The role of fibrinolytic system proteins in cholesterol gallstone formation

Background: accelerated nucleation, supersaturation of bile, and biliary st asis are known to be key factors in cholesterol gallstone formation, The me chanisms through which these factors interact to form stones are still inco mpletely understood. Among the proteins now known to he present in bile are several components of the fibrinolytic system: tissue plasminogen activato r, urokinase-like plasminogen activator, and plasminogen activator inhibito rs 1 and 2. The concentrations of plasminogen activator inhibitors 1 and 2 in gallbladder bile are increased in patients with gallstones, The aim of t his study was to determine whether these fibrinolytic system proteins oct a s pro-nucleating agents for cholesterol gallstone formation. Methods: Nucle ation assays were done on gallbladder bile from eight cholesterol stone pat ients and eight control patients, The effects of tissue plasminogen activat or, urokinase-like plasminogen activator, and plasminogen activator inhibit ors 1 and 2 on cholesterol crystal appearance time (CCAT) were tested, by d irect observation using polarizing microscopy, after measurement of biliary lipids and calculation of cholesterol saturation indices. Results: There w as no significant difference in cholesterol saturation indices between bile that nucleated and bile that did not (mean, 2.0 +/- 1.5 versus 1.8 +/- 0.5 ). When all samples in which nucleation occurred were compared. tissue plas minogen activator significantly shortened CCAT median from 4.75 days (range . 2-21) to 3.5 days (2.5-18) (P < 0.05). This was similar to the effect of fibronectin (3.75 days; range, 2-20, a known pro-nucleator used as a nuclea tion accelerating control (P < 0.05). None of the other fibrinolytic system proteins significantly accelerated CCAT. Conclusions: The results of this study suggest that tissue plasminogen activator may act as a pro-nucleating agent for cholesterol gallstone formation in gallbladder bile.