INCREASED BILIARY PROTEIN PRECEDES GALLSTONE FORMATION

Although nucleation is critical to the pathogenesis of cholesterol gal lstones, the factors responsible for this process are poorly defined. Numerous potential nucleating agents have been identified in the bile of humans and animals with ch cholelithiasis, including mucus, calcium , and bilirubin. Recent Studies have shown that patients with choleste rol crystals and gallstones have increased biliary total protein, sugg esting that protein may be a previously unrecognized nucleating factor . We tested the hypothesis that biliary total protein is increased pri or to cholesterol gallstone formation. Prairie dogs were maintained on either control (N = 22) or 0.4% cholesterol-enriched chow (N = 18) fo r up to 18 weeks. Cholesterol-fed animals were classified as pregallst one (N = 12) or gallstone (N = 6) based on gross examination of the ga llbladder bile. Both hepatic and gallbladder biles were then analyzed for lipid, bile acid, calcium, and protein content, Cholesterol feedin g was associated with increased gallbladder concentrations of choleste rol, phospholipids, and calcium in the pregallstone and gallstone grou ps. Biliary total protein was significantly elevated in the pregallsto ne (5.8 +/- 0.4 mg/ml, P < 0.001) and gallstone animals (6.0 +/- 0.6 m g/ml, P < 0.001) as compared to controls (3.8 +/- 0.3 mg/ml). Regressi on analysis showed positive correlations between gallbladder bile tota l protein and the gallbladder bile cholesterol saturation index (CSI) (P < 0.001), as well as between gallbladder total protein and calcium (P < 0.001). Although the hepatic bile CSI was elevated in cholesterol -fed animals, total protein remained unchanged, suggesting that the al teration in biliary protein is a gallbladder phenomenon. The finding t hat gallbladder bile total protein increases during crystal agglomerat ion indicates that high concentrations of biliary total protein in com bination with elevated levels of calcium may promote cholesterol cryst al nucleation and gallstone formation.