Interaction of hemolytic anemia and genotype on hemolysis-induced gallstone formation in mice

We previously reported that nb/nb mice with hereditary hemolytic anemia spontaneously developed calcium bilirubinate pigment gallstones. To assess the extent to which gallstone formation and bile composition is gene dependent, we transferred the hemolytic process by transplanting bone marrow from nb/nb mice into a nonhemolytic, but histocompatible genotype, W/Wv mice. Hematologic parameters of transplanted W/Wv mice were nearly identical to those of nb/nb mice. Like nb/nb mice, the percentage of transplanted mice with gallstones increased with the duration of the hemolysis and occurred twice as often in female mice as in male mice (37% vs. 19%; p less than 0.05). However, the rate of gallstone formation in transplanted mice was one-third less than that in nb/nb mice (3.6% per month vs. 5.5%; p less than 0.05). Analysis of hepatic bile revealed that (a) marrow-transplanted mice had higher concentrations of unconjugated bilirubin due to hemolysis (p less than 0.05) and of total bile acids determined by the W/Wv genotype (p less than 0.001) than their respective nb/nb counterparts and (b) transplanted mice with stones had a significantly lower proportion of cholic acid (p less than 0.005) and higher proportion of keto-bile acids (p less than 0.005) than transplanted mice without stones, suggesting that the cholic acid concentration may retard stone formation. These data indicate that the hemolytic process is the primary determinant of pigment gallstone formation in these mice and is influenced by the following factors: (a) duration of the hemolytic process, (b) gender, and (c) the genotype that regulates the composition of biliary components like bile acids.