- Cholelithiasis is the presence of cholesterol, pigment, or mixed stones (calculi) within the gallbladder.
- Synonym(s): gallstones
- Uncommon at <10 years
- Most gallstones in children are pigment stones associated with blood dyscrasias.
- Increased in Native Americans and Hispanics
- Increases with age by 1–3% per year; peaks at 7th decade; 2% of the U.S. population develops gallstones annually.
- Population: 8–10% of the United States; gallstones present in 20% >65 years of age
- Predominant sex: female > male (2 to 3:1)
Etiology and Pathophysiology
- Gallstone formation is a complex process mediated by genetic, metabolic, immune, and environmental factors. Gallbladder sludge (a mixture of cholesterol crystals, calcium bilirubinate granules, and mucin gel matrix) serves as the nidus for gallstone formation.
- Production of bile supersaturated with cholesterol (cholesterol stones) from excess cholesterol secretion precipitates as microcrystals that aggregate and expand. Stone formation is enhanced by biliary stasis or impaired gallbladder motility.
- Decrease in bile content of either phospholipid (lecithin) or decreased bile salt secretion
- 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 inflammatory bowel disease (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)
- Age (peak in 60s to 70s)
- Female gender, pregnancy, multiparity, obesity, and metabolic syndrome
- Caucasian, Hispanic, or Native American descent
- High-fat diet rich in cholesterol
- Cholestasis or impaired gallbladder motility in association with prolonged fasting, long-term total parenteral nutrition (TPN), and rapid weight loss
- Hereditary (p.D19H variant for the hepatic canalicular cholesterol transporter ABCG5/ABG8)
- Short gut syndrome, terminal ileal resection, inflammatory bowel disease
- Hemolytic disorders (hereditary spherocytosis, sickle cell anemia, etc.), cirrhosis (black/pigment stones)
- Medications (birth control pills, estrogen replacement therapy at high doses, and long-term corticosteroid or cytostatic therapy)
- Viral hepatitis, biliary tract infection and stricture (promotes intraductal formation of pigment stones)
- Ursodiol (Actigall) taken during rapid weight loss prevents gallstone formation.
- Regular exercise and dietary modification may reduce the incidence of gallstone formation.
- Lipid-lowering drugs (statins) may prevent cholesterol stone formation by reducing bile cholesterol saturation.
Commonly Associated Conditions
90% of people with gallbladder carcinoma have gallstones.
- Mostly asymptomatic (80%): 2% become symptomatic each year. Over their lifetime, <1/2 of patients with gallstones develop symptoms.
- Episodic right upper quadrant or epigastric pain lasting >15 minutes and sometimes radiating to the back (biliary colic), usually postprandially; pain sometimes awakens the patient from sleep; most patients develop recurrent symptoms after the first episode of biliary colic.
- Nausea, vomiting; indigestion or bloating sensation; fatty food intolerance
- Physical exam is usually normal in patients with cholelithiasis in the absence of an acute attack.
- Epigastric and/or right upper quadrant tenderness (Murphy sign) is traditional physical finding—associated with cholecystitis.
- Charcot triad: fever, jaundice, right upper quadrant pain
- Reynold pentad: fever, jaundice, right upper quadrant pain, hemodynamic instability, mental status changes; classically associated with ascending cholangitis
- Flank and periumbilical ecchymoses (Cullen sign and Grey-Turner sign) in patients with acute hemorrhagic pancreatitis
- Courvoisier sign: palpable mass in the right upper quadrant in patient with obstructive jaundice most commonly due to tumors within the biliary tree or pancreas
- Peptic ulcer diseases and gastritis
- Gallbladder cancer
- Gallbladder polyps
- Acalculous cholecystitis
- Biliary dyskinesia
Diagnostic Tests & Interpretation
No lab study is specific for cholelithiasis.
Initial Tests (lab, imaging)
- Leukocytosis and elevated C-reactive protein level are associated with acute calculus cholecystitis.
- Ultrasound is the preferred imaging modality. US detects gallstones in 97–98% of patients.
- Thickening of the gallbladder wall (≥5 mm), pericholecystic fluid, and direct tenderness when the probe is pushed against the gallbladder (sonographic Murphy sign) are associated with acute cholecystitis.
- CT scan has no advantage over US except in detecting distal common bile duct stones.
- MR cholangiopancreatography (MRCP) is reserved for cases of suspected common bile duct stones. MRCP is recommended as a secondary imaging study if ultrasonography does not clearly demonstrate acute cholecystitis or gallstones (1)[C].
- Endoscopic US is as sensitive as endoscopic retrograde cholangiopancreatography (ERCP) for detection of common bile duct stones in patients with gallstone pancreatitis.
- Hepatobiliary iminodiacetic acid (HIDA) scan is useful in diagnosing acute cholecystitis secondary to cystic duct obstruction. It is also useful in differentiating acalculous cholecystitis from other causes of abdominal pain. False-positive results in fasting state, insufficient resistance of the sphincter of Oddi, and gallbladder agenesis.
