:123745
    [Google Scholar]
  149. 149.
    Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A et al. 2004. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127:26174
    [Google Scholar]
  150. 150.
    Tang V, Cofer ZC, Cui S, Sapp V, Loomes KM, Matthews RP. 2016. Loss of a candidate biliary atresia susceptibility gene, add3a, causes biliary developmental defects in zebrafish. J. Pediatr. Gastroenterol. Nutr. 63:52430
    [Google Scholar]
  151. 151.
    Ningappa M, Min J, Higgs BW, Ashokkumar C, Ranganathan S, Sindhi R. 2015. Genome-wide association studies in biliary atresia. Wiley Interdiscip. Rev. Syst. Biol. Med. 7:26773
    [Google Scholar]
  152. 152.
    Zhao C, Lancman JJ, Yang Y, Gates KP, Cao D et al. 2022. Intrahepatic cholangiocyte regeneration from an Fgf-dependent extrahepatic progenitor niche in a zebrafish model of Alagille syndrome. Hepatology 75:56783
    [Google Scholar]
  153. 153.
    Ellis JL, Bove KE, Schuetz EG, Leino D, Valencia CA et al. 2018. Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency. Hepatology 67:153145
    [Google Scholar]
  154. 154.
    Chen S, Li P, Wang Y, Yin Y, de Ruiter PE et al. 2020. rotavirus infection and cytopathogenesis in human biliary organoids potentially recapitulate biliary atresia development. mBio 11:e01968-20
    [Google Scholar]
  155. 155.
    Ghanekar A, Kamath BM. 2016. Cholangiocytes derived from induced pluripotent stem cells for disease modeling. Curr. Opin. Gastroenterol. 32:21015
    [Google Scholar]
  156. 156.
    Tian L, Ye Z, Kafka K, Stewart D, Anders R et al. 2019. Biliary atresia relevant human induced pluripotent stem cells recapitulate key disease features in a dish. J. Pediatr. Gastroenterol. Nutr. 68:5663
    [Google Scholar]
  157. 157.
    Vats R, Kaminski TW, Pradhan-Sundd T. 2021. Intravital imaging of hepatic blood biliary barrier in live mice. Curr. Protoc. 1:e256
    [Google Scholar]
  158. 158.
    Pradhan-Sundd T, Vats R, Russell JO, Singh S, Michael AA et al. 2018. Dysregulated bile transporters and impaired tight junctions during chronic liver injury in mice. Gastroenterology 155:121832.e24
    [Google Scholar]
  159. 159.
    Poch T, Krause J, Casar C, Liwinski T, Glau L et al. 2021. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis. J. Hepatol. 75:41423
    [Google Scholar]
  160. 160.
    Chung BK, Ogaard J, Reims HM, Karlsen TH, Melum E. 2022. Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis. Hepatol. Commun. 6:253850
    [Google Scholar]
  161. 161.
    MacParland SA, Liu JC, Ma XZ, Innes BT, Bartczak AM et al. 2018. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun. 9:4383
    [Google Scholar]
  162. 162.
    Trauner M, Fuchs CD. 2022. Novel therapeutic targets for cholestatic and fatty liver disease. Gut 71:194209
    [Google Scholar]
  163. 163.
    Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL et al. 2022. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol. Hepatol. 7:83042
    [Google Scholar]
/content/journals/10.1146/annurev-pathmechdis-031521-025623
Loading
/content/journals/10.1146/annurev-pathmechdis-031521-025623
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error