Skip to main content
SpringerLink
Log in

Cholangiocyte Biology as Relevant to Cystic Liver Diseases

  • Chapter
  • First Online:
Fibrocystic Diseases of the Liver

Part of the book series: Clinical Gastroenterology ((CG))

Summary

Polycystic liver diseases are hereditary disorders that affect the biliary epithelium, often in conjunction with the renal tubule epithelium. Characterized by the progressive formation of cysts throughout the liver and kidney, they can often lead to severe life-threatening complications. Polycystins and fibrocystin, the defective proteins in the dominant and in the recessive form of the disease, respectively, are mainly expressed in the primary (nonmotile) cilia of cholangiocytes, the epithelial cells that line the intrahepatic biliary tree. Important clues for understanding the pathogenesis of cystic diseases come from understanding the biology and pathobiology of cholangiocytes. In this chapter, cholangiocyte function and morphology is first briefly described, with particular emphasis on the regulation of their secretory properties and the complex intercellular signaling. Then, we discuss a number of possible mechanisms leading to cyst formation and progressive growth of the cysts. In both autosomal dominant and recessive forms, liver cysts arise from an aberrant development of intrahepatic bile duct epithelium. During cyst expansion, different factors, including excessive fluid secretion, extracellular matrix remodeling, increased proliferation of the epithelial cells lining the cyst, and aberrant hypervascularization around the cyst wall, variably take part in promoting progressive cyst growth. Many of these factors act via autocrine mechanisms. Each of them represents a possible target for therapies aimed at reducing the growth of liver cysts.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: Disorders of biliary epithelia. Gastroenterology 2004;127, 1565–1577.

    Article  CAS  PubMed  Google Scholar 

  2. Strazzabosco M, Fabris L. Functional anatomy of normal bile ducts. Anat Rec (Hoboken) 2008;291, 653–660.

    Google Scholar 

  3. Glaser S, Francis H, Demorrow S et al. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 2006;12, 3523–3536.

    CAS  PubMed  Google Scholar 

  4. Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 2001;33, 738–750.

    Article  CAS  PubMed  Google Scholar 

  5. Strazzabosco M. New insights into cholangiocyte physiology. J Hepatol 1997;27, 945–952.

    Article  CAS  PubMed  Google Scholar 

  6. Strazzabosco M, Spirli C, Okolicsanyi L. Pathophysiology of the intrahepatic biliary epithelium. J Gastroenterol Hepatol 2000;15, 244–253.

    Article  CAS  PubMed  Google Scholar 

  7. Lenzen R, Elster J, Behrend C, et al. Bile acid-independent bile flow is differently regulated by glucagon and secretin in humans after orthotopic liver transplantation. Hepatology 1997;26, 1272–1281.

    CAS  PubMed  Google Scholar 

  8. Cho WK, Boyer JL. Vasoactive intestinal polypeptide is a potent regulator of bile secretion from rat cholangiocytes. Gastroenterology 1999;117, 420–428.

    Article  CAS  PubMed  Google Scholar 

  9. Alvaro D, Alpini G, Jezequel AM, et al. Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions. J Clin Invest 1997;100, 1349–1362.

    Article  CAS  PubMed  Google Scholar 

  10. Cho WK, Boyer JL. Characterization of ion transport mechanisms involved in bombesin-stimulated biliary secretion in rat cholangiocytes. J Hepatol 1999;30, 1045–1051.

    Article  CAS  PubMed  Google Scholar 

  11. Gong AY, Tietz PS, Muff MA et al. Somatostatin stimulates ductal bile absorption and inhibits ductal bile secretion in mice via SSTR2 on cholangiocytes. Am J Physiol 2003;284, C1205–C1214.

    CAS  Google Scholar 

  12. Caligiuri A, Glaser S, Rodgers RE et al. Endothelin-1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes. Am J Physiol 1998;275, G835–G846.

