Download PDF
Semin Liver Dis 2023; 43(01): 001-012
DOI: 10.1055/s-0042-1758833
Review Article

Recent Advances in Intrahepatic Biliary Epithelial Heterogeneity

Ashleigh Little
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
,
Abigail Medford
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
,
April O'Brien
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
,
Jonathan Childs
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
,
Sharon Pan
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
,
Jolaine Machado
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
,
Sanjukta Chakraborty
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
,
Shannon Glaser
1   Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
› Author Affiliations Funding This work was supported by the Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, the NIH grants DK110035 to S.G.
› Further Information
    Permissions and Reprints


Abstract

Biliary epithelium (i.e., cholangiocytes) is a heterogeneous population of epithelial cells in the liver, which line small and large bile ducts and have individual responses and functions dependent on size and location in the biliary tract. We discuss the recent findings showing that the intrahepatic biliary tree is heterogeneous regarding (1) morphology and function, (2) hormone expression and signaling (3), response to injury, and (4) roles in liver regeneration. This review overviews the significant characteristics and differences of the small and large cholangiocytes. Briefly, it outlines the in vitro and in vivo models used in the heterogeneity evaluation. In conclusion, future studies addressing biliary heterogeneity's role in the pathogenesis of liver diseases characterized by ductular reaction may reveal novel therapeutic approaches.

Keywords

cholangiocyte - heterogeneity - senescence - cell signaling


Publication History

Article published online:
15 December 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol 2019; 16 (05) 269-281
    CrossrefPubMedGoogle Scholar
  • 2 Roberts SK, Ludwig J, Larusso NF. The pathobiology of biliary epithelia. Gastroenterology 1997; 112 (01) 269-279
    CrossrefPubMedGoogle Scholar
  • 3 Han Y, Glaser S, Meng F. et al. Recent advances in the morphological and functional heterogeneity of the biliary epithelium. Exp Biol Med (Maywood) 2013; 238 (05) 549-565
    CrossrefPubMedGoogle Scholar
  • 4 Kalra A, Yetiskul E, Wehrle CJ, Tuma F. Physiology, Liver. StatPearls; 2022
    Google Scholar
  • 5 Alpini G, Roberts S, Kuntz SM. et al. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver. Gastroenterology 1996; 110 (05) 1636-1643
    CrossrefPubMedGoogle Scholar
  • 6 Bort R, Zaret KS. Embryonic Development of the Liver. Wiley; 2009: 17-25
    Google Scholar
  • 7 Tabibian JH, Masyuk AI, Masyuk TV, O'Hara SP, LaRusso NF. Physiology of cholangiocytes. Compr Physiol 2013; 3 (01) 541-565
    CrossrefPubMedGoogle Scholar
  • 8 Antoniou A, Raynaud P, Cordi S. et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 2009; 136 (07) 2325-2333
    CrossrefPubMedGoogle Scholar
  • 9 Tam PKH, Yiu RS, Lendahl U, Andersson ER. Cholangiopathies - towards a molecular understanding. EBioMedicine 2018; 35: 381-393
    CrossrefPubMedGoogle Scholar
  • 10 Si-Tayeb K, Lemaigre FP, Duncan SA. Organogenesis and development of the liver. Dev Cell 2010; 18 (02) 175-189
    CrossrefPubMedGoogle Scholar
  • 11 Camp JG, Sekine K, Gerber T. et al. Multilineage communication regulates human liver bud development from pluripotency. Nature 2017; 546 (7659): 533-538
    CrossrefPubMedGoogle Scholar
  • 12 Strazzabosco M, Fabris L. Functional anatomy of normal bile ducts. Anat Rec (Hoboken) 2008; 291 (06) 653-660
    CrossrefPubMedGoogle Scholar
  • 13 Glaser SS, Gaudio E, Rao A. et al. Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium. Lab Invest 2009; 89 (04) 456-469
    CrossrefPubMedGoogle Scholar
  • 14 Ludwig J. New concepts in biliary cirrhosis. Semin Liver Dis 1987; 7 (04) 293-301
