Cholelithiasis manifests in cholesterol, pigment, or mixed stones formed and contained in the gallbladder.

• Synonym(s): Gallstones

ALERT
Pediatric Considerations

• Uncommon at < 10 years of age
• Associated with blood dyscrasia
• Most gallstones in pediatric population are pigment stones.

Incidence

• Increased in Native Americans and Hispanics
• Increases with age by 1–3% per year; peaks at 7th decade
• 2% of the US population develops gallstones annually.

Prevalence

• Population: 8–10% of US
• Predominant sex: Female > Male (2–3:1)

• Age (peak in 60–70s)
• Female gender
• Caucasian, Hispanic, or Native American descent
• Hereditary (such as patients carrying the p.D19H variant for the hepato-canalicular cholesterol transporter ABCG5/ABG8 have an increased risk for gallstones)
• Metabolic syndrome (ie, obesity, dyslipidemia, hypertension, and type 2 diabetes)
• Pregnancy and multiparity
• Cholestasis in association with prolonged fasting and long-term total parenteral nutrition
• Rapid weight loss following bariatric surgery
• Metabolic changes in association with short gut syndrome, terminal ileal resection, and inflammatory bowel disease
• Hemolytic disorders (eg, hereditary spherocytosis and sickle cell anemia) and cirrhosis (for black or pigment stones)
• Medications (such as early use of birth control pills; estrogen replacement therapy at high doses)
• Biliary tract infection (such as liver flukes) and stricture (for intraductal formation of brown pigment stones)

Genetics
Animal studies indicate that gallstone formation is a dominant trait determined by at least 2 genes; susceptible strains fail to down-regulate cholesterol synthesis during cholesterol feeding.

• Ursodiol (Actigall) taken during rapid weight loss prevents gallstone formation (1)[A]
• Regular exercise and dietary modification may reduce the incidence of gallstone formation.

Gallstone formation is a complex process mediated by genetic, metabolic, immune, and environmental factors.

• Production of bile supersaturated with cholesterol (cholesterol stones)
• Decrease in bile content of either phospholipid (lecithin) or bile salts
• Biliary stasis or impaired gallbladder motility
• Generation of excess unconjugated bilirubin in patients with hemolytic diseases; passage of excess bile salt into the colon with subsequent absorption of excess unconjugated bilirubin in patients with IBD or after distal ileal resection (black or pigment stones)
• Hydrolysis of conjugated bilirubin or phospholipid by bacteria in patients with biliary tract infection or stricture (brown stones or primary bile duct stones, rare in the Western world and common in Asia )

90% of people with gallbladder carcinoma have gallstones.

• Mostly asymptomatic (80%):
  • 5–10% become symptomatic each year.
  • Over their lifetime, < 1/2 of the patients with gallstones develop symptoms.
• Episodic right upper quadrant or epigastric pain lasting longer than 15 minutes and sometimes radiating to the back (biliary colic), usually postprandially; the majority of patients will develop recurrent symptoms after the first episode.
• Nausea
• Vomiting
• Fatty food intolerance (not proven)
• Indigestion or bloating sensation

• Physical exam is usually normal in patients with cholelithiasis.
• Epigastric and/or right upper quadrant tenderness (Murphy’s sign) when in association with cholecystitis
• Fever and jaundice in patients with choledocholithiasis and cholangitis; jaundice can also be caused by extrinsic compression of the bile duct by a stone in the gallbladder or cystic duct (Mirizzi syndrome).
• Flank and periumbilical ecchymoses (Cullen sign and Grey-Turner sign) in patients with acute hemorrhagic pancreatitis
• In patients with concomitant acute calculus cholecystitis and gallbladder cancer, a mass in the right upper quadrant may be palpated.