    CAS  PubMed  Google Scholar 

  13. Spirli C, Granato A, Zsembery K et al. Functional polarity of Na+/H+ and Cl–/\({\rm{HCO}}_3^ - \) exchangers in a rat cholangiocyte cell line. Am J Physiol 1998;275, G1236–G1245.

    CAS  PubMed  Google Scholar 

  14. Mennone A, Biemesderfer D, Negoianu D et al. Role of sodium/hydrogen exchanger isoform NHE3 in fluid secretion and absorption in mouse and rat cholangiocytes. Am J Physiol Gastrointest Liver Physiol 2001;280, G247–G254.

    CAS  PubMed  Google Scholar 

  15. Masyuk AI, Masyuk TV, Splinter PL et al. Cholangiocyte Cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling. Gastroenterology 2006;131, 911–920.

    Article  CAS  PubMed  Google Scholar 

  16. Zsembery Á, Spirlì C, Granato A et al. Purinergic regulation of acid/base transport in human and rat biliary epithelial cell lines. Hepatology 1998;28, 914–920.

    Article  CAS  PubMed  Google Scholar 

  17. Fiorotto R, Spirli C, Fabris L et al. Ursodeoxycholic acid stimulates cholangiocyte fluid secretion in mice via CFTR-dependent ATP secretion. Gastroenterology 2007;133, 1603–1613.

    Article  CAS  PubMed  Google Scholar 

  18. Strazzabosco M, Fabris L, Spirli C. Pathophysiology of cholangiopathies. J Clin Gastroenterol 2005;39, S90–S102.

    Article  PubMed  Google Scholar 

  19. Desmet VJ. Histopathology of chronic cholestasis and adult ductopenic syndrome. Clin Liver Dis 1998;2, 249–264.

    Article  CAS  PubMed  Google Scholar 

  20. Zeisberg M, Kalluri R. Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis. Front Biosci 2008;13, 6991–6998.

    Article  CAS  PubMed  Google Scholar 

  21. Willis BC, duBois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc 2006;3, 377–382.

    Article  CAS  PubMed  Google Scholar 

  22. Rygiel KA, Robertson H, Marshall HL et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest 2007;88, 112–123.

    Article  PubMed  Google Scholar 

  23. Omenetti A, Porrello A, Jung Y et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 2008;118, 3331–3342.

    CAS  PubMed  Google Scholar 

  24. 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, 191–199.

    Article  CAS  PubMed  Google Scholar 

  25. 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, 121–137.

    Article  CAS  PubMed  Google Scholar 

  26. 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, 1198–1209.

    Article  CAS  PubMed  Google Scholar 

  27. Huang BQ, Masyuk TV, Muff MA et al. Isolation and characterization of cholangiocyte primary cilia. Am J Physiol Gastrointest Liver Physiol 2006;291, G500–G509.

    Article  CAS  PubMed  Google Scholar 

  28. Masyuk AI, Masyuk TV, LaRusso NF. Cholangiocyte primary cilia in liver health and disease. Dev Dyn 2008;237, 2007–2012.

    Article  CAS  PubMed  Google Scholar 

  29. Masyuk TV, Huang BQ, Ward CJ et al. Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat. Gastroenterology 2003;125, 1303–1310.

    Article  CAS  PubMed  Google Scholar 

  30. Praetorius HA, Spring KR. A physiological view of the primary cilium. Ann Rev Physiol 2005;67, 515–529.

    Article  CAS  Google Scholar 

  31. Nauli SM, Alenghat FJ, Ying L et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003;33, 129–137.

    Article  CAS  PubMed  Google Scholar 

  32. Low SH, Vasanth S, Larson CH et al. Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell 2006;10, 57–69.

    Article  CAS  PubMed  Google Scholar 

  33. Weimbs T. Polycystic kidney disease and renal injury repair: Common pathways, fluid flow, and the function of Polycystin-1. Am J Physiol Renal Physiol 2007;293, F1423–F1432.

    Article  CAS  PubMed  Google Scholar 

  34. Shillingford JM, Murcia NS, Larson CH et al. The mTOR pathway is regulated by Polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA 2006;103, 5466–5471.