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Franchitto A, Onori P, Renzi A. et al. Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. Ann Transl Med 2013; 1 (03) 27
    PubMedGoogle Scholar
  • 16 Saxena R, Theise N. Canals of Hering: recent insights and current knowledge. Semin Liver Dis 2004; 24 (01) 43-48
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Glaser S, Francis H, Demorrow S. et al. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 2006; 12 (22) 3523-3536
    CrossrefPubMedGoogle Scholar
  • 18 Gissen P, Arias IM. Structural and functional hepatocyte polarity and liver disease. J Hepatol 2015; 63 (04) 1023-1037
    CrossrefPubMedGoogle Scholar
  • 19 Roskams TA, Theise ND, Balabaud C. et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 2004; 39 (06) 1739-1745
    CrossrefPubMedGoogle Scholar
  • 20 Mansini AP, Peixoto E, Thelen KM, Gaspari C, Jin S, Gradilone SA. The cholangiocyte primary cilium in health and disease. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4, Pt B): 1245-1253
    CrossrefPubMedGoogle Scholar
  • 21 Lanzoni G, Cardinale V, Carpino G. The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: a new reference frame for disease and regeneration. Hepatology 2016; 64 (01) 277-286
    CrossrefPubMedGoogle Scholar
  • 22 Krishna M. Microscopic anatomy of the liver. Clin Liver Dis (Hoboken) 2013; 2 (Suppl. 01) S4-S7
    CrossrefPubMedGoogle Scholar
  • 23 Benedetti A, Bassotti C, Rapino K, Marucci L, Jezequel AM. A morphometric study of the epithelium lining the rat intrahepatic biliary tree. J Hepatol 1996; 24 (03) 335-342
    CrossrefPubMedGoogle Scholar
  • 24 Ishii M, Vroman B, LaRusso NF. Isolation and morphologic characterization of bile duct epithelial cells from normal rat liver. Gastroenterology 1989; 97 (05) 1236-1247
    CrossrefPubMedGoogle Scholar
  • 25 Sato K, Meng F, Giang T, Glaser S, Alpini G. Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4, Pt B): 1262-1269
    CrossrefPubMedGoogle Scholar
  • 26 Mancinelli R, Franchitto A, Glaser S. et al. GABA induces the differentiation of small into large cholangiocytes by activation of Ca(2+) /CaMK I-dependent adenylyl cyclase 8. Hepatology 2013; 58 (01) 251-263
    CrossrefPubMedGoogle Scholar
  • 27 Mancinelli R, Franchitto A, Gaudio E. et al. After damage of large bile ducts by gamma-aminobutyric acid, small ducts replenish the biliary tree by amplification of calcium-dependent signaling and de novo acquisition of large cholangiocyte phenotypes. Am J Pathol 2010; 176 (04) 1790-1800
    CrossrefPubMedGoogle Scholar
  • 28 Hall C, Sato K, Wu N. et al. Regulators of cholangiocyte proliferation. Gene Expr 2017; 17 (02) 155-171
    CrossrefPubMedGoogle Scholar
  • 29 Gaudio E, Onori P, Pannarale L, Alvaro D. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: a morphological study. Gastroenterology 1996; 111 (04) 1118-1124
    CrossrefPubMedGoogle Scholar
  • 30 Alpini G, Ulrich C, Roberts S. et al. Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation. Am J Physiol 1997; 272 (2, Pt 1): G289-G297
    PubMedGoogle Scholar
  • 31 Liedtke C, Luedde T, Sauerbruch T. et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair 2013; 6 (01) 19
    CrossrefPubMedGoogle Scholar
  • 32 Fickert P, Stöger U, Fuchsbichler A. et al. A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am J Pathol 2007; 171 (02) 525-536
    CrossrefPubMedGoogle Scholar
  • 33 Aizarani N, Saviano A. , Sagar et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 2019; 572 (7768): 199-204
    CrossrefPubMedGoogle Scholar
  • 34 Francis HL, Demorrow S, Franchitto A. et al. Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms. Lab Invest 2012; 92 (02) 282-294
    CrossrefPubMedGoogle Scholar
  • 35 Komuta M, Govaere O, Vandecaveye V. et al. Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes. Hepatology 2012; 55 (06) 1876-1888
    CrossrefPubMedGoogle Scholar
  • 36 Li B, Dorrell C, Canady PS, Wakefield L. Identification and isolation of clonogenic cholangiocyte in mouse. Methods Mol Biol 2019; 1905: 19-27
    CrossrefPubMedGoogle Scholar
