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

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 less than 0.01) regardless of CDCA dose. After 24 months of therapy, canalicular microvilli and pericanalicular ectoplasm continued to be abnormal (p less than 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.