    Article  CAS  PubMed  Google Scholar 

  35. Alvaro D, Onori P, Alpini G et al. Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease. Am J Pathol 2008;172, 321–332.

    Article  CAS  PubMed  Google Scholar 

  36. Condac E, Silasi-Mansat R, Kosanke S et al. Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis. Proc Natl Acad Sci USA 2007;104, 9416–9421.

    Article  CAS  PubMed  Google Scholar 

  37. Fischer E, Legue E, Doyen A et al. Defective planar cell polarity in polycystic kidney disease. Nat Genet 2006;38, 21–23.

    Article  CAS  PubMed  Google Scholar 

  38. Ward CJ, Yuan D, Masyuk TV et al. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet 2003;12, 2703–2710.

    Article  CAS  PubMed  Google Scholar 

  39. Menezes LF, Cai Y, Nagasawa Y et al. Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm. Kidney Int 2004;66, 1345–1355.

    Article  CAS  PubMed  Google Scholar 

  40. Wang S, Luo Y, Wilson PD et al. The autosomal recessive polycystic kidney disease protein is localized to primary cilia, with concentration in the basal body area. J Am Soc Nephrol 2004;15, 592–602.

    Article  PubMed  Google Scholar 

  41. Troskams VD. Embryology of extra- and intrahepatic Bile Ducts, the ductal plate. Anat Rec Adv Integr Anat Evol Biol 2008;291, 628–635.

    Article  Google Scholar 

  42. Desmet VJ. Congenital diseases of intrahepatic bile ducts: Variations on the theme “ductal plate malformation”. Hepatology 1992;16, 1069–1083.

    Article  CAS  PubMed  Google Scholar 

  43. Koptides M, Deltas CC. Autosomal dominant polycystic kidney disease: Molecular genetics and molecular pathogenesis. Hum Genet 2000;107, 115–126.

    Article  CAS  PubMed  Google Scholar 

  44. Wu G, Somlo S. Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. Mol Genet Metab 2000;69, 1–15.

    Article  CAS  PubMed  Google Scholar 

  45. Shibazaki S, Yu Z, Nishio S et al. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum Mol Genet 2008;17, 1505–1516.

    Article  CAS  PubMed  Google Scholar 

  46. Everson GT, Emmett M, Brown WR et al. Functional similarities of hepatic cystic and biliary epithelium: Studies of fluid constituents and in vivo secretion in response to secretin. Hepatology 1990;11, 557–565.

    Article  CAS  PubMed  Google Scholar 

  47. Vandenburgh HH. Mechanical forces and their second messengers in stimulating cell growth in vitro. Am J Physiol Regul Integr Comp Physiol 1992;262, R350–R355.

    CAS  Google Scholar 

  48. Tanner GA, McQuillan PF, Maxwell MR et al. An in vitro test of the cell stretch-proliferation hypothesis of renal cyst enlargement. J Am Soc Nephrol 1995;6, 1230–1241.

    CAS  PubMed  Google Scholar 

  49. Roman RM, Fitz JG. Emerging roles of purinergic signaling in gastrointestinal epithelial secretion and hepatobiliary function. Gastroenterology 1999;116, 964–979.

    Article  CAS  PubMed  Google Scholar 

  50. Schwiebert EM, Zsembery A. Extracellular ATP as a signaling molecule for epithelial cells. Biochim Biophys Acta (BBA) – Biomembranes 2003;1615, 7–32.

    Article  CAS  Google Scholar 

  51. Wilson PD, Hovater JS, Casey CC et al. ATP release mechanisms in primary cultures of epithelia derived from the cysts of polycystic kidneys. J Am Soc Nephrol 1999;10, 218–229.

    CAS  PubMed  Google Scholar 

  52. Persu A, Devuyst O. Transepithelial chloride secretion and cystogenesis in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2000;15, 747–750.

    Article  CAS  PubMed  Google Scholar 

  53. Xu N, Glockner J, Rossetti S et al. Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis. J Nephrol 2006;19, 529–534.