Lab

• No lab study is specific for cholelithiasis
• Leukocytosis and elevated C-reactive protein level are associated with acute calculus cholecystitis

Imaging

• Ultrasound (best technique to diagnose gallstones and differentiate from cholecystitis). Ultrasound can detect gallstones in 97–98% of patients. Thickening of the gallbladder wall (5 mm or greater), pericholecystic fluid, and direct tenderness when the probe is pushed against the gallbladder (sonographic Murphy sign) are all radiographic signs of acute calculus cholecystitis.
• CT scan (no advantage over ultrasound except in detecting distal common bile duct stones)
• MRCP is reserved for cases of suspected common bile duct stones due to high cost
• Endoscopic ultrasound (EUS) has been shown to be as sensitive as endoscopic retrograde cholangiopancreatography (ERCP) for detection of common bile duct stones in patients with gallstone pancreatitis.
• HIDA scan is useful in differentiating acalculous cholecystitis from other causes of abdominal pain. False-positive results can arise from fasting status or insufficient resistance of the sphincter of Oddi.
• 10–30% of gallstones are radiopaque calcium or pigment-containing gallstones and are more likely to be visible on plain x-ray. A “porcelain gallbladder” is a calcified gallbladder, visible by x-ray; associated with gallbladder cancer (25%).

Pathological Findings

• Pure cholesterol stones have a white or slightly yellow color.
• Pigment stones may be black or brown. Black stones contain polymerized calcium bilirubinate, most often secondary to cirrhosis or hemolysis, and almost always form in the gallbladder. Brown stones are associated with biliary tract infection, caused by bile stasis, and as such may form either in the bile ducts or gallbladder.

• Peptic ulcer diseases
• Gastritis
• Hepatitis
• Pancreatitis
• Cholangitis
• Gallbladder cancer
• Gallbladder polyps
• Acalculous cholecystitis
• Biliary dyskinesia
• Biliary tree stricture
• Choledocholithiasis
• Choledochocyst
• Coronary artery disease
• Esophageal motility disorders
• Appendicitis
• Pneumonia
• Renal stones

ALERT
Geriatric Considerations
Age alone should not alter the therapy plan.

First Line

• Analgesics for pain relief
• Oral dissolution therapy is rarely used today
• Antibiotics is indicated in patients with signs of acute cholecystitis
• Prophylactic antibiotics in low-risk patients do not prevent infections for laparoscopic cholecystectomies (2)[A]

Second Line
NSAIDs may have a role in pain relief, given that prostaglandins are important in the development of pain.

General Measures

• Treat only symptomatic gallstones and observe asymptomatic stones
• Attempt conservative therapy during pregnancy. If necessary, perform surgery preferentially in the 2nd trimester.
• Prophylactic cholecystectomy for patients with large gallstones (>2–3 cm), calcified (porcelain) gallbladder (risk for gallbladder cancer), and patients with recurrent pancreatitis due to microlithiasis
• In morbidly obese patients, simultaneous cholecystectomy may be performed in combination with bariatric procedures in effort to reduce later stone-related complications.

Issue for Referral
Patients with retained or recurrent bile duct stones following cholecystectomy should be refered to gastroenterology for ERCP.

• Surgical intervention should be considered for patients who have symptomatic cholelithiasis or gallstone-related complications such as cholecystitis (3)[B].
• Laparoscopic cholecystectomy is currently the standard of care for most cases (4)[B]. In well-selected patients, transumbilical single-port laparoscopic cholecystectomy (TUSPLC) is a novel and promising method for the treatment of symptomatic cholelithiasis. Natural orifice transluminal endoscopic surgery (NOTES) may become an alternative in the near future:
  • Surgery-related complications include common bile duct injury (0.5%), right hepatic duct/artery injury, cystic duct or duct of Luschka leak, biloma formation, or bile duct stricture in the long term.
  • Conversion to open procedure based on the judgment of the operating surgeon
  • Intraoperative cholangiogram (IOC) may help delineate bile duct anatomy when dissection proves difficult. Selective or routine use of IOC is a topic of debate, but may be associated with earlier recognition and decreased incidence of bile duct injury (5)[B].
• Open cholecystectomy is indicated for gallbladder cancer diagnosed preoperatively.
• Percutaneous cholecystostomy (PC) in high-risk patients with cholecystitis or gallbladder empyema. PC may also be used in patients with symptoms of cholecystitis for >72 hrs in which altered anatomy might significantly increase the surgical risk. Interval cholecystectomy is usually advisable after the resolution of cholecystitis and optimization of associated medical conditions to prevent recurrent cholecystitis.

