Increased biliary protein precedes gallstone formation


Although nucleation is critical to the pathogenesis of cholesterol gallstones, the factors responsible for this process are poorly defined. Numerous potential nucleating agents have been identified in the bile of humans and animals with cholelithiasis, including mucus, calcium, and bilirubin. Recent studies have shown that patients with cholesterol crystals and gallstones have increased biliary total protein, suggesting that protein may be a previously unrecognized nucleating factor. We tested the hypothesis that biliary total protein is increased prior to cholesterol gallstone formation. Prairie dogs were maintained on either control (N=22) or 0.4% cholesterol-enriched chow (N=18) for up to 18 weeks. Cholesterol-fed animals were classified as pregallstone (N=12) or gallstone (N=6) based on gross examination of the gallbladder bile. Both hepatic and gallbladder biles were then analyzed for lipid, bile acid, calcium, and protein content. Cholesterol feeding was associated with increased gallbladder concentrations of cholesterol, phospholipids, and calcium in the pregallstone and gallstone groups. Biliary total protein was significantly elevated in the pregallstone (5.8±0.4 mg/ml,P<0.001) and gallstone animals (6.0±0.6 mg/ml,P<0.001) as compared to controls (3.8±0.3 mg/ml). Regression analysis showed positive correlations between gallbladder bile total 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 alteration in biliary protein is a gallbladder phenomenon. The finding that gallbladder bile total protein increases during crystal agglomeration indicates that high concentrations of biliary total protein in combination with elevated levels of calcium may promote cholesterol crystal nucleation and gallstone formation.

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Correspondence to Dr. Joel J. Roslyn MD.

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Supported by a grant from the Department of Veterans Affairs.

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James Moser, A., Abedin, M.Z. & Roslyn, J.J. Increased biliary protein precedes gallstone formation. Digest Dis Sci 39, 1313–1320 (1994).

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Key words

  • biliary protein
  • nucleation
  • gallstones