Basics
Description
Cholelithiasis is defined by the presence of cholesterol and/or pigment stones in the gallbladder. Rare in infancy and childhood, it is usually found incidentally on an ultrasound. Risk factors in children include obesity, hemolytic disease, cystic fibrosis (CF), Crohn disease, and long-term total parenteral nutrition (TPN).
Epidemiology
- Cholelithiasis is relatively uncommon in childhood and adolescence; however, the incidence is increasing.
- Gallstones occurring in utero and in infancy have been described.
- Obesity is associated with up to 40% of the gallstones observed in all children and the majority of children with no underlying medical conditions. Obesity is estimated to increase the risk of gallstones in children by over 5-fold.
- Canadian Eskimos and Native Africans have the lowest risk of cholelithiasis.
- Native Americans, Swedes, Scandinavians, and Czechs have the highest risk.
- Pigment stones are more prevalent in prepubertal children, whereas cholesterol stones are predominant in adolescence and adulthood.
Incidence
- Prior to puberty, the incidence of gallstones is equal in males and females. After puberty, the incidence increases in females.
Prevalence
- The prevalence of cholelithiasis in children and adolescents reported in the literature is ~1.9-4.0%.
- In obese children, the prevalence is 2%.
- In children with sickle cell disease, the prevalence is 17-29%.
Risk Factors
- Acute renal failure
- Anatomic abnormalities (biliary stricture, duodenal diverticulum)
- CF
- Chronic hemolysis (sickle cell disease, thalassemia, spherocytosis, malaria)
- Chronic overnutrition with carbohydrate and triglyceride-rich, low-fiber diet
- Down syndrome
- Family history
- Female gender (>4 times higher odds than males)
- Hepatobiliary disease/cirrhosis
- Ineffective erythropoiesis (vitamin B12 and folate deficiencies)
- Medications (estrogens, octreotide, clofibrate, furosemide, cyclosporine, ceftriaxone, oral contraceptives)
- Necrotizing enterocolitis
- Obesity
- Pregnancy/parity
- Prematurity
- Prolonged fasting/low-calorie diets/rapid weight loss (generally at least ≥10%)
- Severe Crohn disease of the ileum and/or ileal resection
- TPN
- Trauma/abdominal surgery or bariatric surgery
- Hispanic ethnicity
Genetics
- Mutations have been identified in genes encoding the ABC transporters for phosphatidylcholine (adenosine triphosphate-binding cassette, subfamily B), for bile salts (ABCB11), or for cholesterol 7a-hydroxylase (CYP7A1), the CCK-A receptor (CCKAR), and the CF gene (CFTR).
- ABCB4 is also known as MDR3 (multidrug-resistant 3 glycoprotein). MDR3 is 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.
General Prevention
Exercise and dietary modifications can decrease gallstone formation.
Pathophysiology
- Bile is an aqueous solution of lipids with bile salts, phospholipids, and cholesterol. Changes in the proportion of bile constituents, nucleation (aggregation of cholesterol crystals), changes in gallbladder motility, or infection can lead to stone formation.
- Stone types: pigment, cholesterol, calcium carbonate, and mixed
- Black pigment stones are associated with increased unconjugated bilirubin:
- Hemolytic diseases
- Abnormal erythropoiesis
- Enterohepatic circulation of unconjugated bilirubin
- Ileal resection, Crohn disease
- CF
- Brown pigment stones are associated with infection.
- The solubility of cholesterol in bile depends on bile salts and phospholipid concentrations. Cholesterol stones are associated with the following:
- A decrease in bile salt pool
- Decreased bile acid synthesis
- Hypersecretion of cholesterol into the bile
- Gallbladder stasis (weight loss, pregnancy, long-term TPN)
- Increased biliary mucus secretion
- Medications: furosemide, ceftriaxone, cyclosporine
Diagnosis
History
- Gallstones in children are most commonly incidental findings on abdominal ultrasound.
