Black and brown pigment
gallstones are morphologically, compositionally, and clinically distinct. Black stones form primarily in the gallbladder in sterile bile and are associated with advanced age, chronic
hemolysis,
alcoholism,
cirrhosis,
pancreatitis, and
total parenteral nutrition. Brown stones form not only within the gallbladder but also within the intrahepatic and extrahepatic ducts; they are uniformly infected with enteric bacteria and are usually associated with ascending
cholangitis. Brown stones are related to juxtapapillary duodenal
diverticula and are the predominant type of de novo common bile duct stones.
Cholecystectomy is usually curative in black pigment stone disease, whereas stones often recur after
cholecystectomy for brown stone disease. The pathogenesis of black stones is probably related to nonbacterial, nonenzymatic hydrolysis of
bilirubin conjugates. At the pH of bile, this results in two monohydrogenated
bilirubin anions that precipitate with
calcium ions.
Bilirubin monoconjugates that are increased in several conditions, such as
Gilbert's syndrome and chronic
hemolysis, may play a pivotal role in black stone formation as a source of unconjugated monohydrogenated
bilirubin and as a possible co-precipitant with
calcium. The precipitation of
calcium carbonate and
phosphate is influenced by local gallbladder factors. Brown pigment stones are formed in bile infected with enteric bacteria that elaborate hydrolytic
enzymes:
beta-glucuronidase,
phospholipase A, and conjugated
bile acid hydrolase. The resulting
anions of
bilirubin and
fatty acids form insoluble
calcium salts. We used nb/nb mice with a chronic
hemolytic anemia as a model of
hemolysis-induced black stone disease. The presence of 40%
bilirubin monoconjugates in mouse
gallstones indicated the importance of this moiety in the pathogenesis of black stones. Other data obtained by marrow
transplantation experiments in mice revealed the relative importance of genotype versus the
hemolytic anemia on determinants such as biliary
bile acid composition and
mucin secretory glands in the mouse gallbladder neck. Additional physical chemical studies of the interaction of unconjugated
bilirubin in model bile solutions will be helpful in further delineating the pathogenesis of both black and brown pigment
gallstones.