- Cholecystokinin (CCK)-HIDA is specifically used to diagnose gallbladder dysmotility (biliary dyskinesia).
- 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.
- Pure cholesterol stones are white or slightly yellow.
- Pigment stones may be black or brown. Black stones contain polymerized calcium bilirubinate, most often secondary to cirrhosis or hemolysis; these 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.
- Treat symptomatic cholelithiasis.
- Conservative therapy is preferred during pregnancy. Surgery in the 2nd trimester if necessary.
- Prophylactic cholecystectomy for patients with calcified (porcelain) gallbladder (risk for gallbladder cancer), patients with large stones (>3 cm), patients with sickle cell disease, patients planning an organ transplant, and patients with recurrent pancreatitis due to microlithiasis
- In morbidly obese patients, simultaneous cholecystectomy may be performed in combination with bariatric procedures (2) to reduce subsequent stone-related comorbidities.
Gallstones are more common in the elderly. Age alone should not alter the therapeutic plan.
- Analgesics for pain relief
- NSAIDs are the first-choice treatment for pain control equivalent to opioid therapy (2)[A].
- Opioids are an option for patients who cannot tolerate or fail to respond to NSAIDs.
- Antibiotics for patients with acute cholecystitis
- Prophylactic antibiotics in low-risk patients do not prevent infections during laparoscopic cholecystectomy (3,4)[A].
Issues For Referral
Patients with retained or recurrent bile duct stones following cholecystectomy should be referred for ERCP.
- Surgery should be considered for patients who have symptomatic cholelithiasis or gallstone-related complications (cholecystitis) or in asymptomatic patients with immune suppression, calcified gallbladder, or family history of gallbladder cancer. Open or laparoscopic cholecystectomy (LC) has similar mortality and complication rates. LC offers less pain and quicker recovery. In well-selected patients, single-incision LC (SILC) and robotic LC are novel methods for the treatment of symptomatic cholelithiasis. SILC has not been shown to be superior to conventional multiport LC in terms of pain and risk of complications (5)[A]. Natural orifice transluminal endoscopic surgery (NOTES) is investigational. Surgery-related complications include common bile duct injury (0.5%), right hepatic duct/artery injury, retained stones, duct leak, biloma formation, and bile duct stricture.
- Conversion to open procedure is based on clinical judgment. Male gender, previous upper abdominal surgery, thickened gallbladder wall, and acute cholecystitis increase the likelihood of need to convert to an open procedure.
- In 10–15% of patients with symptomatic cholelithiasis, common bile duct (CBD) stones are detected by intraoperative cholangiogram (IOC). CBD stone(s) can be removed by laparoscopic CBD exploration or postoperative ERCP.
- IOC helps delineate bile duct anatomy when dissection is difficult. Routine use of IOC is debatable but may be associated with decreased incidence of bile duct injury.
- Early LC (<24 hours after diagnosis of biliary colic) decreases hospital stay and operating time (6)[A].
- For patients with acute cholecystitis, early LC (<7 days of clinical presentation) seems safe and may shorten the total hospital stay versus delayed LC (>6 weeks after index admission with acute cholecystitis) (7)[A].
- Percutaneous cholecystostomy (PC) is used in high-risk patients with cholecystitis or gallbladder empyema. Interval cholecystectomy is advisable.
- Symptomatic patients who are not candidates for surgery or those who have small gallstones (5 mm or smaller) in a functioning gallbladder with a patent cystic duct are candidates for oral dissolution therapy (Actigall). However, the recurrence rate is >50% once the medication is discontinued.
- Extracorporeal shock wave lithotripsy is a noninvasive therapeutic alternative for symptomatic patients who are not candidates for surgery. It is useful for breaking down large bile duct stones before ERCP. Complications include biliary pancreatitis, hepatic hematoma, incomplete ductal stone clearance and recurrence, and so forth.
For patients with symptomatic cholelithiasis, laparoscopic cholecystectomy is typically an outpatient procedure. For patients with complications (i.e., cholecystitis, cholangitis, pancreatitis), inpatient care is necessary.
- Acute phase: NPO, IV fluids, and antibiotics
- Adequate pain control with narcotics and/or NSAIDs
Follow-up RecommendationsPatient Monitoring
- Follow for signs of symptomatic cholelithiasis
- Patients on oral dissolution agents should be followed with serial liver enzyme, serum cholesterol, and imaging studies.
A low-fat diet may be helpful.
- Change in lifestyle (e.g., regular exercise) and dietary modification (low-fat diet and reduction of total caloric intake) 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 within the biliary tree.
- Acute cholecystitis (90–95% secondary to gallstones)
- Gallstone pancreatitis
- Common bile duct stones with obstructive jaundice and acute cholangitis
- Biliary-enteric fistula and gallstone ileus; Bouveret syndrome is a variant of gallstone ileus where the gallstone lodges in the duodenum or pylorus causing a gastric outlet obstruction.
