Pigment gallstones are a major cause of biliary tract disease in Americans and account for about 1/3 of the half-million cholecystectomies performed yearly. From our data it is clear that patients in the general population have pigment stones, and from other studies that patients with hemolysis and cirrhosis have a high incidence of pigment stones. Yet, the etiology of pigment stones is unknown. Human studies of bile obtained at cholecystectomy or by duodenal drainage are of limited value since changes in bile may reflect the presence of stones or cholecystitis. Furthermore prospective studies in man would require decades of observation. Thus, an animal model of human pigment stone disease is ideal. Our preliminary data showed the 78% of female nb/nb mice with a hereditary anemia developed pigment stones, almost identical in composition to a human pigment stone. Our objective is to determine the pathogenesis, prevention and treatment of human pigment stones by utilizing this mouse model and by applying the techniques of bile and stone analysis used in human studies to this model. This study will examine the natural history, epidemiology, and gallbladder and liver pathology of nb/nb mice which develop pigment stones. Sibling controls will be used. The role of diet, biliary tract infection and other genetic factors will be assessed. During each study, isotopic precursors of heme, glycine and delta-aminolevulenic acid will be injected i.p. to determine whether bilirubin in stones is derived primarily from red cell or hepatic heme sources. Bilirubin in bile will be assessed for its relative proportions and types of conjugates. Bile calcium and bile acid levels will be measured. The association of bacteria with pigment stones will be assessed by analyzing stones, bile and gallbladder for metabolic products and components of bacteria by gas chromatographic-mass spectroscopic analysis. The effect of the anemia independent of other genetic factors will be assessed by bone marrow transplants from nb/nb mice to cogenic strains of mice without pigment stones. Implications of these mouse studies on human disease are clear: If pigment stones can be prevented in mice, the next step is to evaluate high risk patients.