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Biliary Cirrhosis

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Molecular Pathology of Liver Diseases

Part of the book series: Molecular Pathology Library ((MPLB,volume 5))

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Abstract

Cholangiopathies are defined as pathologic conditions in which bile ducts are primary targets of disease. Together, these conditions account for approximately of one fifth adult liver transplants and the majority of pediatric liver transplants worldwide [1, 2]. While there are multiple individual conditions that make up the cholangiopathic spectrum, the end-stage of disease in each of these is biliary cirrhosis.

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References

  1. Ghobrial RM, Amersi F, McDiarmid SV, Busuttil RW. Pediatric liver transplantation. In: Maddrey WC, Schiff ER, Sorrell MF, editors. Transplantation of the liver. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 79–99.

    Google Scholar 

  2. Keefe EB. Selection of patients for liver transplantation. In: Maddrey WC, Schiff ER, Sorrell MF, editors. Transplantation of the liver. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 5–34.

    Google Scholar 

  3. Goodman ZD, Ishak KG. Hepatic histopathology. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff’s diseases of the liver, vol. 1. 8th ed. Philadelphia: Lippincott-Raven; 1999. p. 53–117.

    Google Scholar 

  4. Strazzabosco M, Fabris L, Spirli C. Pathophysiology of cholangiopathies. J Clin Gastroenterol. 2005;39:S90–102.

    Article  PubMed  Google Scholar 

  5. Alpini G, McGill JM, Larusso NF. The pathobiology of biliary ­epithelia. Hepatology. 2002;35:1256–68.

    Article  PubMed  CAS  Google Scholar 

  6. Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol. 2002;36:200–9.

    Article  PubMed  Google Scholar 

  7. Kruglov EA, Jain D, Dranoff JA. Isolation of primary rat liver fibroblasts. J Investig Med. 2002;50:179–84.

    Article  PubMed  Google Scholar 

  8. Mak KM, Lieber CS. Portal fibroblasts and myofibroblasts in baboons after long-term alcohol consumption. Arch Pathol Lab Med. 1986;110:513–6.

    PubMed  CAS  Google Scholar 

  9. Ramadori G, Saile B. Mesenchymal cells in the liver—one cell type or two? Liver. 2002;22:283–94.

    Article  PubMed  CAS  Google Scholar 

  10. Tuchweber B, Desmouliere A, Bochaton-Piallat ML, Rubbia-Brandt L, Gabbiani G. Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat. Lab Invest. 1996;74:265–78.

    PubMed  CAS  Google Scholar 

  11. Uchio K, Tuchweber B, Manabe N, Gabbiani G, Rosenbaum J, Desmouliere A. Cellular retinol-binding protein-1 expression and modulation during in vivo and in vitro myofibroblastic differentiation of rat hepatic stellate cells and portal fibroblasts. Lab Invest. 2002;82:619–28.

    Article  PubMed  CAS  Google Scholar 

  12. Colombo C. Liver disease in cystic fibrosis. Curr Opin Pulm Med. 2007;13:529–36.

    Article  PubMed  Google Scholar 

  13. Desmouliere A, Tuchweber B, Gabbiani G. Role of the myofibroblast differentiation during liver fibrosis. J Hepatol. 1995;22:61–4.

    PubMed  CAS  Google Scholar 

  14. Knittel T, Kobold D, Saile B, Grundmann A, Neubauer K, Piscaglia F, et al. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology. 1999;117:1205–21.

    Article  PubMed  CAS  Google Scholar 

  15. Brenner DA, Waterboer T, Choi SK, Lindquist JN, Stefanovic B, Burchardt E, et al. New aspects of hepatic fibrosis. J Hepatol. 2000;32:32–8.

    Article  PubMed  CAS  Google Scholar 

  16. Friedman SL, Maher JJ, Bissell DM. Mechanisms and therapy of hepatic fibrosis: report of the AASLD Single Topic Basic Research Conference. Hepatology. 2000;32:1403–8.

    Article  PubMed  CAS  Google Scholar 

  17. Clouzeau-Girard H, Guyot C, Combe C, Moronvalle-Halley V, Housset C, Lamireau T, et al. Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices. Lab Invest. 2006;86:275–85.

