LithGenes and Genetic Analysis of Cholesterol Gallstone Formation

Epidemiologic investigations, clinical observations, and family and twin studies in humans, as well as gallstone prevalence investigations in inbred mouse models, support the concept that cholesterol cholelithiasis could result from a complex interaction of environmental factors and the effects of multiple undetermined genes. Quantitative trait locus (QTL) analysis is a powerful genetic method for identifying primary rate-limiting genetic defects and discriminating them from secondary downstream lithogenic effects caused by mutations of the primary genes, and the subsequent positional cloning of such genes responsible for QTLs, followed by the use of manufactured mouse strains with “knockout” or “knockin” of the genes, could lead to the discovery of lithogenic actions of gallstone ( LITH ) genes. The combined use of genomic strategies and phenotypic studies in inbred strains of mice has successfully resulted in the identification of many candidate LITH genes. Because there is exceptionally close homology between mouse and human genomes, the orthologous human LITH genes can be identified from the mouse study. The discovery of LITH genes and more fundamental knowledge concerning the genetic determinants and molecular mechanisms underlying the formation of cholesterol gallstones in humans will pave the way for critical diagnostic and prelithogenic preventive measures for this exceptionally prevalent digestive disease.

Cholesterol cholelithiasis is one of the most prevalent digestive diseases, resulting in a considerable financial and social burden worldwide. In the United States, at least 20 million Americans (12% of adults) are affected. Each year, approximately 1 million new cases are discovered, and more than 700,000 cholecystectomies are performed, making this one of the most common elective abdominal operations. Although many gallstones are silent, approximately one-third eventually cause symptoms and complications. In addition, the unavoidable complications result in 3000 deaths (0.12% of all deaths) annually. In the year 2000, more than 750,000 outpatient clinic visits and more than 250,000 hospitalizations were the result of gallstone-induced gastrointestinal symptoms. As a result, there was a median inpatient charge of $11,584, and medical expenses for the treatment of gallstones exceeded $6 billion. Because the prevalence of gallstones is increasing because of the worldwide obesity epidemic with associated insulin resistance, a key feature of the metabolic syndrome, it is imperative to find potential ways to prevent the formation of gallstones.

During the past 50 years, it has been established that the primary pathophysiologic defect in most cholelithogenic humans is hepatic hypersecretion of biliary cholesterol, which may be accompanied by normal, high, or (less commonly) low secretion rates of biliary bile salts or phospholipids, inducing unphysiological cholesterol supersaturation of gallbladder bile. Recent studies on humans and mouse models have shown that interactions of 5 defects ( Fig. 1 ) result in nucleation and crystallization of cholesterol monohydrate crystals in bile and eventually gallstone formation. These are (1) genetic factors and Lith genes; (2) unphysiological supersaturation with cholesterol due to hepatic hypersecretion of biliary lipids; (3) accelerated phase transitions of cholesterol; (4) dysfunctional gallbladder motility accompanied by immune-mediated gallbladder inflammation, as well as hypersecretion of mucins and accumulation of mucin gel in the gallbladder lumen; and (5) increased amounts of cholesterol from the intestinal source due to high efficiency of cholesterol absorption or slow intestinal motility which aids hydrophobe absorption and augments second bile salt synthesis by the anaerobic microflora. Growth of solid platelike cholesterol monohydrate crystals to form gallstones is a consequence of persistent hepatic hypersecretion of biliary cholesterol together with gallbladder mucin hypersecretion and gel formation and with incomplete evacuation by the gallbladder as a result of its impaired motility function.