Gallstones form when substances normally dissolved or suspended in bile precipitate and gradually aggregate into solid material. The exact mechanism differs between cholesterol and pigment stones. Cholesterol stones generally arise when bile becomes supersaturated with cholesterol, when crystallisation and nucleation are promoted, and when gallbladder emptying is insufficient to clear crystals. Pigment stones form when bilirubin-related material precipitates, often because bilirubin production or biliary conditions favour the formation of insoluble pigment compounds. Gallstone formation is therefore a process involving bile chemistry, gallbladder motility, intestinal and hepatic physiology, genetics and environmental risk factors.
Cholesterol supersaturation is a major mechanism in cholesterol gallstones. Cholesterol is normally transported in bile in a form that remains soluble because of bile salts and phospholipids. When cholesterol concentration becomes excessive relative to these solubilising components, cholesterol can crystallise. Mucus within the gallbladder can help retain crystals, while impaired gallbladder contraction can prolong the time available for crystals to grow and combine. Over time, microscopic crystals can develop into macroscopic stones. This explains why factors affecting cholesterol metabolism and gallbladder emptying can substantially alter gallstone risk.
Obesity is an important risk factor for gallstones, particularly cholesterol stones. Increased hepatic cholesterol synthesis and secretion can increase the cholesterol concentration of bile, while obesity-related metabolic changes can affect gallbladder function. Importantly, the relationship is not simply that heavier people eat more fat. Gallstone risk reflects complex metabolic changes associated with adipose tissue, insulin resistance and lipid metabolism. People with obesity therefore have increased risk even though individual dietary patterns vary considerably.
Rapid weight loss can also promote gallstone formation, creating an important distinction between obesity-related risk and the consequences of losing weight too quickly. During rapid weight reduction, large amounts of cholesterol can be mobilised from adipose tissue and secreted into bile, while very low food intake can reduce gallbladder stimulation and emptying. Bariatric surgery can therefore be followed by an increased risk of gallstones, particularly during substantial rapid weight loss. This does not mean that weight loss should be avoided when medically appropriate; rather, weight management should generally be planned in a nutritionally adequate and clinically appropriate manner.
Oestrogen contributes to some of the sex-related differences in gallstone risk. Women have a higher incidence of gallstones, and pregnancy, hormone replacement therapy and some hormonal contraceptives can increase risk because oestrogen can increase cholesterol secretion into bile. Pregnancy also affects gallbladder motility, which can promote bile stasis. Age further increases risk, and a family history indicates that inherited differences in cholesterol metabolism, bile composition or gallbladder function can contribute to susceptibility. These factors often interact rather than acting independently.
Pigment gallstones have different causes. Excess bilirubin in bile can favour precipitation of calcium bilirubinate and formation of pigment stones. Chronic haemolytic anaemias, in which red blood cells are continuously destroyed, increase bilirubin production and therefore increase the risk of pigment stones. Liver cirrhosis and biliary infection are also associated with gallstone formation. Pigment stones can be divided broadly into black and brown forms, with different clinical associations; brown pigment stones are particularly associated with infection and stasis within bile ducts.
Intestinal diseases can influence gallstone risk because the normal circulation of bile acids depends partly on intestinal absorption and reabsorption. Conditions such as Crohn's disease that affect the terminal ileum can interfere with this process and alter bile composition. Metabolic syndrome, diabetes, high triglycerides and low HDL cholesterol are also associated with increased risk. Cirrhosis can alter bile composition and hepatic metabolism, while infections of the biliary tract can promote certain pigment stones. These associations show that gallstone formation can reflect systemic metabolic, intestinal, haematological and hepatic conditions rather than an isolated gallbladder problem.
Diet influences risk primarily through its relationship with body weight, metabolic health and the pattern of weight change. NHS information identifies a diet high in fat and low in fibre as a risk factor, while NIDDK also identifies diets high in calories and refined carbohydrates as associated with greater risk. Nevertheless, gallstones cannot be attributed to dietary fat alone, and people with very different diets can develop them. Some risk factors, including age, sex, genetics and certain medical conditions, cannot be modified. Prevention therefore focuses on maintaining a healthy weight, avoiding extreme rapid weight loss and managing relevant metabolic and medical conditions rather than trying to eliminate one food group.
