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Cholelithiasis is defined by the presence of cholesterol or pigmented stones in the gallbladder. Risk factors in children include obesity, hemolytic disease, cystic fibrosis (CF), Crohn disease, and long-term total parenteral nutrition (TPN). Gallstone disease can affect the pancreaticobiliary system, liver, and small bowel.
- Cholelithiasis is relatively uncommon in childhood and adolescence. However, the incidence is increasing secondary to improved diagnostic modalities and the rise in pediatric obesity.
- Gallstones occurring in utero and in infancy have been described.
- Canadian Eskimos and Native Africans have the lowest risk of cholelithiasis.
- Native Americans (Pima Indians), Hispanics, Swedes, Scandinavians, and Czechs have the highest risk.
- Ascertaining the incidence of gallstones in otherwise healthy children is difficult because the majority of cases are asymptomatic.
- The incidence of cholecystectomy for gallstones in children appears to be rising, especially in association with nonhemolytic or cholesterol gallstones
- Incidence is believed to be equal in males and females before puberty. After puberty, the incidence increases in females.
- The prevalence of cholelithiasis in children and adolescents reported in the literature is ~1.9–4.0%.
- In children with sickle cell disease (SCD), the prevalence of gallstones has been reported to be anywhere between 15% and 36%.
- Pigment stones are more prevalent in prepubertal children, whereas cholesterol stones are predominant in adolescence and adulthood.
- Acute renal failure
- Anatomic abnormalities (biliary stricture, duodenal diverticulum)
- Chronic hemolysis (SCD, thalassemia, hereditary spherocytosis, pyruvate kinase deficiency, malaria)
- Diabetes mellitus
- Down syndrome
- Ethnic background (e.g., Hispanic)
- Family history
- Female gender
- Genetic predilection
- Hepatobiliary disease/cirrhosis
- Ineffective erythropoiesis (vitamin B12 and folate deficiencies)
- Lack of physical activity
- Medications (estrogens, octreotide, clofibrate, furosemide, cyclosporine, ceftriaxone, oral contraceptives)
- Necrotizing enterocolitis
- Obesity/metabolic syndrome: Pediatric obesity is estimated to increase the risk of gallstones by over 5-fold.
- Prolonged fasting/low-calorie diets/rapid weight loss
- Severe Crohn disease of ileum and/or ileal resection
- Trauma, surgery (i.e., abdominal, bariatric, cardiac)
- Mutations have been identified in genes encoding the ABC transporters for phosphatidylcholine (adenosine triphosphate–binding cassette, subfamily B), bile salts (ABCB11), and cholesterol 7α-hydroxylase (CYP7A1).
- CCK-A receptor (CCKAR) and CF gene (CFTR) mutations have been reported as well.
- ABCB4 is also known as multidrug-resistant 3 glycoprotein (MDR3). MDR3 codes for a phospholipid translocator in the hepatocyte membrane involved in biliary phosphatidylcholine excretion. MDR3 deficiency can cause severe neonatal liver disease, but mutations in MDR3 have also been associated with cholelithiasis, cholestasis of pregnancy, and biliary cirrhosis.
- Variants of ABCG8 and UGT1A1 associated with bile acid metabolism and Gilbert syndrome are risk factors for cholelithiasis.
- Other gene polymorphisms are currently under investigation in humans.
- Exercise and dietary modifications can decrease gallstone formation. This includes high-fiber intake, diet low in saturated fatty acids and refined carbohydrates, and moderate physical activity.
- Prevention of gallstone formation involves treating underlying risk factors (small enteral feedings in addition to TPN, early pancreatic enzyme supplements in CF patients, alternative forms of contraception in high-risk patients, and weight control in obese patients with known hemolytic disease).
- Bile is an aqueous solution of bile salts, bilirubin, phospholipids, and cholesterol. Changes in the proportion of bile constituents (e.g., cholesterol supersaturation), nucleation (aggregation of cholesterol crystals), gallbladder hypomotility, or infection can lead to stone formation.
- Biliary sludge may progress to stone formation.
- Stone types are classified depending on constituents: pigment (black and brown), cholesterol, and mixed.
- Black pigment stones are associated with:
- Increased unconjugated bilirubin
- Congenital or acquired hemolytic anemias
- Abnormal erythropoiesis
- Enterohepatic circulation of unconjugated bilirubin
- Increased unconjugated bilirubin
- Brown pigment stones are associated with common bile duct infection. Parasitic etiologies are public health concerns in developing countries.
- Cholesterol stones are the most common and are associated with the following:
- A decrease in bile salt pool
- Decreased bile acid synthesis
- Gallbladder stasis (weight loss, pregnancy, long-term TPN)
- Hypersecretion of cholesterol into bile
- Increased biliary mucus secretion
- Medications: furosemide, ceftriaxone, cyclosporine
- Cholesterol or pigment stones have been reported with ileal resection, ileal Crohn disease, and CF.
Commonly Associated Conditions
- Hemolytic disease
- Crohn disease (terminal ileal disease) or ileal resection
- TPN dependence