Cholesterol gallstone disease

Summary

With a prevalence of 10–15% in adults in Europe and the USA, gallstones are the most common digestive disease needing admission to hospital in the West. The interplay between interprandial and postprandial physiological responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major achievement in the field. We highlight scientific advances in protein and gene regulation of cholesterol absorption, synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease. We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for gene targeting in therapy.

Introduction

Gallstones are abnormal masses of a solid mixture of cholesterol crystals, mucin, calcium bilirubinate, and proteins that have affected people for centuries:¹ multiple gallstones were found in a mummified Egyptian priestess,² but the disease was first described in 1507 by a Florentine pathologist, Antonio Benivenius.³ The Swiss medic Paracelsus viewed gallstones as a consequence of “tartaric” disease.⁴ With a prevalence of 10–15% in adults in Europe and the USA, gallstone disease is one of the most common and most expensive to treat of digestive disorders that need admission to hospital.5, 6 Every year in the USA, more than one million people are newly diagnosed with gallstones, and about 700 000 individuals have cholecystectomies.⁷ In 1882, in the first open cholecystectomy Langenbuch successfully removed the gallbladder of a 43-year-old man who had had gallstones for 16 years.⁸ This technique remained the gold standard therapy for symptomatic gallstones for over a century, although medical treatment with bile acids was first described in the late 19th century.9, 10 After a report of complete dissolution of gallstones by bile acids in 1937,¹¹ oral bile acid litholysis with chenodeoxycholic acid as a method for removing cholesterol gallstones emerged in the 1970s,¹² and litholysis with ursodeoxycholic acid in the 1980s.¹³ Extracorporeal shockwave lithotripsy plus oral bile acids for symptomatic gallstones was introduced first in 1986 in Munich.¹⁴ Later, several studies proved that gallstones recur in 30–50% of cases, 5 years after bile salts therapy or lithotripsy.15, 16 In 1987, Mouret¹⁷ undertook the first laparoscopic cholecystectomy, which is today the treatment of choice for symptomatic gallstones.

In the human gallbladder, three types of gallstones exist, depending on the major constituents: pure cholesterol, pure pigment, and mixed (small amounts of calcium and bilirubin salts). Pigment stones appear in two major forms: black and brown. Whereas black pigment stones result from haemolysis and consist primarily of calcium bilirubinate, brown pigment stones are associated with infections of the biliary tract (bacterial and helminthic) and are more frequent in Asia or occur after cholecystectomy as de novo common bile duct stones.¹⁸ Cholesterol gallstone disease results from a complex interaction of genetic and environmental risk factors. Discoveries linking gene transcription, protein function, lipid metabolism, and regulation of biliary lipid secretion in the formation of cholesterol gallstones provide the impetus to review our understanding of the disease.