**2.6 Genetics**

Various lithogenic gene variants have been found linked to formation of gall stones. Genome-wide association study (GWAS) have found a hepatobiliary cholesterol transporter ABCG8 [p.D19H] as the most common genetic risk factor for gall stones [36]. Mutations in the ABCB4, ABCB11, CFTR [cystic fibrosis transmembrane conductance regulator] CYP7A1 gene causes gallstones by alteration in bile composition and secretion. Gall stone has been reported as initial symptom in early

#### **Figure 1.**

*Ceftriaxone induced pseudolithiasis.*

childhood due to compound heterozygous mutation in ABCB4 gene (linked to progressive familial intrahepatic cholestasis type 3), these children are at risk of further developing decompensated chronic liver disease [37]. NPC1L1 [Niemann-Pick C1-Like 1] is responsible for intestinal and hepatobiliary cholesterol absorption. Functional studies showed that loss of function mutations of NPC1L1 are associated with decreased intestinal cholesterol absorption, changes in plasma low-density lipoprotein cholesterol levels decrease the reuptake of cholesterol from bile and thus promoting biliary cholesterol supersaturation. Gilbert promoter variant of the UDP glucuronosyl transferase gene [UGT1A1], appears to be an additional risk factor for gallstone risk. Studies have found that individuals predisposed to gall stone are characterized by an increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, pointing to enhanced whole-body sterol clearance. An ethnic gradient in the ratios of phytosterols to cholesterol precursors (highest in Germans) is also apparent which correlates negatively with susceptibility to gallstones [38].

#### **2.7 Obesity**

In adults the association between obesity with cholelithiasis is well known. A higher incidence of cholelithiasis has also been noticed in obese children [39]. Obese children and those with a higher mean BMI (>21.5) are at higher risk of cholelithiasis and more symptomatic compared to children with a normal BMI [9]. It is recommended that children with biliary symptoms or cholelithiasis, as well as unclear ultrasonography of the bile ducts with a BMI of 23 or more should routinely undergo MRCP to rule out choledocholithiasis. There is mechanical hypothesis for more prevalence of choledocholithiasis in obese children which postulates that higher body fat content in the abdominal wall causes greater intraabdominal pressure, resulting in external pressure on the wall of the gallbladder, this relatively higher pressure in the sub-hepatal region may results in a direct stimulus which further leads to dislodgment of the stone/sludge from the gallbladder into the extrahepatic biliary tree system, causing obstruction of the bile duct. The incidence of obesity in children rising in the some parts of world, the incidence of symptomatic cholelithiasis will also increase. Prevalence of cholelithiasis is significantly higher in patients with NAFLD (non-alcoholic fatty liver disease) [40].
