Ultrastructural Evidence of Intrahepatic Cholestasis Before and After Chenodeoxycholic Acid Therapy in Patients with Cholelithiasis: The National Cooperative Gallstone Study

Authors

  • M. James Phillips,

    1. University of Toronto, Toronto, Canada M5G 115; Yale University School of Medicine, New Haven, Connecticut 06510; and George Washington University, Washington, D.C. 20037
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  • Rosemarie L. Fisher,

    Corresponding author
    1. University of Toronto, Toronto, Canada M5G 115; Yale University School of Medicine, New Haven, Connecticut 06510; and George Washington University, Washington, D.C. 20037
    • Rosemarie L. Fisher, M.D., Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510
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  • Deborah W. Anderson,

    1. University of Toronto, Toronto, Canada M5G 115; Yale University School of Medicine, New Haven, Connecticut 06510; and George Washington University, Washington, D.C. 20037
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  • Shu-Ping Lan,

    1. University of Toronto, Toronto, Canada M5G 115; Yale University School of Medicine, New Haven, Connecticut 06510; and George Washington University, Washington, D.C. 20037
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  • John M. Lachin,

    1. University of Toronto, Toronto, Canada M5G 115; Yale University School of Medicine, New Haven, Connecticut 06510; and George Washington University, Washington, D.C. 20037
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  • James L. Boyer

    1. University of Toronto, Toronto, Canada M5G 115; Yale University School of Medicine, New Haven, Connecticut 06510; and George Washington University, Washington, D.C. 20037
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  • The contents of this publication do not necessarily reflect the views or policies of the Department nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

  • The members of the Steering Committee were: Richard A. Baum; Robert. L. Habig; Russell F. Hanson; Theodore Hersh; N. C. Hightower; Alan F. Hofmann; Elliott C. Lasser; Jay W. Marks; Hagop Mekhjian; Ronald Okun; Robert A. Schaefer; Leslie J. Schoenfield; Lawrence Shaw; Roger D. Soloway; Johnson L. Thistle; Fred P. Thomas; and Malcolm P. Tyor (affiliations; University of Maryland; Duke University; University of Minnesota; Emory University; Scott & White Clinic; University of California at San Diego; Cedars-Sinai Medical Center and the University of California at Los Angeles; George Washington University; University of Pennsylvania; Ohio State Univesity; New York Hospital-Cornell Medical Center; and the Mayo Clinic).

Abstract

Electron microscopy was performed to assess potential hepatotoxicity before and after 9 and 24 months of chenodeoxycholic acid (CDCA) therapy (375 or 750 mg, daily) in 103 patients with cholelithiasis. Prior to treatment, 64% of the biopsies demonstrated ultrastructural evidence of intrahepatic cholestasis, manifested by abnormal bile canaliculi, thickened pericanalicular ectoplasm, and retention of biliary material within liver cells or pericellular spaces. After 9 months of CDCA therapy, several changes (including increased free cytoplasmic “biliary pigment,” decreased canalicular microvilli, and increased pericanalicular ectoplasm) consistent with intrahepatic cholestasis became more prevalent (63% prior to therapy, 89% at 9 months, p < 0.01) regardless of CDCA dose. After 24 months of therapy, canalicular microvilli and pericanalicular ectoplasm continued to be abnormal (p < 0.01).

This study indicates that ultrastructural evidence of intrahepatic cholestasis is a common subclinical abnormality in patients with cholelithiasis which increases during CDCA therapy, changes which could represent either the natural history of cholelithiasis or CDCA toxicity. A drug effect is suggested by the lack of correlation of these abnormalities with the duration of cholelithiasis prior to CDCA treatment and their “increasing” prevalence after only 9 months of therapy. In addition, canalicular membrane lesions developed in two patients which were similar to lithocholate toxicity in animals. It is not known whether these abnormalities would result in clinically significant hepatoxicity if therapy is continued for longer than 24 months.

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