ROLE OF HYPERBILIRUBINEMIA IN THE IMPAIRMENT OF OSTEOBLAST PROLIFERATION-ASSOCIATED WITH CHOLESTATIC JAUNDICE

Because the osteoporosis occurring in chronic cholestatic liver diseas e (CCLD) is associated with decreased bone formation and is reversible by liver transplantation, substances retained in plasma during choles tasis may impair osteoblast function, This hypothesis was tested using a new bioassay that measures plasma mitogenic activity (PMA) for norm al human osteoblast-like (hOB) cells, In 29 jaundiced patients, mean P MA was 56.4% (P < 0.001) of that in 29 age- and sex-matched normal sub jects, and the decrease in PMA was similar in the 14 with CCLD and the 15 with other causes of jaundice. Bile acids and bilirubin are the tw o major groups of products retained during cholestasis. The common con jugated bile acids and bilirubin were added to normal human plasma in concentrations simulating those found in patients with CCLD. Various b ile salts had no effect on PMA whereas unconjugated bilirubin decrease d PMA in a dose-dependent fashion (r = -0.98, P < 0.0001) without affe cting cell viability, Relatively selective removal of bilirubin from t he plasma by photobleaching normalized the decreased PMA in five jaund iced patients but produced no apparent change in five normal subjects, These data support the hypothesis that hyperbilirubinemia or possibly other photolabile substances impair osteoblast proliferative capacity and thus may play a major role in the pathogenesis of the osteoporosi s associated with CCLD.