  • 37 Sampaziotis F, Muraro D, Tysoe OC. et al. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science 2021; 371 (6531): 839-846
    CrossrefPubMedGoogle Scholar
  • 38 Sampaziotis F, de Brito MC, Madrigal P. et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol 2015; 33 (08) 845-852
    CrossrefPubMedGoogle Scholar
  • 39 Maroni L, Haibo B, Ray D. et al. Functional and structural features of cholangiocytes in health and disease. Cell Mol Gastroenterol Hepatol 2015; 1 (04) 368-380
    CrossrefPubMedGoogle Scholar
  • 40 Sato K, Meng F, Venter J, Giang T, Glaser S, Alpini G. Author correction: the role of the secretin/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles. Sci Rep 2018; 8 (01) 11238
    CrossrefPubMedGoogle Scholar
  • 41 Luo ZL, Cheng L, Wang T. et al. Bile acid transporters are expressed and heterogeneously distributed in rat bile ducts. Gut Liver 2019; 13 (05) 569-575
    CrossrefPubMedGoogle Scholar
  • 42 Priester S, Wise C, Glaser SS. Involvement of cholangiocyte proliferation in biliary fibrosis. World J Gastrointest Pathophysiol 2010; 1 (02) 30-37
    CrossrefPubMedGoogle Scholar
  • 43 Salas-Silva S, Simoni-Nieves A, Chávez-Rodríguez L, Gutiérrez-Ruiz MC, Bucio L, Quiroz LEG. Mechanism of cholangiocellular damage and repair during cholestasis. Ann Hepatol 2021; 26: 100530
    CrossrefPubMedGoogle Scholar
  • 44 Francis H, Glaser S, Ueno Y. et al. cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway. J Hepatol 2004; 41 (04) 528-537
    CrossrefPubMedGoogle Scholar
  • 45 Glaser S, Lam IP, Franchitto A. et al. Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation. Hepatology 2010; 52 (01) 204-214
    CrossrefPubMedGoogle Scholar
  • 46 Dutta AK, Khimji AK, Kresge C. et al. Identification and functional characterization of TMEM16A, a Ca2+-activated Cl- channel activated by extracellular nucleotides, in biliary epithelium. J Biol Chem 2011; 286 (01) 766-776
    CrossrefPubMedGoogle Scholar
  • 47 Woo K, Sathe M, Kresge C. et al. Adenosine triphosphate release and purinergic (P2) receptor-mediated secretion in small and large mouse cholangiocytes. Hepatology 2010; 52 (05) 1819-1828
    CrossrefPubMedGoogle Scholar
  • 48 Lesage G, Glaser SS, Gubba S. et al. Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology 1996; 111 (06) 1633-1644
    CrossrefPubMedGoogle Scholar
  • 49 Zhang N, Bai H, David KK. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell 2010; 19 (01) 27-38
    CrossrefPubMedGoogle Scholar
  • 50 Lazaridis KN, LaRusso NF. The cholangiopathies. Mayo Clin Proc 2015; 90 (06) 791-800
    CrossrefPubMedGoogle Scholar
  • 51 Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 2004; 127 (05) 1565-1577
    CrossrefPubMedGoogle Scholar
  • 52 Salas-Silva S, Simoni-Nieves A, Lopez-Ramirez J. et al. Cholangiocyte death in ductopenic cholestatic cholangiopathies: mechanistic basis and emerging therapeutic strategies. Life Sci 2019; 218: 324-339
    CrossrefPubMedGoogle Scholar
  • 53 Yang F, Gaudio E, Onori P, Wise C, Alpini G, Glaser SS. Mechanisms of biliary damage. J Cell Death 2010; 3: 13-21
    CrossrefPubMedGoogle Scholar
  • 54 Alpini G, Glaser SS, Ueno Y. et al. Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation. Am J Physiol 1998; 274 (04) G767-G775
    PubMedGoogle Scholar
  • 55 LeSage GD, Glaser SS, Marucci L. et al. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. Am J Physiol 1999; 276 (05) G1289-G1301
    PubMedGoogle Scholar
  • 56 Strazzabosco M, Fabris L. Development of the bile ducts: essentials for the clinical hepatologist. J Hepatol 2012; 56 (05) 1159-1170
    CrossrefPubMedGoogle Scholar
  • 57 Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol 2015; 62 (04) 934-945
    CrossrefPubMedGoogle Scholar
  • 58 Trussoni CE, O'Hara SP, LaRusso NF. Cellular senescence in the cholangiopathies: a driver of immunopathology and a novel therapeutic target. Semin Immunopathol 2022; 44 (04) 527-544
    CrossrefPubMedGoogle Scholar
  • 59 Kamimoto K, Kaneko K, Kok CY, Okada H, Miyajima A, Itoh T. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. eLife 2016; 5 DOI: 10.7554/eLife.15034.
