**2. Pathogenesis**

Bile is mainly made up of water, bilirubin, cholesterol, bile pigments, and phospholipids. Imbalance in bile constituents [cholesterol, phospholipids, and bile salts] is the main cause of gallstone formation. Gallstone formation starts from the sedimentation of cholesterol, bile pigments, and calcium salts which are insoluble [7]. By composition gallstones are divided into cholesterol gallstones or pigment stones. Unlike adults where mixed cholesterol gallstones are more common in adults, pigment stones are more common in children except adolescent girls.

#### **2.1 Biliary sludge**

Biliary sludge is mixture of mucin, calcium bilirubinate and cholesterol crystals, seen with prolonged fasting, sickle-cell disease, total parenteral nutrition, pregnancy and treatment with drugs like ceftriaxone, octreotide etc. [8]. Biliary sludge may resolve spontaneously or on removal of causative agent or may progress to gallstone development. Persistent sludge may give rise to complication like pancreatitis or cholangitis.

#### **2.2 Cholesterol stones**

Cholesterol supersaturation of bile with stasis predisposes to cholesterol gallstone formation, increased concentration of cholesterol also elevates the rate of crystallization leading to gallstone formation [9]. The cholesterol content is usually greater than 50%, with minimal calcium content, cholesterol stones are solitary, yellow-white, hard, crystalline, faceted, round, and smooth [10]. These stones are not radiopaque. Formation of cholesterol stones occurs due to hypersecretion of cholesterol, increased mucin production, and decreased gallbladder motility. Cholesterol stones are not commonly seen in children except adolescent girls. The risk factors for cholesterol stone formation in children include obesity, Hispanic ethnicity, family history, female sex (after puberty), and non-alcoholic fatty liver disease.

#### **2.3 Pigment stones**

Black pigment stones are formed due to supersaturation of bile with calcium bilirubinate [(to excess bilirubin) and are seen in haemolytic disorders and in association with total parenteral nutrition. These stones are commonly seen with hereditary haemolytic anaemias such as sickle cell disease, hereditary spherocytosis and thalassemia. Pigment stones are also seen with cirrhosis, total parenteral nutrition, ileal disease and ceftriaxone use. Black pigment stones are black to brown in color, hard, shiny, and crystalline, multiple, size of less than 5 mm, composed mainly of bile pigment polymer (40%) followed by calcium carbonate or phosphate, salts, cholesterol and mucin glycoprotein. Persons with Gilbert syndrome, are at increased risk for black pigment gallstones due to increased bilirubin production and a decrease in the bilirubin diphosphate-glucuronosyltransferase activity. Other etiologies for pigmented stones include medications such as ceftriaxone and octreotide. A decrease in the enterohepatic circulation of bile acids (seen with ileal disease or after ileal resection) is another predisposing factor for black stone formation. The mechanism responsible for gallstone formation in this setting is an interruption in the normal enterohepatic circulation of the endogenous bile salt pool [11].

Brown pigment stones are brown to orange in color, soft, greasy, multiple, and smooth composed mainly of calcium bilrubinate [60%] followed by, calcium palmitate, stearate soaps, cholesterol and mucin glycoprotein. Brown pigment stones are distinctly seen in the setting of a bacterial/parasitic infection and biliary stasis. These are also seen in bile duct anomaly and cirrhosis. These are more often seen in the bile ducts than in the gall bladder [12].