    Article  PubMed  CAS  Google Scholar 

  18. Jhandier MN, Kruglov EA, Lavoie EG, Sevigny J, Dranoff JA. Portal fibroblasts regulate the proliferation of bile duct epithelia via expression of NTPDase2. J Biol Chem. 2005;280:22986–92.

    Article  PubMed  CAS  Google Scholar 

  19. Kinnman N, Francoz C, Barbu V, Wendum D, Rey C, Hultcrantz R, et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab Invest. 2003;83:163–73.

    PubMed  CAS  Google Scholar 

  20. Kinnman N, Housset C. Peribiliary myofibroblasts in biliary type liver fibrosis. Front Biosci. 2002;7:d496–503.

    Article  PubMed  CAS  Google Scholar 

  21. Ramadori G, Saile B. Portal tract fibrogenesis in the liver. Lab Invest. 2004;84:153–9.

    Article  PubMed  Google Scholar 

  22. Doctor RB, Dahl R, Fouassier L, Kilic G, Fitz JG. Cholangiocytes exhibit dynamic, actin-dependent apical membrane turnover. Am J Physiol Cell Physiol. 2002;282:C1042–52.

    Article  PubMed  CAS  Google Scholar 

  23. LaRusso NF. Morphology, physiology, and biochemistry of biliary epithelia. Toxicol Pathol. 1996;24:84–9.

    Article  PubMed  CAS  Google Scholar 

  24. Alpini G, Glaser S, Robertson W, Rodgers RE, Phinizy JL, Lasater J, et al. Large but not small intrahepatic bile ducts are involved in secretin- regulated ductal bile secretion. Am J Physiol. 1997;272:G1064–74.

    PubMed  CAS  Google Scholar 

  25. Fitz JG. Regulation of cholangiocyte secretion. Semin Liver Dis. 2002;22:241–9.

    Article  PubMed  CAS  Google Scholar 

  26. Kato A, Gores GJ, LaRusso NF. Secretin stimulates exocytosis in isolated bile duct epithelial cells by a cyclic AMP-mediated mechanism. J Biol Chem. 1992;267:15523–9.

    PubMed  CAS  Google Scholar 

  27. Roberts SK, Ludwig J, LaRusso NF. The pathobiology of biliary epithelia. Gastroenterology. 1997;112:269–79.

    Article  PubMed  CAS  Google Scholar 

  28. Sirica AE, Nathanson MH, Gores GJ, Larusso NF. Pathobiology of biliary epithelia and cholangiocarcinoma: proceedings of the Henry M. and Lillian Stratton Basic Research Single-Topic Conference. Hepatology. 2008;48:2040–6.

    Article  PubMed  Google Scholar 

  29. Carruthers JS, Kalifat SR, Steiner JW. The ductular cell reaction of rat liver in extrahepatic cholestasis: II. The proliferation of connective tissue. Exp Mol Pathol. 1962;1:377–96.

    Article  PubMed  CAS  Google Scholar 

  30. Popper H, Udenfriend S. Hepatic fibrosis: correlation of ­biochemical and morphologic investigations. Am J Med. 1970;49:707–21.

    Article  PubMed  CAS  Google Scholar 

  31. Friedman SL, Rockey DC, McGuire RF, Maher JJ, Boyles JK, Yamasaki G. Isolated hepatic lipocytes and Kupffer cells from ­normal human liver: morphological and functional characteristics in primary culture. Hepatology. 1992;15:234–43.

    Article  PubMed  CAS  Google Scholar 

  32. Friedman SL, Roll FJ. Isolation and culture of hepatic lipocytes, Kupffer cells, and sinusoidal endothelial cells by density gradient centrifugation with Stractan. Anal Biochem. 1987;161:207–18.

    Article  PubMed  CAS  Google Scholar 

  33. Herbst H, Frey A, Heinrichs O, Milani S, Bechstein WO, Neuhaus P, et al. Heterogeneity of liver cells expressing procollagen types I and IV in vivo. Histochem Cell Biol. 1997;107:399–409.

    Article  PubMed  CAS  Google Scholar 

  34. Magness ST, Bataller R, Yang L, Brenner DA. A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology. 2004;40:1151–9.