    CrossrefPubMedGoogle Scholar
  • 60 Raven A, Lu WY, Man TY. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 2017; 547 (7663): 350-354
    CrossrefPubMedGoogle Scholar
  • 61 Michalopoulos GK, Khan Z. Liver stem cells: experimental findings and implications for human liver disease. Gastroenterology 2015; 149 (04) 876-882
    CrossrefPubMedGoogle Scholar
  • 62 He J, Lu H, Zou Q, Luo L. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 2014; 146 (03) 789-800.e8
    CrossrefPubMedGoogle Scholar
  • 63 Cantz T, Manns MP, Ott M. Stem cells in liver regeneration and therapy. Cell Tissue Res 2008; 331 (01) 271-282
    CrossrefPubMedGoogle Scholar
  • 64 Francis H, Glaser S, Demorrow S. et al. Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway. Am J Physiol Cell Physiol 2008; 295 (02) C499-C513
    CrossrefPubMedGoogle Scholar
  • 65 Pisarello MJ, Loarca L, Ivanics T, Morton L, LaRusso N. MicroRNAs in the cholangiopathies: pathogenesis, diagnosis, and treatment. J Clin Med 2015; 4 (09) 1688-1712
    CrossrefPubMedGoogle Scholar
  • 66 Andrews TS, Atif J, Liu JC. et al. Single-cell, single-nucleus, and spatial RNA sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity. Hepatol Commun 2022; 6 (04) 821-840
    CrossrefPubMedGoogle Scholar
  • 67 Onofrio FQ, Hirschfield GM, Gulamhusein AF. A practical review of primary biliary cholangitis for the gastroenterologist. Gastroenterol Hepatol (N Y) 2019; 15 (03) 145-154
    PubMedGoogle Scholar
  • 68 Tag CG, Sauer-Lehnen S, Weiskirchen S. et al. Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J Vis Exp 2015; (96). DOI: 10.3791/52438.
    CrossrefPubMedGoogle Scholar
  • 69 McDaniel K, Meng F, Wu N. et al. Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice. Hepatology 2017; 65 (02) 544-559
    CrossrefPubMedGoogle Scholar
  • 70 Manco R, Clerbaux LA, Verhulst S. et al. Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury. J Hepatol 2019; 70 (06) 1180-1191
    CrossrefPubMedGoogle Scholar
  • 71 LeSagE G, Alvaro D, Benedetti A. et al. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats. Gastroenterology 1999; 117 (01) 191-199
    CrossrefPubMedGoogle Scholar
  • 72 Glaser S, Alvaro D, Francis H. et al. Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt. Am J Physiol Gastrointest Liver Physiol 2006; 290 (04) G813-G826
    CrossrefPubMedGoogle Scholar
  • 73 Lesage G, Glaser S, Ueno Y. et al. Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis. Am J Physiol Gastrointest Liver Physiol 2001; 281 (01) G182-G190
    CrossrefPubMedGoogle Scholar
  • 74 Renzi A, DeMorrow S, Onori P. et al. Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats. Hepatology 2013; 57 (03) 1130-1141
    CrossrefPubMedGoogle Scholar
  • 75 DiGregorio N, Sharma S. Physiology, Secretin. StatPearls; 2022
    Google Scholar
  • 76 Sato K, Meng F, Venter J, Giang T, Glaser S, Alpini G. The role of the secretin/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles. Sci Rep 2017; 7 (01) 11183
    CrossrefPubMedGoogle Scholar
  • 77 Duffy AM, Bouchier-Hayes DJ, Harmey JH. Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signalling by VEGF. Madame Curie Bioscience Database [Internet]. Landes Bioscience; 2000–2013. Accessed October 20, 2022 at: https://www.ncbi.nlm.nih.gov/books/NBK6482/
    PubMedGoogle Scholar
  • 78 Gaudio E, Barbaro B, Alvaro D. et al. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism. Gastroenterology 2006; 130 (04) 1270-1282
    CrossrefPubMedGoogle Scholar
  • 79 Mancinelli R, Onori P, Gaudio E. et al. Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1. Am J Physiol Gastrointest Liver Physiol 2009; 297 (01) G11-G26
    CrossrefPubMedGoogle Scholar
  • 80 Orlowski M, Sarao MS. Physiology, Follicle Stimulating Hormone. Treasure Island, FL: StatPearls Publishing; 2022
    Google Scholar
  • 81 Onori P, Gaudio E, Franchitto A, Alpini G, Francis H. Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes. World J Gastrointest Pathophysiol 2010; 1 (02) 38-49
    CrossrefPubMedGoogle Scholar
  • 82 Bone & Soft Tissue. Laboratory Investigation 2011; 91 (01) 8-24 DOI: 10.1038/labinvest.2011.15.