- Biliary colic, pancreatitis, obstructive jaundice, cholangitis, or other complications should be excluded.
- Intolerance to fatty food rarely exists in children.
- The history should always include questions concerning
- Previous episodes of right upper quadrant (RUQ) abdominal pain
- Any risk factors for hemolysis
- History of prematurity and necrotizing enterocolitis
- Family history of cholelithiasis
- Nutritional history
- Medication use
- Surgical history
- Associated medical conditions (e.g., short gut syndrome, ileal disease)
Physical Exam
- The physical exam may be completely normal or may uncover the acute abdomen of pancreatitis.
- Murphy sign (tenderness on palpation of the RUQ of the abdomen associated with inspiration) may be elicited in adolescents.
- Silent gallstones present coincidentally in infants and young children.
- Classic symptoms of RUQ pain (Murphy sign) and vomiting are more common in older children and adolescents.
- Younger children present with nonspecific symptoms including obstructive jaundice and mild elevation in transaminases.
- Fever is unusual in all age groups and often indicates the development of rare complications in children:
- Cholecystitis
- Choledocholithiasis
- Cholangitis
- Gallbladder perforation
- Pancreatitis develops in 8% of patients with gallstones and is the most common complication.
- Pancreatitis is more common in obese adolescents who have undergone rapid weight reduction, as reported in the adult population.
Diagnostic Tests & Interpretation
Lab
- Laboratory tests should include a complete blood count, urinalysis, amylase, lipase, fractionated bilirubin, alkaline phosphatase, γ-glutamyltransferase (GGT), and transaminase levels.
- Results should typically be within normal ranges.
- Abnormal results may suggest infection, obstruction, or another disease process.
Imaging
- Ultrasound
- Diagnostic procedure of choice
- Noninvasive with high sensitivity and specificity
- Plain radiography
- May not be useful as the majority of gallstones in children are not radiopaque.
- Magnetic resonance cholangiopancreatography (MRCP) is useful to define anatomy in hepatobiliary disease and identify choledocholithiasis.
Diagnostic Procedures/Other
- Endoscopic retrograde cholangiopancreatography (ERCP)
- Diagnostic for choledocholithiasis
- Also therapeutic for removal of stones, stenting, or decompression of the biliary tree.
- Surgery should be considered for symptomatic patients.
Pathologic Findings
Black pigment stones are associated with hemolysis and cirrhosis. Brown pigment stones are typically mixed in composition, while cholesterol stones can vary from yellow to green or brown.
Differential Diagnosis
- Acalculous gallbladder disease
- Biliary dyskinesia
- Cholecystitis
- Common bile duct stones
- Congenital biliary anomalies
- Hydrops of the gallbladder (may be associated with Kawasaki disease)
Treatment
Medication
- Spontaneous resolution in asymptomatic children is common, without the need for frequent medication use.
- Ursodeoxycholic acid (UDCA) suppresses hepatic cholesterol synthesis and secretion and can improve gallbladder muscle contractility by decreasing muscle cell cholesterol content in the plasma membranes.
Additional Treatment
General Measures
- Primary prevention
- High-fiber intake, diet low in saturated fatty acid and nuts, and moderate physical activity
- Children with asymptomatic gallstones should only be observed.
- During infancy, there is a chance for spontaneous stone dissolution, especially if cholelithiasis is linked to TPN.
- In children who are dependent on TPN and in patients with short-bowel syndrome, pseudoobstruction, inflammatory bowel disease, or a hemoglobinopathy, gallstones should be removed.
- Prevention of gallstone formation is done by treating underlying risk factors (small enteral feedings in addition to TPN, early pancreatic enzyme supplements in patients with CF, using alternative forms of contraception in high-risk populations, and weight control in obese infants and children with known hemolytic disease).
- Pigment stone formation increases with age.
- Sickle cell patients should have the gallbladder removed when stones are identified.