    Article  PubMed  CAS  Google Scholar 

  35. Saile B, Matthes N, Neubauer K, Eisenbach C, El-Armouche H, Dudas J, et al. Rat liver myofibroblasts and hepatic stellate cells differ in CD95-mediated apoptosis and response to TNF-alpha. Am J Physiol Gastrointest Liver Physiol. 2002;283:G435–44.

    PubMed  CAS  Google Scholar 

  36. Wells RG, Kruglov E, Dranoff JA. Autocrine release of TGF-beta by portal fibroblasts regulates cell growth. FEBS Lett. 2004;559:107–10.

    Article  PubMed  CAS  Google Scholar 

  37. Dranoff JA, Wells RG. Portal fibroblasts: underappreciated mediators of biliary fibrosis. Hepatology. 2010;51(4):1438–44.

    Article  PubMed  Google Scholar 

  38. Frangogiannis NG, Entman ML. Chemokines in myocardial ischemia. Trends Cardiovasc Med. 2005;15:163–9.

    Article  PubMed  CAS  Google Scholar 

  39. Marra F. Chemokines in liver inflammation and fibrosis. Front Biosci. 2002;7:d1899–914.

    Article  PubMed  CAS  Google Scholar 

  40. Yamamoto T. Pathogenic role of CCL2/MCP-1 in scleroderma. Front Biosci. 2008;13:2686–95.

    Article  PubMed  CAS  Google Scholar 

  41. Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, et al. Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol. 1998;152:423–30.

    PubMed  CAS  Google Scholar 

  42. Tsuneyama K, Harada K, Yasoshima M, Hiramatsu K, Mackay CR, Mackay IR, et al. Monocyte chemotactic protein-1, -2, and -3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis. J Pathol. 2001;193:102–9.

    Article  PubMed  CAS  Google Scholar 

  43. Ramm GA, Shepherd RW, Hoskins AC, Greco SA, Ney AD, Pereira TN, et al. Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment. Hepatology. 2009;49:533–44.

    Article  PubMed  CAS  Google Scholar 

  44. Demetris AJ, Fontes P, Lunz 3rd JG, Specht S, Murase N, Marcos A. Wound healing in the biliary tree of liver allografts. Cell Transplant. 2006;15 Suppl 1:S57–65.

    Article  PubMed  Google Scholar 

  45. Ezure T, Sakamoto T, Tsuji H, Lunz 3rd JG, Murase N, Fung JJ, et al. The development and compensation of biliary cirrhosis in interleukin-6-deficient mice. Am J Pathol. 2000;156:1627–39.

    Article  PubMed  CAS  Google Scholar 

  46. Yokoyama T, Komori A, Nakamura M, Takii Y, Kamihira T, Shimoda S, et al. Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-kappaB and -MAPK signaling pathways. Liver Int. 2006;26:467–76.

    Article  PubMed  CAS  Google Scholar 

  47. Liu Z, Sakamoto T, Yokomuro S, Ezure T, Subbotin V, Murase N, et al. Acute obstructive cholangiopathy in interleukin-6 deficient mice: compensation by leukemia inhibitory factor (LIF) suggests importance of gp-130 signaling in the ductular reaction. Liver. 2000;20:114–24.

    Article  PubMed  CAS  Google Scholar 

  48. Yasoshima M, Kono N, Sugawara H, Katayanagi K, Harada K, Nakanuma Y. Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells: in situ and culture study. Lab Invest. 1998;78:89–100.

    PubMed  CAS  Google Scholar 

  49. Kruglov EA, Nathanson RA, Nguyen T, Dranoff JA. Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. Am J Physiol Gastrointest Liver Physiol. 2005;290(4):G765–71.

    Article  PubMed  Google Scholar 

  50. Sedlaczek N, Jia JD, Bauer M, Herbst H, Ruehl M, Hahn EG, et al. Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis. Am J Pathol. 2001;158:1239–44.

    Article  PubMed  CAS  Google Scholar 

  51. Kobayashi H, Hayashi N, Hayashi K, Yamataka A, Lane GJ, Miyano T. Connective tissue growth factor and progressive fibrosis in biliary atresia. Pediatr Surg Int. 2005;21:12–6.

