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Mechanisms of Drug-Induced Cholestasis

  • Chapter
Drug-Induced Hepatotoxicity

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 121))

Abstract

Cholestasis means stagnation of bile, and includes biochemical, morphological, and physiological features. Clinically determined signs and symptoms result from accumulation in blood of compounds normally excreted in bile, such as bilirubin, bile acids, cholesterol, alkaline phosphatase,5’-nucleotidase,γ-glutamyltranspeptidase,leucine amino peptidase, lipoprotein X. and immunoglobulin. The response of these compounds and the time course for elevation in serum varies after bile duct legation (KAPLAN et al. 1979: FREDERIKS et al. 1990) and after different homeostatic toxins (KEEFFE et al.1979). Hyperbilirubinemia in combination with elevated serum alkaline phosphataseis typically a reliable laboratory parameter, and determination of serum bile acid concentration has been proposed as a semi quantitative measure of cholestasis (BERRY and REICHEN 1983). Cholestasis may be definedmorphologically as visible accumulation of bile pigments in the canaliculi andhepatocytes, dilation of the canalicular space with a reduction of microvilli,feathery degeneration, accumulation of copper, and Mallory body-like cytoplasmicinclusions. Finally, the simplest functional definition of cholestasis is adecrease in bile flow. Cholestasis can be due to either a failure to secrete bile(intrahepatic) or to a mechanical obstruction (extrahepatic cholestasis) of thebile ducts. Laboratory tests may reflect the severity of cholestasis, but they donot identify the etiology of the disorder or distinguish between extra- andintrahepatic forms. Additional information on cholestasis may be found elsewhere(ZYSSET and REICHEN 1988: REICHEN and SIMON 1988: KING and BLITZER 1990: VORE 1991: FEUER and DIFONZO 1992: FALLON et al. 1993). Numerousconsult other comprehensive reviews (ZIMMERMAN and LEWIS 1987: HORSMANS and HARVENGT 1991). A recent issue of Seminars in Liver Diseases was devotedexclusively to cholestasis (LESTER 1993). This chapter will present potentialmechanisms by which chemicals can induce cholestasis and ten overview severalknown cholestatic agents. one problem with each of the mechanismsdiscussed is that it is not known whether any of these changes is a primarymechanism or a secondary consequence of cholestasis.

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Authors
  1. J. B. Watkins III
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  2. C. D. Klaassen
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Editor information

Editors and Affiliations

  1. Department of Pathology Division of Experimental Pathology, University of Toronto, Medical Sciences Building, 1 King’s College Circle, M5S 1A8, Toronto, Ontario, Canada

    Ross G. Cameron M.D., Ph.D.

  2. Department of Clinical Biochemistry Banting Institute, University of Toronto, Room 521, 100 College Street, M5G 1L5, Toronto, Ontario, Canada

    George Feuer Ph.D.

  3. Parke-Davis Pharmaceutical Research Division Department of Pathology and Experimental Toxicology, Warner Lambert Company, 2800 Plymouth Road, 48105, Ann Arbor, MI, USA

    Felix A. de la Iglesia M.D.

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© 1996 Springer-Verlag Berlin Heidelberg

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Watkins, J.B., Klaassen, C.D. (1996). Mechanisms of Drug-Induced Cholestasis. In: Cameron, R.G., Feuer, G., de la Iglesia, F.A. (eds) Drug-Induced Hepatotoxicity. Handbook of Experimental Pharmacology, vol 121. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-61013-4_7

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  • DOI: https://doi.org/10.1007/978-3-642-61013-4_7

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64657-7

  • Online ISBN: 978-3-642-61013-4

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