Etiology

Approximately 90% of gallstones in developed countries are composed of cholesterol.[1][2][4][19]​ Cholesterol stones form in the gallbladder but can migrate into the common bile duct, occurring in about 10% to 15% of patients presenting for cholecystectomy.[20]

Some risk factors for cholesterol gallstones are modifiable, such as obesity, total parenteral nutrition, rapid weight reduction after weight loss surgery, and drugs (e.g., octreotide, ceftriaxone).[21][22][23][24][25][26] Others, such as age, genetic factors, and female sex are not modifiable.[3][4][5][6]

Approximately 15% of all gallstones are black pigment stones.[2][7][27] The pigment material consists of polymerized calcium bilirubinate. Patients with chronic hemolytic anemia, cirrhosis, cystic fibrosis, and ileal diseases are at highest risk of developing black pigment stones.[1][2]

Brown pigment gallstones form de novo in bile ducts as a result of stasis and infection.[1] They typically consist of calcium bilirubinate, calcium salts of long-chain fatty acids, cholesterol, and mucin (glycoproteins primarily from bacterial biofilms). In developed countries, brown pigment stones usually arise following bacterial infection or from partial biliary obstruction, such as inflammatory strictures (e.g., primary biliary cirrhosis) or malignancy (e.g., cholangiocarcinoma).[1][2][7] In South East Asia, the major risk is chronic infectious cholangitis associated with biliary parasites such as Clonorchis sinensis, Opisthorchis species, and Fasciola hepatica.[1][7]

Pathophysiology

Cholesterol cholelithiasis occurs as a result of three principal defects: bile supersaturated with cholesterol, accelerated nucleation, and gallbladder hypomotility such that this abnormal bile stagnates.

Cholesterol supersaturation of gallbladder bile occurs primarily when the liver secretes excessive amounts of cholesterol compared with its solubilizing agents (bile salts and lecithin). Precipitation of cholesterol microcrystals in the gallbladder then follows, initiated by the presence of nucleating agents (primarily biliary glycoproteins such as mucin). Impaired gallbladder contractility causes the cholesterol-rich bile to stagnate and be retained in the gallbladder. These microcrystals collect in a mucin scaffold and grow into overt gallstones.[19]

Symptoms and complications of cholelithiasis result when stones obstruct the cystic and/or bile ducts. Biliary pain occurs when a stone transiently obstructs the cystic duct. More persistent obstruction leads to acute cholecystitis.

Stones that pass into the biliary tract can cause obstruction at the ampulla of Vater, leading to reflux of pancreaticobiliary secretions back into the pancreatic duct, which can trigger activation of pancreatic enzymes, leading to acute biliary pancreatitis. Risk factors for acute biliary pancreatitis are multiple small stones (<5 mm), a dilated cystic duct, and normal gallbladder contractility.[28][29][30]

Mirizzi syndrome, an uncommon condition, occurs when a large gallstone becomes lodged in the neck of the gallbladder or in the cystic duct, compressing or causing inflammation of the common bile duct. The result is biliary obstruction and jaundice.[31]

If a gallstone erodes through the gallbladder wall, a cholecystoenteric fistula can develop, leading obstruction either in the duodenum (Bouveret syndrome) or more distally in an otherwise healthy small intestine, causing gallstone ileus.[32]

Classification

Types of stones in the biliary tract

Cholesterol gallstones

  • Approximately 90% of gallstones in developed countries are composed of cholesterol.[1][2] These form in the gallbladder.

  • Risk factors include genetics and family history, obesity, metabolic syndrome, sudden weight reduction (e.g., following weight loss surgery), age, and female sex hormones.[3][4][5][6]

Black pigment gallstones

  • Around 15% of gallstones are black pigment stones, which consist of polymerized calcium bilirubinate.[1][2][7]

  • Risk factors are age, chronic hemolytic anemia, cirrhosis, cystic fibrosis, and ileal disease.[1][2]

Brown pigment stones (ductal stones)

  • These stones form in the bile ducts as a result of stasis and infection.[1] They consist of unconjugated bilirubin and calcium salts of long-chain fatty acids.

  • In developed countries, brown pigment stones usually arise following bacterial infection or from partial biliary obstruction, such as inflammatory strictures (e.g., primary biliary cirrhosis) or malignancy (e.g., cholangiocarcinoma).[1][2][7] In South East Asia, the major risk is chronic infectious cholangitis associated with biliary parasites such as Clonorchis sinensis, Opisthorchis species, and Fasciola hepatica.[1][7]

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