Epidemiology
Cholelithiasis occurs in approximately 10% to 15% of adults in the US and Europe.[2]
The highest prevalence of cholelithiasis is in American Indian populations, followed by Northern Europeans.[2][10] Prevalence rates are relatively low in Sub-Saharan Africa and Asia.[7][11][12]
Despite its high prevalence, cholelithiasis is generally asymptomatic in over 80% of people.[2][13] Gallstone-related symptoms or complications, however, develop in 1% to 2% of previously asymptomatic individuals each year.[1][2][9][14][15][16][17] Once biliary colic has developed, over 50% of patients will go on to experience recurrent pain, while up to 3% per year develop complications (e.g., acute cholecystitis, cholangitis, acute pancreatitis).[2][9][18]
Risk factors
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.[6][7][36][37]
Body mass index (BMI) >30, particularly abdominal or centripetal obesity, is a strong risk factor for gallstones.[1][21][39][40][41] Diabetes mellitus and insulin resistance, and the metabolic syndrome (consisting of abdominal obesity, hypertension, elevated fasting blood sugar levels, hypertriglyceridemia, and low high-density lipoprotein levels), also convey an increased risk of cholesterol gallstone formation and complicated disease when gallstones do occur.[1][21][26][39][42][42][43] The postulated mechanisms are elevated hepatic cholesterol secretion, depressed bile salt synthesis, increased pronucleating agents like mucin, and/or impaired gallbladder motility.[1][19]
A significant association exists between gallstone disease and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism is unclear.[19][44][45] Although cholelithiasis and NAFLD conditions share common risk factors (obesity, insulin resistance, diabetes), evidence suggests that NAFLD is an independent risk factor for gallstone disease and for more severe gallstone disease.[19][45]
Prolonged fasting causes gallbladder hypomotility and increases cholesterol excretion into bile.[46] 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 heightened risk of developing gallstones following the surgery, presumably because weight loss mobilizes excessive cholesterol into bile while bile acid secretion is decreased.[24] Weight loss surgery commonly causes formation of biliary sludge; most concretions disappear but some evolve into gallstones that persist.[47]
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.[23] 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.[48]
Octreotide, a somatostatin analog, impairs gallbladder and small intestinal motility, leading to gallbladder stasis, increased production of secondary bile acids, and cholesterol stone formation.[22] Short-term use of octreotide is not usually problematic, but the risk increases with the duration of treatment.[49]
Crohn disease commonly involves the terminal ileum; terminal ileum disease is associated with an increased risk of gallstones, in particular pigment stones.[7][53] Excessive bile salts escape into the colon to increase the solubility of bilirubin pigment; more bilirubin pigment is absorbed and consequently more pigment returns to the liver. This results in excessive secretion of bile pigment and black pigment stones.[54] Cholesterol stones also form; bile acid malabsorption leads to a deficiency of cholesterol, such that the bile becomes overly saturated with cholesterol and stone formation.[55]
Sickle cell disease (SCD) and beta-thalassemia are hereditary hemolytic anemias, in which excessive breakdown of hemoglobin leads to a large output of bilirubin and consequent black pigment stone formation. Stones present at a young age, and often require cholecystectomy.[1] In SCD, sickling can cause bile duct ischemia. Cholecystectomy is often needed relatively early in life in patients with SCD due to confounding symptoms of abdominal pain associated with sickle cell crises, cholelithiasis, and sickle-cell intrahepatic cholestasis.[56]
Gallstones are common in patients with liver cirrhosis, with a prevalence of 25% to 30% in this population.[57] This is likely related to abnormal pigment secretion, gallbladder hypomobility, and elevated estrogen levels in those with cirrhosis. Both cholesterol and black pigment stones occur, although black pigment stones are more common.[7][58]
Cystic fibrosis is a risk factor for gallstones due to bile acid malabsorption and hyperbilirubinemia.[54]
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