Cholelithiasis occurs in approximately 10% to 15% of adults in the US and Europe.[4][5] Age, obesity, and female sex hormones are important aetiological factors.[4][6] The prevalence rates are relatively low in Africa and Asia.[7][8]

Despite its high prevalence, cholelithiasis is generally asymptomatic in >80% of people.[5][9] Biliary pain, however, develops in 1% to 2% of previously asymptomatic individuals each year.[10][11][12][13] Once biliary colic has developed, about 50% of patients will go on to experience recurrent pain while up to 3% are at increased risk of complications: acute cholecystitis, cholangitis, or acute pancreatitis. In patients with asymptomatic stones, 0.1% to 0.3% will experience a major complication per year.[12][14]

Risk factors

The frequency of gallstones rises noticeably after the age of 40 years to become 4 to 10 times more likely in older individuals, peaking at 70 to 79 years.[4][15] Age correlates positively with increased cholesterol secretion and saturation; yet the stone type found in advanced age tends to be pigment.

Women have 2 to 3 times higher frequency of gallstones than men.[23] The basis may be increased cholesterol secretion into bile.

Body mass index (BMI) >30, diabetes mellitus and insulin resistance, and metabolic syndrome all convey an increased risk of cholesterol gallstone formation.[24][25][26][27] The postulated mechanisms are elevated hepatic cholesterol secretion, depressed bile salt synthesis, increased pronucleating agents like mucin, and/or impaired gallbladder motility. 

There is an increased prevalence of gallstones in some families.[16] Monozygotic twin studies show a higher concordance for gallstone disease than dizygotic twins.[17]

Genome-wide association studies have revealed a number of susceptibility genes for cholesterol gallstone disease: ABCG8 p.D19H (increasing cholesterol excretion); UGT1A1 in male carriers of the Gilbert syndrome variant rs6742078 (presumably the secreted bilirubin pigment functioning as the nucleating agent); SULT2A1, GCKR, and CYP7A1, which are all located in or near genes involved in cholesterol or bile acid metabolism; low frequency missense variants in SLC10A2, encoding the apical sodium-dependent ileal bile acid transporter;[18] and TM4SF4, a gene implicated in liver regeneration and pancreatic development, although its role in gallstone disease is unclear.[28][29]

Increasing levels of oestrogen heighten cholesterol saturation of bile, making women more prone to developing sludge and gallstones.[30] Higher levels of progesterone also cause gallbladder hypomotility.

Exogenous oestrogen with hormone replacement therapy increases the risk of gallstones, probably as a result of increased cholesterol secretion into bile; this risk is not associated with oral contraceptives.[31]

A significant association exists between gallstone disease and non-alcoholic liver disease (OR 1.55; 95% CI 1.31 to 1.82); however, the underlying mechanism is unclear.[32] Both conditions share common risk factors of obesity, insulin resistance, and diabetes.

Prolonged fasting causes gallbladder hypomotility and increases cholesterol excretion into bile. The resulting overly saturated bile and bile stasis increase the risk for developing gallstones.

Patients undergoing bariatric surgery, already at risk for stone formation because of obesity, are at increased risk of developing gallstones following the surgery; weight loss presumably mobilising excessive cholesterol into bile while bile acid secretion is decreased. Bariatric surgery commonly causes formation of biliary sludge; most concretions disappear but some evolve into gallstones that persist.[33]

TPN, frequently employed in conditions with marked weight loss, causes gallbladder hypomotility. The weight loss and stasis increase the risk for cholesterol stone formation.

Certain medications are associated with an increased risk of cholelithiasis:

  • Octreotide, a somatostatin analogue, impairs gallbladder and small intestinal motility leading to gallbladder stasis, heightened production of secondary bile acids, and cholesterol stone formation.[34] 

  • Glucagon-like peptide-1 analogues are associated with an increased risk of bile duct and gallbladder disease.[35]

  • Ceftriaxone has been associated with pigment stone development from the drug precipitating in bile.[36]

Crohn's disease commonly involves the terminal ileum and is associated with an increased risk of gallstones.[37] The basis is bile salt malabsorption creating a deficiency, such that the bile becomes overly saturated with cholesterol. A further important component is excessive bile salts escaping into the colon to increase the solubility of bilirubin pigment, thus enhancing its absorption and return to the liver. The resultant excessive secretion of bile pigment produces black pigment stones.[38]

Sickle cell disease and beta-thalassaemia are hereditary haemolytic anaemias. Heightened haemoglobin production yields increased bilirubin, leading to pigment stone formation. Such black pigment stones present at a young age and typically require cholecystectomy, especially in sickle cell disease because of confounding symptoms of abdominal pain associated with sickle cell crises.

In the US, these populations have the highest prevalence of gallstones, reaching rates of 50% among men and 70% among women aged >50 years.[39][40][41]

The role of specific diets is not clear. Those high in refined carbohydrates and fat (triglycerides) and low in fibre are associated with gallstones.[42][43][44] Fruit and vegetable consumption is correlated with a reduced risk of cholelithiasis.[45]

A meta-analysis found that infection of the gallbladder with Helicobacter pylori was associated with an increased risk of cholelithiasis and chronic cholecystitis (odds ratio 3.02).[46]

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