    Article  PubMed  Google Scholar 

  52. Kobayashi H, Tamatani T, Tamura T, Kusafuka J, Koga H, Yamataka A, et al. The role of monocyte chemoattractant protein-1 in biliary atresia. J Pediatr Surg. 2006;41:1967–72.

    Article  PubMed  Google Scholar 

  53. Shinoda H, Tasaka S, Fujishima S, Yamasawa W, Miyamoto K, Nakano Y, et al. Elevated CC chemokine level in bronchoalveolar lavage fluid is predictive of a poor outcome of idiopathic pulmonary fibrosis. Respiration. 2009;78:285–92.

    Article  PubMed  CAS  Google Scholar 

  54. Distler JH, Akhmetshina A, Schett G, Distler O. Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis. Rheumatology (Oxford). 2009;48:98–103.

    Article  CAS  Google Scholar 

  55. Fernandez-Martinez E, Perez-Alvarez V, Tsutsumi V, Shibayama M, Muriel P. Chronic bile duct obstruction induces changes in plasma and hepatic levels of cytokines and nitric oxide in the rat. Exp Toxicol Pathol. 2006;58:49–58.

    Article  PubMed  CAS  Google Scholar 

  56. Yu J, Lavoie EG, Sheung N, Sevigny J, Dranoff JA. IL-6 transcriptionally downregulates portal fibroblast NTPDase2 expression via specific promoter elements. In: Digestive diseases week (AASLD). Washington, DC: ScholarOne, Inc.; 2007.

    Google Scholar 

  57. Burnstock G. Development and perspectives of the purinoceptor concept. J Auton Pharmacol. 1996;16:295–302.

    Article  PubMed  CAS  Google Scholar 

  58. Burnstock G. P2 purinoceptors: historical perspective and classification. In: Chadwick DJ, Goode JA, editors. P2 purinoceptors: localization, function and transduction mechanisms (Ciba Foundation Symposium 198). Chichester: Wiley; 1996. p. 1–34.

    Google Scholar 

  59. Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev. 1998;50:413–92.

    PubMed  CAS  Google Scholar 

  60. Barnard EA, Webb TE, Simon J, Kunapuli SP. The diverse series of recombinant P2Y purinoceptors. Ciba Found Symp. 1996;198:166–80.

    PubMed  CAS  Google Scholar 

  61. Burnstock G. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci. 2001;22:182–8.

    Article  PubMed  CAS  Google Scholar 

  62. la Sala A, Ferrari D, Corinti S, Cavani A, Di Virgilio F, Girolomoni G. Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses. J Immunol. 2001;166:1611–7.

    PubMed  Google Scholar 

  63. Doctor RB, Johnson S, Brodsky KS, Amura CR, Gattone V, Fitz JG. Regulated ion transport in mouse liver cyst epithelial cells. Biochim Biophys Acta. 2007;1772:345–54.

    Article  PubMed  CAS  Google Scholar 

  64. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, et al. International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev. 2006;58:281–341.

    Article  PubMed  CAS  Google Scholar 

  65. Dranoff JA, Masyuk AI, Kruglov EA, LaRusso NF, Nathanson MH. Polarized expression and function of P2Y ATP receptors in rat bile duct epithelia. Am J Physiol Gastrointest Liver Physiol. 2001;281:G1059–67.

    PubMed  CAS  Google Scholar 

  66. Salter KD, Fitz JG, Roman RM. Domain-specific purinergic signaling in polarized rat cholangiocytes. Am J Physiol Gastrointest Liver Physiol. 2000;278:G492–500.

    PubMed  CAS  Google Scholar 

  67. Dranoff JA, Kruglov EA, Robson SC, Braun N, Zimmermann H, Sevigny J. The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver. Hepatology. 2002;36:1135–44.

    Article  PubMed  CAS  Google Scholar 

  68. Harada H, Chan CM, Loesch A, Unwin R, Burnstock G. Induction of proliferation and apoptotic cell death via P2Y and P2X receptors, respectively, in rat glomerular mesangial cells. Kidney Int. 2000;57:949–58.

