Debits and credits: a current account of cholesterol gall stone disease.

Leading articleDebits and credits: a current account of cholesterol gall stone diseaseThe past 25 years has seen both progress and disappointment in our understanding of cholesterol cholelithiasis.Although there was much activity in the latter part of the 19th century' 2the developments during the late 1950s and early 60s laid the foundation for our present concepts of gall stone formation which culminated in the dissolution of stones by drug therapy. PathogenesisAn improved understanding of bile acid chemistry,3 the development of techniques permitting clarification of bile acid physiology and of the enterohepatic circulation"6 and an appreciation of the solubility relationship of cholesterol in bile,7 8 provided the background against which cholesterol gall stone disease appeared as the consequence of a metabolic disorder whereby the liver secretes bile saturated, or supersaturated with cholesterol.The concept of a primary hepatic defect was encouraged by reports of an abnormality in the rate binding enzymes for biliary lipid synthesis: an increased activity of 3-hydroxy-3 methylglutaryl-CoA (HMG-CoA) reductase (rate limiting for the synthesis of cholesterol) and a decreased 7ot-hydroxylase activity (rate limiting for the synthesis of bile acids).9Subjects with this hepatic defect secrete bile saturated with cholesterol and can form crystals, microspheroliths and stones.This relatively simple and4attractive hypothesis has been found wanting.It is now apparent that in many non-obese individuals with gall stones the hepatic HMG CoA reductase activity does not differ from stone-free persons.10" Patients with cholesterol gall stones may have a smaller total body pool of bile acids, but nonetheless the bile salt secretion will be normal12 and the correlation between total bile acid pool size and biliary cholesterol saturation is poor.13It is possible that the small pool of bile acids is related to increased recycling of bile acids within the enterohepatic circulation, which reflects the capacity of the gall bladder to fill and empty.14It is recognised that nocturnal storage in the gall bladder is an important factor determining cholesterol saturation of bile.'3 15 Any statement regarding the metabolic background to the formation of cholesterol gall stones must take account of the numerous conditions known to be associated with an increased prevalence of gall stones: race, age, sex, obesity, high calorie diet, disease of the distal ileum, clofibrate therapy, cystic fibrosis, diabetes mellitus, use of oral contraceptives and, more recently, total parenteral nutrition.'6-9An awareness of the many factors known to influence biliary cholesterol secretion and saturation has 1021