We hypothesize that the fundamental defect in cholesterol gallstone disease is the secretion of abnormal bile supersaturated with cholesterol. Puzzling differences in bile composition in "control" non-stone-bearing human populations are resolved by considering prevalence data. Populations with a high prevalence of disease yield a control group with a high proportion of potential stone formers, while populations with low prevalence yield controls with few, if any, potential stone formers.
Two basic possibilities exist which could account for abnormal bile production: (1) decreased mean secretion rate of bile salts; or (2) excess cholesterol secretion in the face of normal bile salt secretion rates. While there is some evidence to suggest that the former applies to some patients with gallstones, the problem remains unresolved. Finally, it is also possible that the gallbladder-Oddi's sphincter axis may influence hepatic bile salt metabolism and secretion, and, therefore, abnormal bile production.