- This strategy will decrease the risk of cholecystitis and other complications and will also help to differentiate between biliary colic and sickle cell crisis.
- Patients with a history of cholecystitis are at increased risk for further episodes (69% will have biliary colic within 2 years and 6% will require cholecystectomy).
Surgery/Other Procedures
- Laparoscopic cholecystectomy is the procedure of choice in symptomatic children.
- Lithotripsy using shock waves has not been approved for use in children.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Asymptomatic patients: Monitor for onset of symptoms; no use for repeat imaging or labs unless symptomatic.
- Symptomatic patients: Consider cholecystectomy.
Additional Reading
- Buch S, Schafmayer C, V ¶lzke H, et al. Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition. Gastroenterology. 2010;139(6):1942-1951. [View Abstract]
- Guarino MP, Cong P, Cicala M, et al. Ursodeoxycholic acid improves muscle contractility and inflammation in symptomatic gallbladders with cholesterol gallstones. Gut. 2007;56(6):815-820. [View Abstract]
- Lucena JF, Herrero JI, Quiroga J, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis. Gastroenterology. 2003;124(4):1037-1042. [View Abstract]
- Mehta S, Lopez ME, Chumpitazi BP, et al. Clinical characteristics and risk factors for symptomatic pediatric gallbladder disease. Pediatrics. 2012;129(1):e82-e88. [View Abstract]
- Rosmorduc O, Hermelin B, Boelle PY, et al. ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology. 2003;125(2):452-459. [View Abstract]
Codes
ICD09
- 574.2 Calculus of gallbladder without mention of cholecystitis, without mention of obstruction
- 574.21 Calculus of gallbladder without mention of cholecystitis, with obstruction
- 574 Calculus of gallbladder with acute cholecystitis, without mention of obstruction
- 574.01 Calculus of gallbladder with acute cholecystitis, with obstruction
- 574.1 Calculus of gallbladder with other cholecystitis
- 574.11 Calculus of gallbladder with other cholecystitis, with obstruction
- 574.2 Calculus of gallbladder without mention of cholecystitis
- 574.1 Calculus of gallbladder with other cholecystitis, without mention of obstruction
- 574 Calculus of gallbladder with acute cholecystitis
ICD10
- K80.20 Calculus of gallbladder w/o cholecystitis w/o obstruction
- K80.21 Calculus of gallbladder w/o cholecystitis with obstruction
- K80.01 Calculus of gallbladder w acute cholecystitis w obstruction
- K80.00 Calculus of gallbladder w acute cholecyst w/o obstruction
- K80.18 Calculus of gallbladder w oth cholecystitis w/o obstruction
- K80.0 Calculus of gallbladder with acute cholecystitis
- K80.19 Calculus of gallbladder w oth cholecystitis with obstruction
- K80.2 Calculus of gallbladder without cholecystitis
SNOMED
- 266474003 calculus in biliary tract (disorder)
- 77528005 cholelithiasis with obstruction (disorder)
- 29484002 Cholelithiasis AND cholecystitis without obstruction
- 50450007 Cholelithiasis AND cholecystitis with obstruction
FAQ
- Q: Does my child with CF have a greater problem with gallstones?
- A: Yes. Children with CF may have more frequent development of gallstones than children without CF. Reports of gallstones while on UDCA therapy have also been noted.
- Q: Why does my child with sickle cell disease have gallstones?
- A: Because the hemolytic process involves breakdown of hemoglobin, which produces bilirubin. This process may accelerate the formation of pigmented gallstones.
- Q: If my child has repeated attacks of RUQ abdominal pain and there are gallstones in the gallbladder, should he have surgery? What kind?
- A: Yes. Laparoscopic cholecystectomy is typically recommended.
- Q: Does obesity increase my child's risk of gallstones?
- A: Yes. Obesity is associated with up to 40% of the gallstones observed in all children.