For patients with symptomatic cholelithiasis, laparoscopic cholecystectomy has become an outpatient procedure; for patients who developed gallstone-related complications (ie, cholecystitis, cholangitis, and pancreatitis), inpatient care is necessary.

Initial Stabilization

• Patients are treated during the acute phase with nothing by mouth (NPO), intravenous fluids, and antibiotics.
• Adequate pain control with narcotics and/or nonsteroidal anti-inflammatory drugs (NSAIDs) are also needed.

Patient Monitoring

• Medical attention if asymptomatic stones become symptomatic
• Patients on oral dissolution agents should be followed up with liver enzyme, serum cholesterol, and imaging studies.

A low-fat diet may be helpful.

• Change in lifestyle (eg, regular exercise) and dietary modification (low-fat diet and reduction of total calorie intake) may reduce gallstone-related hospitalizations.
• Patients with asymptomatic gallstones should be educated about the typical symptoms of biliary colic and gallstone-related complications.

• < 1/2 of patients with gallstones become symptomatic.
• Cholecystectomy: Mortality < 0.5% elective, 3–5% emergency; morbidity < 10% elective, 30–40% emergency
• ~10–15% of the patients will have associated choledocholithiasis.
• After cholecystectomy, stones may recur in the bile duct.

• Acute cholecystitis (90–95% secondary to gallstones)
• Gallbladder empyema
• Gallstone pancreatitis
• Acute cholangitis
• Common bile duct stones with obstructive jaundice
• Biliary-enteric fistula
• Gallstone ileus
• Gallbladder perforation
• Peritonitis and sepsis
• Liver abscess
• Gallbladder cancer
• Mirizzi syndrome (bile duct obstruction caused by gallstones lodged in gallbladder or cystic duct)

• Lammert F, Miquel JF. Gallstone disease: From genes to evidence-based therapy. J Hepatol. 2008;: [PMID:18308417]

Cholangitis (acute); Cholecystitis; Choledocholithiasis

• 574.00 Calculus of gallbladder with acute cholecystitis, without mention of obstruction
• 574.10 Calculus of gallbladder with other cholecystitis, without mention of obstruction
• 574.20 Calculus of gallbladder without mention of cholecystitis, without mention of obstruction

266474003 Calculus in biliary tract (disorder)

• Laparoscopic cholecystectomy has become the most frequently used procedure; lithotripsy and oral dissolution therapy may be considered in rare circumstances.
• Acute acalculous cholecystitis is associated with bile stasis and gallbladder ischemia.
• Prophylactic cholecystectomy is not indicated in patients with diabetes and asymptomatic gallstones. There is no evidence that asymptomatic diabetics are at increased risk of developing complications of gallstone disease.
• The best imaging modality for the diagnosis of gallstones is transabdominal ultrasound (sensitivity of 97% and specificity of 95%); not sensitive for occult gallstones or microlithiasis (stones smaller than 5 mm).
• Think of gallstones in the post-bariatric surgery patient complaining of "gas pains" as they are adjusting to their new diet.

Hongyi Cui, MD, PhD
John J. Kelly, MD

1. Uy MC, Talingdan-Te MC, Espinosa WZ et al. Ursodeoxycholic Acid in the Prevention of Gallstone Formation after Bariatric Surgery: A Meta-analysis. Obes Surg. 2008;: [PMID:18574646]
2. Choudhary A, Bechtold ML, Puli SR et al. Role of Prophylactic Antibiotics in Laparoscopic Cholecystectomy: A Meta-Analysis. J Gastrointest Surg. 2008;:  [PMID:16352891]
3. Bellows CF , Berger DH , Crass RA . Management of gallstones. Am Fam Phys. 2005;72:637–642.  [PMID:16432812]
4. Shamiyeh A, Wayand W. Current status of laparoscopic therapy of cholecystolithiasis and common bile duct stones. Dig Dis. 2005;23:119-26 [PMID:16352891]
5. Connor S, Garden OJ. Bile duct injury in the era of laparoscopic cholecystectomy. Br J Surg. 2006;93:158-68 [PMID:16432812]