    Article  PubMed  CAS  Google Scholar 

  69. Burnstock G. Purinergic signaling and vascular cell proliferation and death. Arterioscler Thromb Vasc Biol. 2002;22:364–73.

    Article  PubMed  Google Scholar 

  70. Wilden PA, Agazie YM, Kaufman R, Halenda SP. ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways. Am J Physiol. 1998;275:H1209–15.

    PubMed  CAS  Google Scholar 

  71. Schafer R, Sedehizade F, Welte T, Reiser G. ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells. Am J Physiol Lung Cell Mol Physiol. 2003;285:L376–85.

    PubMed  Google Scholar 

  72. Turner CM, Ramesh B, Srai SK, Burnstock G, Unwin RJ. Altered ATP-sensitive P2 receptor subtype expression in the Han:SPRD cy/+ rat, a model of autosomal dominant polycystic kidney disease. Cells Tissues Organs. 2004;178:168–79.

    Article  PubMed  CAS  Google Scholar 

  73. Dranoff JA, Kruglov E, Toure J, Braun N, Zimmermann H, Jain D, et al. The ectonucleotidase NTPDase2 is selectively down-regulated in biliary fibrosis. J Invest Med. 2004;52:475–82.

    Article  CAS  Google Scholar 

  74. Marra F, Romanelli RG, Giannini C, Failli P, Pastacaldi S, Arrighi MC, et al. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells. Hepatology. 1999;29:140–8.

    Article  PubMed  CAS  Google Scholar 

  75. Yu J, Lavoie EG, Sheung N, Tremblay JJ, Sevigny J, Dranoff JA. IL-6 downregulates transcription of NTPDase2 via specific promoter elements. Am J Physiol Gastrointest Liver Physiol. 2008;294:G748–56.

    Article  PubMed  CAS  Google Scholar 

  76. Hanley PJ, Musset B, Renigunta V, Limberg SH, Dalpke AH, Sus R, et al. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in ­macrophages. Proc Natl Acad Sci U S A. 2004;101:9479–84.

    Article  PubMed  CAS  Google Scholar 

  77. Shigemoto-Mogami Y, Koizumi S, Tsuda M, Ohsawa K, Kohsaka S, Inoue K. Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5. J Neuro­chem. 2001;78:1339–49.

    Article  PubMed  CAS  Google Scholar 

  78. Yu J, Sheung N, Soliman EM, Spirli C, Dranoff JA. Transcriptional regulation of IL-6 in bile duct epithelia by extracellular ATP. Am J Physiol Gastrointest Liver Physiol. 2009;296:G563–71.

    Article  PubMed  CAS  Google Scholar 

  79. Communi D, Robaye B, Boeynaems JM. Pharmacological characterization of the human P2Y11 receptor. Br J Pharmacol. 1999;128:1199–206.

    Article  PubMed  CAS  Google Scholar 

  80. Torres B, Zambon AC, Insel PA. P2Y11 receptors activate ­adenylyl cyclase and contribute to nucleotide-promoted cAMP formation in MDCK-D(1) cells. A mechanism for nucleotide-mediated autocrine-paracrine regulation. J Biol Chem. 2002;277:7761–5.

    Article  PubMed  CAS  Google Scholar 

  81. Sakamoto T, Liu Z, Murase N, Ezure T, Yokomuro S, Poli V, et al. Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy. Hepatology. 1999;29:403–11.

    Article  PubMed  CAS  Google Scholar 

  82. Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal PS, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology. 2007;133:80–90.

    Article  PubMed  Google Scholar 

  83. Desmet V, Roskams T, Van Eyken P. Ductular reaction in the liver. Pathol Res Pract. 1995;191:513–24.

    Article  PubMed  CAS  Google Scholar 

  84. Hata S, Namae M, Nishina H. Liver development and regeneration: from laboratory study to clinical therapy. Dev Growth Differ. 2007;49:163–70.

    Article  PubMed  CAS  Google Scholar 

  85. Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M. Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 2003;10:265–81.

    Article  PubMed  Google Scholar 

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Dranoff, J.A. (2011). Biliary Cirrhosis. In: Monga, S. (eds) Molecular Pathology of Liver Diseases. Molecular Pathology Library, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7107-4_31

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