- Gallbladder cancer
- Mirizzi syndrome (extrinsic bile duct obstruction caused by gallstones lodged in gallbladder or cystic duct)
- Brown LM, Rogers SJ, Cello JP, et al. Cost-effective treatment of patients with symptomatic cholelithiasis and possible common bile duct stones. J Am Coll Surg. 2011;212(6):1049–1060.
- Gurusamy KS, Samraj K. Cholecystectomy versus no cholecystectomy in patients with silent gallstones. Cochrane Database Syst Rev. 2007;(1):CD006230. [PMID:20118803]
- Keus F, Gooszen HG, van Laarhoven CJ. Open, small-incision, or laparoscopic cholecystectomy for patients with symptomatic cholecystolithiasis. An overview of Cochrane Hepato-Biliary Group reviews. Cochrane Database Syst Rev. 2010;(1):CD008318. [PMID:21444220]
- Society for Surgery of the Alimentary Tract. SSAT patient care guidelines. Treatment of gallstone and gallbladder disease. J Gastrointest Surg. 2007;11(9):1222–1224. [PMID:17253585]
- 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;18(12):1532–1538. [PMID:23751985]
- Zehetner J, Pelipad D, Darehzereshki A, et al. Single-access laparoscopic cholecystectomy versus classic laparoscopic cholecystectomy: a systematic review and meta-analysis of randomized controlled trials. Surg Laparosc Endosc Percutan Tech. 2013;23(3):235–243. [PMID:23315094]
- K80.00 Calculus of gallbladder w acute cholecyst w/o obstruction
- K80.01 Calculus of gallbladder w acute cholecystitis w obstruction
- K80.18 Calculus of gallbladder w oth cholecystitis w/o obstruction
- K80.19 Calculus of gallbladder w oth cholecystitis with obstruction
- K80.20 Calculus of gallbladder w/o cholecystitis w/o obstruction
- K80.21 Calculus of gallbladder w/o cholecystitis with obstruction
- 574.00 Calculus of gallbladder with acute cholecystitis, without mention of obstruction
- 574.01 Calculus of gallbladder with acute cholecystitis, with obstruction
- 574.10 Calculus of gallbladder with other cholecystitis, without mention of obstruction
- 574.11 Calculus of gallbladder with other cholecystitis, with obstruction
- 574.20 Calculus of gallbladder without mention of cholecystitis, without mention of obstruction
- 574.21 Calculus of gallbladder without mention of cholecystitis, with obstruction
- 235919008 gallbladder calculus (disorder)
- 25924004 Calculus of gallbladder with cholecystitis (disorder)
- 266474003 calculus in biliary tract (disorder)
- 29484002 Cholelithiasis AND cholecystitis without obstruction
- 50450007 Cholelithiasis AND cholecystitis with obstruction
- 59771005 Calculus of gallbladder with acute cholecystitis (disorder)
- 699050007 Calculus of gallbladder with acute and chronic cholecystitis (disorder)
- 77528005 cholelithiasis with obstruction (disorder)
- Most patients with gallstones are asymptomatic.
- Transabdominal ultrasound is the preferred imaging modality for diagnosis of cholelithiasis (sensitivity, 97%; specificity, 95%).
- Laparoscopic cholecystectomy is the preferred procedure for symptomatic cholelithiasis; 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 asymptomatic gallstones.
Hongyi Cui, MD, PhD
- American College of Radiology. ACR appropriateness criteria: right upper quadrant pain. http://www.acr.org/~/media/ACR/Documents/AppCriteria/Diagnostic/RightUpper...
- Colli A, Conte D, Valle SD, et al. Meta-analysis: nonsteroidal anti-inflammatory drugs in biliary colic. Aliment Pharmacol Ther. 2012;35(12):1370–1378. [PMID:22540869]
- Sanabria A, Dominguez LC, Valdivieso E, et al. Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy. Cochrane Database Syst Rev. 2010;(12):CD005265. [PMID:21154360]
- Zhou H, Zhang J, Wang Q, et al. Meta-analysis: antibiotic prophylaxis in elective laparoscopic cholecystectomy. Aliment Pharmacol Ther. 2009;29(10):1086–1095. [PMID:19236313]
- Gurusamy KS, Vaughan J, Rossi M, et al. Fewer-than-four ports versus four ports for laparoscopic cholecystectomy. Cochrane Database Syst Rev. 2014;(2):CD007109. [PMID:24558020]
- Gurusamy KS, Koti R, Fusai G, et al. Early versus delayed laparoscopic cholecystectomy for uncomplicated biliary colic. Cochrane Database Syst Rev. 2013;(6):CD007196. [PMID:23813478]
- Gurusamy KS, Davidson C, Gluud C, et al. Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis. Cochrane Database Syst Rev. 2013;(6):CD005440. [PMID:23813477]
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