Advertisement

Cholestasis

  • Michael H. Trauner
Chapter
Part of the Molecular Pathology Library book series (MPLB, volume 5)

Abstract

Secretion of bile is an important excretory route for a wide range of endogenous and exogenous compounds, also known as endobiotics (e.g., bile acids, bilirubin, cholesterol, phospholipids) and xenobiotics (e.g., drugs and their metabolites), which may become toxic when accumulating in the liver [1–3]. Bile acids, the major component of bile, are not only essential for the digestion and absorption of lipids from the intestinal lumen, but also have multiple endocrine functions as regulators of hepatic glucose and lipid metabolism, liver regeneration, inflammation, and intestinal bacterial flora [1]. Cholestasis is an impairment of bile secretion which is typically characterized by reduced bile flow and retention of biliary constituents (normally secreted into bile) in blood, liver, as well as extrahepatic organs and tissues [3]. Histopathologically, cholestasis is characterized by bilirubinostasis with bile plugs and cholate-stasis with feathery degeneration of (mainly periportal) hepatocytes [4]. An excellent, generally applicable definition of cholestasis, irrespective of the cause and etiology, has been coined by Serge Erlinger describing this condition as “failure of bile to reach the duodenum in sufficient amounts” [5].

Keywords

Bile Acid Cystic Fibrosis Transmembrane Conductance Regulator Bile Salt Export Pump Cystic Fibrosis Transmembrane Conductance Regulator Gene Cholestatic Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grants P18613-B05, P19118-B05 and F3008-B05 (to M.T.) from the Austrian Science Foundation and a GENAU project grant from the Austrian Ministry of Science.

References

  1. 1.
    Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci. 2009;14:2584–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003;83:633–71.PubMedGoogle Scholar
  3. 3.
    Zollner G, Trauner M. Mechanisms of cholestasis. Clin Liver Dis. 2008;12:1–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Li MK, Crawford JM. The pathology of cholestasis. Semin Liver Dis. 2004;24:21–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Erlinger S. What is cholestasis in 1985? J Hepatol. 1985;1:687–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Wagner M, Zollner G, Trauner M. New molecular insights into the mechanisms of cholestasis. J Hepatol. 2009;51:565–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology. 2006;130:908–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Gershwin ME, Mackay IR. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology. 2008;47:737–45.PubMedCrossRefGoogle Scholar
  9. 9.
    Chapman R, Cullen S. Etiopathogenesis of primary sclerosing cholangitis. World J Gastroenterol. 2008;14:3350–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm. 2006;3:231–51.PubMedCrossRefGoogle Scholar
  11. 11.
    Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F, et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology. 2002;123:1238–51.PubMedCrossRefGoogle Scholar
  12. 12.
    Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2004;127:261–74.PubMedCrossRefGoogle Scholar
  13. 13.
    Jacquemin E, de Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology. 2001;120:1448–58.PubMedCrossRefGoogle Scholar
  14. 14.
    Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis. 2001;21:551–62.PubMedCrossRefGoogle Scholar
  15. 15.
    Balistreri WF. Inborn errors of bile acid biosynthesis and transport. Novel forms of metabolic liver disease. Gastroenterol Clin North Am. 1999;28:145–72, vii.Google Scholar
  16. 16.
    Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ. Drug- and estrogen-induced cholestasis trough inhibition of the paepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology. 2000;118:422–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Keitel V, Burdelski M, Vojnisek Z, Schmitt L, Häussinger D, Kubitz R. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology. 2009;50:510–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology. 2001;33:633–46.PubMedCrossRefGoogle Scholar
  19. 19.
    Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol. 2003;38:717–27.PubMedCrossRefGoogle Scholar
  20. 20.
    Zollner G, Wagner M, Fickert P, Silbert D, Gumhold J, Zatloukal K, et al. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. 2007;27:920–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Arrese M, Trauner M. Molecular aspects of bile formation and cholestasis. Trends Mol Med. 2003;9:558–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Banales JM, Prieto J, Medina JF. Cholangiocyte anion exchange and biliary bicarbonate excretion. World J Gastroenterol. 2006;12:3496–511.PubMedGoogle Scholar
  23. 23.
    Fickert P, Trauner M. When lightning strikes twice: the plot thickens for a dual role of the anion exchanger 2 (AE2/SLC4A2) in the pathogenesis and treatment of primary biliary cirrhosis. J Hepatol. 2009;50:633–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I. Oude Elferink RP, Prieto J, Medina JF. Ae2a, b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology. 2008;134:1482–93.PubMedCrossRefGoogle Scholar
  25. 25.
    Phillips MJ, Poucell S, Oda M. Mechanisms of cholestasis. Lab Invest. 1986;54:593–608.PubMedGoogle Scholar
  26. 26.
    Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med. 1998;339:1217–27.PubMedCrossRefGoogle Scholar
  27. 27.
    Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J Clin Gastroenterol. 2005;39 Suppl 2:S111–24.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Internal Medicine, Division of Gastroenterology and HepatologyMedical University of GrazGrazAustria

Personalised recommendations