Epidemiology
Cholelithiasis occurs in approximately 10% to 15% of adults in the US and Europe.[2][10] Age, obesity, and female sex hormones are important aetiological factors.[2][11] The prevalence rates are relatively low in Africa and Asia.[7][11][12]
Cholelithiasis is generally asymptomatic in >80% of people.[13][2] Gallstone-related symptoms or complications, however, develop in 1% to 2% of previously asymptomatic individuals each year.[1][2][9][14][15][16] Once biliary colic has developed, more than 50% of patients will go on to experience recurrent pain, while up to 3% per year develop complications, such as acute cholecystitis, cholangitis, or acute pancreatitis.[2][9][17] In patients with asymptomatic stones, 0.1% to 2% will experience a major complication per year.[18]
Risk factors
Body mass index (BMI) >30, particularly abdominal or centripetal obesity, is a strong risk factor for gallstones.[1][19][36][37][38] Diabetes mellitus and insulin resistance, and metabolic syndrome (consisting of abdominal obesity, hypertension, elevated fasting blood sugar levels, hypertriglyceridaemia and low HDL levels), also convey an increased risk of cholesterol gallstone formation, as well as more complications when gallstones do occur.[1][39][36][40][24][41] The postulated mechanisms are elevated hepatic cholesterol secretion, depressed bile salt synthesis, increased pronucleating agents like mucin, and/or impaired gallbladder motility.[1][29]
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; and TM4SF4, a gene implicated in liver regeneration and pancreatic development, although its role in gallstone disease is unclear.[7][6][42][43]
Increasing levels of oestrogen heighten cholesterol saturation of bile, making women more prone to developing sludge and gallstones.[44] Higher levels of progesterone also cause gallbladder hypomotility, which further exacerbates gallstone formation.[7]
Exogenous oestrogen with hormone replacement therapy may increase the risk of gallstones, probably as a result of increased cholesterol secretion into bile; this risk is not associated with oral contraceptives.[45][24][46]
A significant association exists between gallstone disease and non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanism is unclear.[29][47][48] Both conditions share common risk factors of obesity, insulin resistance, and diabetes; evidence suggests that NAFLD is an independent risk factor for gallstone disease, and specifically for more severe gallstone disease.[29][48]
Prolonged fasting causes gallbladder hypomotility and increases cholesterol excretion into bile.[49] The resulting overly saturated bile and bile stasis increase the risk for developing gallstones.
Patients undergoing weight loss surgery, already at risk for stone formation because of obesity, are at increased risk of developing gallstones following the surgery, presumably because weight loss mobilises excessive cholesterol into bile while bile acid secretion is decreased.[21] Weight loss surgery commonly causes formation of biliary sludge; most concretions disappear but some evolve into gallstones that persist.[50]
TPN, frequently employed in clinical conditions with marked weight loss, causes gallbladder hypomotility and is strongly associated with the development of biliary sludge and gallstone disease.[20] The weight loss and gallbladder stasis increase the risk for cholesterol stone formation; pigment gallstones also form due to calcium bilirubinate sludge associated with TPN.[51]
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.[22] The risk of cholelithiasis increases with the duration of treatment (short-term use of octreotide does not typically increase risk).[52]
Glucagon-like peptide-1 analogues are associated with an increased risk of bile duct and gallbladder disease.[53][54]
Ceftriaxone has been associated with pigment stone development from the drug precipitating in bile.[23][55]
Crohn's disease commonly involves the terminal ileum. Severe terminal ileal disease is associated with an increased risk of gallstones, in particular pigment stones.[56][7] Excessive bile salts escape into the colon to increase the solubility of bilirubin pigment, thus enhancing its absorption and return to the liver, resulting in excessive secretion of bile pigment and producing black pigment stones.[57] Cholesterol stones also form; the basis is bile acid malabsorption, leading to a deficiency, such that the bile becomes overly saturated with cholesterol, and stone formation.[58][56]
Sickle cell disease and beta-thalassaemia are hereditary haemolytic anaemias in which excessive breakdown of haemoglobin leads to large output of bilirubin and consequent pigment stone formation. Affected patients present at a young age with black pigment stones and often require cholecystectomy.[1] In sickle cell disease, bile duct ischaemia secondary to sickling further complicates the clinical picture; cholecystectomy is often needed at a young age in patients with sickle cell disease, due to confounding symptoms of abdominal pain associated with sickle cell crises, cholelithiasis, and sickle-cell intrahepatic cholestasis.[59]
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