The role of fibrinolytic system proteins in cholesterol gallstone formation

Accelerated nucleation, supersaturation of bile, and biliary stasis are known to be key factors in cholesterol gallstone formation. The mechanisms through which these factors interact to form stones are still incompletely understood. Among the proteins now known to be present in bile are several components of the fibrinolytic system: tissue plasminogen activator, urokinase-like plasminogen activator, and plasminogen activator inhibitors 1 and 2. The concentrations of plasminogen activator inhibitors 1 and 2 in gallbladder bile are increased in patients with gallstones. The aim of this study was to determine whether these fibrinolytic system proteins act as pro-nucleating agents for cholesterol gallstone formation.

Nucleation assays were done on gallbladder bile from eight cholesterol stone patients and eight control patients. The effects of tissue plasminogen activator, urokinase-like plasminogen activator, and plasminogen activator inhibitors I and 2 on cholesterol crystal appearance time (CCAT) were tested, by direct observation using polarizing microscopy, after measurement of biliary lipids and calculation of cholesterol saturation indices.

There was 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 plasminogen 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 nucleation accelerating control (P < 0.05). None of the other fibrinolytic system proteins significantly accelerated CCAT.

The results of this study suggest that tissue plasminogen activator may act as a pro-nucleating agent for cholesterol gallstone formation in gallbladder bile.