    CrossrefPubMedGoogle Scholar
  • 83 Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med 2013; 19 (03) 197-209
    CrossrefPubMedGoogle Scholar
  • 84 Alvaro D, Mancino MG, Onori P. et al. Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol 2006; 12 (22) 3537-3545
    CrossrefPubMedGoogle Scholar
  • 85 Aloe L, Rocco ML, Bianchi P, Manni L. Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med 2012; 10: 239
    CrossrefPubMedGoogle Scholar
  • 86 Gigliozzi A, Alpini G, Baroni GS. et al. Nerve growth factor modulates the proliferative capacity of the intrahepatic biliary epithelium in experimental cholestasis. Gastroenterology 2004; 127 (04) 1198-1209
    CrossrefPubMedGoogle Scholar
  • 87 Mawe GM, Hoffman JM. Serotonin signalling in the gut – functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 2013; 10 (08) 473-486
    CrossrefPubMedGoogle Scholar
  • 88 Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009; 60: 355-366
    CrossrefPubMedGoogle Scholar
  • 89 Marzioni M, Glaser S, Francis H. et al. Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin. Gastroenterology 2005; 128 (01) 121-137
    CrossrefPubMedGoogle Scholar
  • 90 Renzi A, Glaser S, Demorrow S. et al. Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors. Am J Physiol Gastrointest Liver Physiol 2011; 301 (04) G634-G643
    CrossrefPubMedGoogle Scholar
  • 91 de Jong IEM, van den Heuvel MC, Wells RG, Porte RJ. The heterogeneity of the biliary tree. J Hepatol 2021; 75 (05) 1236-1238
    CrossrefPubMedGoogle Scholar
  • 92 Assis DN, Debray D. Gallbladder and bile duct disease in cystic fibrosis. J Cyst Fibros 2017; 16 (Suppl. 02) S62-S69
    CrossrefPubMedGoogle Scholar
  • 93 Cnossen WR, Drenth JP. Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management. Orphanet J Rare Dis 2014; 9: 69
    CrossrefPubMedGoogle Scholar
  • 94 Washington MK. Autoimmune liver disease: overlap and outliers. Mod Pathol 2007; 20 (Suppl. 01) S15-S30
    CrossrefPubMedGoogle Scholar
  • 95 Strasser SI, Shulman HM, Flowers ME. et al. Chronic graft-versus-host disease of the liver: presentation as an acute hepatitis. Hepatology 2000; 32 (06) 1265-1271
    CrossrefPubMedGoogle Scholar
  • 96 Buxbaum J, Papademetriou M, Klipfel N, Selby R, Fong TL, Sharma O. Biliary sarcoidosis: early diagnosis minimizes the need for surgery. Am J Respir Crit Care Med 2013; 187 (05) 556-559
    CrossrefPubMedGoogle Scholar
  • 97 Douglass KM, Willner IR, Glenn DJ, Jones RM. Idiopathic adulthood ductopenia causing cirrhosis. ACG Case Rep J 2020; 7 (03) e00349
    CrossrefPubMedGoogle Scholar
  • 98 Banales JM, Marin JJG, Lamarca A. et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17 (09) 557-588
    CrossrefPubMedGoogle Scholar