    PubMed  Google Scholar 

  54. Feranchak AP, Sokol RJ. Cholangiocyte biology and cystic fibrosis liver disease. Semin Liver Dis 2001;21, 471–488.

    Article  CAS  PubMed  Google Scholar 

  55. Yang B, Sonawane ND, Zhao D et al. Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol 2008;19, 1300–1310.

    Article  CAS  PubMed  Google Scholar 

  56. Li H, Findlay IA, Sheppard DN. The relationship between cell proliferation, Cl– secretion, and renal cyst growth: A study using CFTR inhibitors. Kidney Int 2004;66, 1926–1938.

    Article  CAS  PubMed  Google Scholar 

  57. Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease: The major factor determining clinical outcomes. Clin J Am Soc Nephrol 2006;1, 148–157.

    Article  PubMed  Google Scholar 

  58. Gattone VH, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 2003;9, 1323–1326.

    Article  CAS  PubMed  Google Scholar 

  59. Yamaguchi T, Nagao S, Kasahara M et al. Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am J Kidney Dis 1997;30, 703–709.

    Article  CAS  PubMed  Google Scholar 

  60. Masyuk TV, Masyuk AI, Torres VE et al. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3′,5′-cyclic monophosphate. Gastroenterology 2007;132, 1104–1116.

    Article  CAS  PubMed  Google Scholar 

  61. 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, 528–537.

    Article  CAS  PubMed  Google Scholar 

  62. Tietz PS, Alpini G, Pham LD, Larusso NF. Somatostatin inhibits secretin-induced ductal hypercholeresis and exocytosis by cholangiocytes. Am J Pysiol 1995;269, G110–G118.

    CAS  Google Scholar 

  63. Alvaro D, Gigliozzi A, Attili AF. Regulation and deregulation of cholangiocyte proliferation. J Hepatol 2000;33, 333–340.

    Article  CAS  PubMed  Google Scholar 

  64. Merta M, Tesar V, Zima T et al. Cytokine profile in autosomal dominant polycystic kidney disease. IUBMB Life 1997;41, 619–624.

    Article  CAS  Google Scholar 

  65. Munemura C, Uemasu J, Kawasaki H. Epidermal growth factor and endothelin in cyst fluid from autosomal dominant polycystic kidney disease cases: Possible evidence of heterogeneity in cystogenesis. Am J Kidney Dis 1994;24, 561–568.

    CAS  PubMed  Google Scholar 

  66. Gardner KD, Jr, Burnside JS, Elzinga LW, Locksley RM. Cytokines in fluids from polycystic kidneys. Kidney Int 1991;39, 718–724.

    Article  PubMed  Google Scholar 

  67. Nichols MT, Gidey E, Matzakos T et al. Secretion of cytokines and growth factors into autosomal dominant polycystic kidney disease liver cyst fluid. Hepatology 2004;40, 836–846.

    CAS  PubMed  Google Scholar 

  68. Fabris L, Cadamuro M, Fiorotto R et al. Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology 2006;43, 1001–1012.

    Article  CAS  PubMed  Google Scholar 

  69. Alvaro D, Metalli VD, Alpini G et al. The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis. J Hepatol 2005;43, 875–883.

    Article  CAS  PubMed  Google Scholar 

  70. Alvaro D, Onori P, Metalli VD et al. Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. Hepatology 2002;36, 297–304.

    Article  CAS  PubMed  Google Scholar 

  71. Gaudio E, Barbaro B, Alvaro D et al. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism. Gastroenterology 2006;130, 1270–1282.

    Article  CAS  PubMed  Google Scholar 

  72. Libbrecht L, Cassiman D, Desmet V, Roskams T. The correlation between portal myofibroblasts and development of intrahepatic bile ducts and arterial branches in human liver. Liver 2002;22, 252–258.

