The Etiology of Pigment Gallstones
Article first published online: 24 JUL 2008
Copyright © 1984 American Association for the Study of Liver Diseases
Volume 4, Issue S2, pages 215S–222S, September/October 1984
How to Cite
Ostrow, J. D. (1984), The Etiology of Pigment Gallstones. Hepatology, 4: 215S–222S. doi: 10.1002/hep.1840040840
- Issue published online: 24 JUL 2008
- Article first published online: 24 JUL 2008
- United States Veterans Administration
- Extramural Research. Grant Number: AM-32130
- National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases
- National Institutes of Health
- United States Public Health Service
- Otho S.A. Sprague Foundation at Northwestern University Medical School
Pigment gallstones are of two major types, black and earthy brown, each consisting of calcium salts of bilirubin and other anions, along with an unmeasured residue that is largely mucin glycoproteins. Studies in model systems indicate that the small proportion of unconjugated bilirubin in bile is solubilized by bile salts and that the ionized bilirubin is more soluble than the protonated diacid. Solubility is decreased by added lecithin but is unaffected by cholesterol. At the pH of bile, unconjugated bilirubin exists mainly as a monoanion with sufficient solubility in mixed micelles not to precipitate, were it not for the presence of calcium, which forms highly insoluble salts with unconjugated bilirubin anions. Supersaturation of bile with calcium bilirubinates is inhibited by bile salts, which bind calcium, reducing the activity of free calcium ions. When supersaturation occurs, usually due to increased concentrations of bilirubinate anion, nucleation may be initiated by binding of calcium bilirubinate to mucin glycoproteins in bile.
In earthy brown stones, which form mainly in the bile ducts, the pigment is mostly calcium bilirubinate, combined with calcium palmitate. These components form due to hydrolysis, by enzymes in infecting bacteria, of conjugated bilirubin and lecithin, respectively. In black stones, which form mainly in the gallbladder, the pigment is mostly a highly cross-linked network polymer of bilirubin, which is insoluble in all solvents. Concomitant polymerization and oxidation of calcium bilirubinate probably occur in the solid state, after precipitation of the pigment due to hydrolysis of conjugated bilirubin by endogenous β-glucuronidase from the biliary tract and/or liver. This may result from a diet-related decrease in inhibitors of β-glucuronidase in bile. In hemolytic states, increased concentrations of conjugated bilirubin in bile, providing more substrate for hydrolysis, may contribute also to black stone formation. Black stones also contain coprecipitated calcium phosphate and/or carbonate, but the insoluble polymer renders them resistant to physical dissolution therapy.