    Article  PubMed  Google Scholar 

  73. Fabris L, Cadamuro M, Libbrecht L et al. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology 2008;47, 719–728.

    Article  PubMed  Google Scholar 

  74. Desmet V, Roskams T, Van Eyken P. Ductular reaction in the liver. Path Res Practice 1995;191, 513–524.

    CAS  Google Scholar 

  75. Gaudio E, Onori P, Pannarale L, Alvaro D. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: A morphological study. Gastroenterology 1996;111, 1118–1124.

    Article  CAS  PubMed  Google Scholar 

  76. Martinez-Hernandez A, Amenta PS. The hepatic extracellular matrix. II. Ontogenesis, regeneration and cirrhosis. Virch Archiv 1993;423, 77–84.

    Article  CAS  Google Scholar 

  77. Martinez-Hernandez A, Amenta PS. The hepatic extracellular matrix. I. Components and distribution in normal liver. Virch Archiv 1993;423, 1–11.

    Article  CAS  Google Scholar 

  78. Ozaki S, Sato Y, Yasoshima M et al. Diffuse expression of heparin sulfate proteoglycan and connective tissue growth factor in fibrous septa with many mast cells relate to unresolving hepatic fibrosis of congenital hepatic fibrosis. Liver Int 2005;25, 817–828.

    Article  CAS  PubMed  Google Scholar 

  79. Das SK, Vasudevan DM. Genesis of hepatic fibrosis and its biochemical markers. Scand J Clin Lab Invest 2008;68, 260–269.

    Article  CAS  PubMed  Google Scholar 

  80. Preaux AM, Mallat A, Nhieu JT et al. Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions. Hepatology 1999;30, 944–950.

    Article  CAS  PubMed  Google Scholar 

  81. Rankin CA, Itoh Y, Tian C et al. Matrix metalloproteinase-2 in a murine model of infantile-type polycystic kidney disease. J Am Soc Nephrol 1999;10, 210–217.

    CAS  PubMed  Google Scholar 

  82. Berthier CC, Wahl PR, Hir ML et al. Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2008;23, 880–889.

    Article  PubMed  Google Scholar 

  83. Rankin CA, Suzuki K, Itoh Y et al. Matrix metalloproteinases and TIMPS in cultured C57BL/6 J-cpk kidney tubules. Kidney Int 1996;50, 835–844.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Eric Cohen (Department of Internal Medicine, Yale University) for critically reading the chapter. Funding was provided by NIH DK079005, by Yale University Liver Center (NIH DK34989), by PKD Foundation, Grant # 170G08a. The support of Fondazione S. Martino, Bergamo is gratefully acknowledged. CS is a recipient of an ALF/AASLD Liver Scholar ward.

Author information

Authors and Affiliations

  1. Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine and Liver Center, New Haven, CT, USA

    Silvia Lecchi MS, Carlo Spirli PhD, Romina Fiorotto PhD & Mario Strazzabosco MD, PhD

  2. Center for Liver Research (CeLiveR), Ospedali Riuniti Bergamo, Bergamo, Italy

    Luca Fabris MD, PhD & Massimiliano Cadamuro PhD

Authors
  1. Silvia Lecchi MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Fabris MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlo Spirli PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Massimiliano Cadamuro PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Romina Fiorotto PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mario Strazzabosco MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. School of Medicine, Children's Hospital & Regional, University of Washington, Sand Point Way NE. 4800, Seattle, 98105, USA

    Karen F. Murray

  2. St. Paul University Hospital, Harry Hines Blvd. 5939, Dallas, 75390-9258, USA

    Anne M. Larson

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Lecchi, S., Fabris, L., Spirli, C., Cadamuro, M., Fiorotto, R., Strazzabosco, M. (2010). Cholangiocyte Biology as Relevant to Cystic Liver Diseases. In: Murray, K., Larson, A. (eds) Fibrocystic Diseases of the Liver. Clinical Gastroenterology. Humana Press. https://doi.org/10.1007/978-1-60327-524-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-524-8_2

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-523-1

  • Online ISBN: 978-1-60327-524-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation