Cholelithiasis

Cholelithiasis refers to the presence of abnormal concretions (gallstones) in the gallbladder. About 10–20% of American adults have gallstones. Gallstones most commonly consist of cholesterol but may be pigmented (due to hemolysis or infection) or mixed. Cholelithiasis can manifest with biliary colic (postprandial RUQ pain) but is most commonly an incidental finding in asymptomatic individuals. The diagnosis is confirmed by ultrasound. Symptomatic cholelithiasis is managed with laparoscopic cholecystectomy.

See also “Choledocholithiasis”, “Acute cholecystitis”, and “Acute cholangitis.”

	Cholelithiasis	Choledocholithiasis	Acute cholecystitis	Acute cholangitis
Description	Presence of gallstones in the gallbladder	Presence of gallstones in the common bile duct	Acute inflammation of the gallbladder	Bacterial infection of the biliary tract
Mechanism	Bile cholesterol oversaturation, bile stasis, impaired bile acid circulation → precipitation of gallstones in the gallbladder	Cholelithiasis → migration of gallstones into the common bile duct	Cholelithiasis (most common) or biliary sludge → inflammation of gallbladder wall	Choledocholithiasis (most common) → obstruction and stasis within the biliary tract → subsequent bacterial infection
Clinical features	Usually asymptomatic Symptomatic (biliary colic): RUQ pain < 6h	RUQ pain > 6 h Possible jaundice	RUQ pain Fever Murphy sign	Charcot triad: RUQ pain, fever, jaundice Reynold pentad: Charcot cholangitis triad PLUS hypotension and mental status changes
Laboratory findings	Normal	↑ Total bilirubin ↑ GGT ↑ ALP ↑ AST, ALT	↑ WBC, CRP	↑ WBC and CRP ↑ ALP ↑ AST, ALT ↑ Total bilirubin
Diagnostic imaging	US: gallstones with posterior acoustic shadow	US: dilated common bile duct, intrahepatic biliary dilatation MRCP or ERCP: filling defect in the contrast-enhanced duct	US: gallbladder wall thickening and/or edema (double wall sign) HIDA scan: nonvisualization of gallbladder > 4 hours after radioactive tracer administration	US: biliary dilation, and/or evidence of obstruction (e.g., cholelithiasis), pericholecystic inflammation MRCP if diagnosis uncertain
Treatment	Supportive care, analgesics Elective cholecystectomy for: Symptomatic cholelithiasis Asymptomatic cholelithiasis only if at increased risk of gallbladder cancer See “Acute management checklist for biliary colic.”	Supportive care, analgesics Endoscopic stone retrieval Elective cholecystectomy to prevent recurrence See “Acute management checklist for choledocholithiasis.”	Supportive care, analgesics IV antibiotics Cholecystectomy (timing depends on severity) See “Acute management checklist for acute cholecystitis.”	Supportive care, analgesics IV antibiotics Urgent biliary decompression Interval cholecystectomy if gallstones are present or concurrent cholecystitis See “Acute management checklist for acute cholangitis.”

• Sex: ♀ > ♂ (2–3:1)
• Prevalence: approx. 10–20% of the adult population in developed countries
• Peak incidence: : > 40 years

References: ^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

General

• Imbalance in bile salts, lecithin (stabilizer), cholesterol, calcium carbonate, and bilirubin
• Biliary stasis is a key component in gallstone formation.
• Impaired gallbladder emptying (e.g., due to bowel rest, prolonged total parenteral nutrition, pregnancy ) → biliary sludge → bile stasis (cholestasis)

Cholesterol stones (up to 95% of all stones) ^[1][2]

• Risk factors
  • Obesity, insulin resistance, dyslipidemia
  • Female sex
    • Especially during reproductive years due to increased levels of estrogen and progesterone
    • Increased estrogen levels cause increased secretion of bile rich in cholesterol, (lithogenic bile), which can result in the formation of cholesterol gallstones.
    • Increased progesterone levels cause smooth muscle relaxation, decreased gallbladder contraction, and subsequent bile stasis with formation of gallstones.
  • Multiparity or pregnancy
  • Age (> 40 years of age)
  • European, Native American, or Hispanic ancestry
  • Family history
  • Drugs: fibrates (inhibition of cholesterol 7-α hydroxylase), estrogen therapy, oral contraceptives
  • Malabsorption (e.g., Crohn disease, ileal resection, cystic fibrosis)
  • Rapid weight loss
• Pathophysiology: abnormal hepatic cholesterol metabolism → ↑ cholesterol concentration in bile and ↓ bile salts and lecithin → hypersaturated bile → precipitation of cholesterol and calcium carbonate → cholesterol stones or mixed stones

During pregnancy, increased estrogen levels cause increased secretion of lithogenic bile (rich in cholesterol), resulting in the formation of cholesterol gallstones. Increased progesterone levels cause smooth muscle relaxation, decreased and impaired gallbladder contraction, and subsequent bile stasis and formation of gallstones.

Rule of the 6 Fs: Fat, Female, Fertile, Forty, Fair-skinned, Family history.

Black pigment stones (< 10% of all stones) ^[3][4][2]

• Risk factors
  • Chronic hemolytic anemias (e.g., sickle cell disease, hereditary spherocytosis)
  • (Alcoholic) cirrhosis
  • Crohn disease
  • Total parenteral nutrition
  • Advanced age
• Pathophysiology: ↑ hemolysis → increase in circulating unconjugated bilirubin → increased uptake and conjugation of bilirubin → precipitation of bilirubin polymers and stone formation

Mixed/brown pigment stones (< 10% of all stones) ^[3][4][5][2]

• Risk factors: bacterial infections and parasites (e.g., Clonorchis sinensis, Opisthorchis species) in the biliary tract, sclerosing cholangitis ^[2]
• Pathophysiology: infection or infestation → release of β-glucuronidase (by injured hepatocytes and bacteria) → hydrolyzes conjugated bilirubin and lecithin in the bile → increased unconjugated bilirubin and fatty acids → precipitation of calcium carbonate, cholesterol, and calcium bilirubinate (dark color) in bile

• Most gallstones are asymptomatic.
• Biliary colic: constant, dull RUQ pain lasting < 6 hours
  • Especially postprandial: vagal stimulation (e.g., cholecystokinin release following a fatty meal) → gallbladder contraction → attempts to force the stone into the cystic duct
  • May radiate to the epigastrium, right shoulder, and back (referred pain)
• Nausea, vomiting, early satiety
• Bloating, dyspepsia

Only a minority of patients with gallstones are symptomatic!

References: ^[2]

Approach ^[2]

• Asymptomatic cholelithiasis: No diagnostic workup is required.
• Suspected symptomatic cholelithiasis
  • Imaging is essential to confirm a clinical diagnosis of cholelithiasis and rule out concurrent choledocholithiasis.
    • RUQ ultrasound is the preferred initial diagnostic test.
    • MRCP may be considered if ultrasound findings are inconclusive.
  • If choledocholithiasis is suspected : See ''Diagnosis of choledocholithiasis.”
  • If the clinical diagnosis is unclear: See “Diagnosis of acute abdominal pain.”

Laboratory studies

Laboratory studies are typically normal in uncomplicated cholelithiasis but should be ordered to rule out other acute biliary conditions and/or other causes of acute abdominal pain.

• CBC: usually normal
• LFTs: usually normal
• Amylase, lipase: usually normal
• See also “Diagnosis of acute abdominal pain.”

Imaging

RUQ ultrasound

• Indication: best initial test in suspected symptomatic cholelithiasis ^[6][7]
• Characteristic findings ^[6]
  • Cholelithiasis ^[8]
    • Intraluminal highly echogenic foci
    • Strong posterior acoustic shadowing
  • Biliary sludge ^[9][10][11]
    • Low-level echogenic material in the dependent portion of the GB
    • No posterior acoustic shadowing
    • Slow movement with the changing of patient posture

MRI abdomen without and with IV contrast with MRCP ^[6]

• Indications
  • Preferred second-line test if ultrasound findings are inconclusive
  • Suspected choledocholithiasis (see ''Diagnostics'' in choledocholithiasis for further details)
  • MRI without contrast is preferred in pregnant patients. ^[6]
• Supportive findings: well-defined hypointense (on T2) filling defect(s) within the gallbladder lumen ^[12]

CT abdomen with IV contrast ^[6]

• Indications
  • Inconclusive ultrasound findings; MRI is not available
  • Suspected complications and/or differential diagnoses
  • Preoperative planning after confirming the diagnosis
• Supportive findings (of radiopaque stones): well-defined hyperdense structure(s) within the gallbladder lumen
• Disadvantages
  • Only radiopaque stones are detectable (15–20% of stones are radiopaque). ^[13][14]
  • Cannot detect the more common radiolucent pure cholesterol stones

Abdominal x-ray

• Indication: usually performed as part of the routine workup of acute abdominal pain
• Findings and disadvantages: similar to those of CT scan

X-ray and CT scan are rarely diagnostic in cholelithiasis because only 15–20% of stones are radiopaque. Pure cholesterol stones are radiolucent.

Laboratory studies (e.g., WBC count, bilirubin, amylase) are usually normal in uncomplicated cholelithiasis.

Differential diagnosis of RUQ pain

• Abdominal
  • Choledocholithiasis
  • Acute cholecystitis
  • Acute cholangitis
  • Acute hepatic capsule swelling (e.g., acute hepatitis, perihepatitis, congestive hepatopathy)
  • Gastroesophageal reflux, gastritis, gastrointestinal ulcers
  • Early appendicitis
  • Acute pancreatitis
  • Right-sided diverticulitis
  • Sphincter of Oddi dysfunction
• Extra-abdominal
  • Nephrolithiasis
  • Posterior wall infarct
• See also “Differential diagnosis of acute abdomen.”

Differential diagnoses of intraluminal gallbladder wall pathology

• Cholangiocarcinoma (see biliary cancer)
• Gallbladder polyp
  • Definition: benign tumor of the gallbladder wall with low metastatic potential
  • Epidemiology
    • 5% of polyps are adenomas, which are premalignant ^[2]
    • Up to 50% of polyps > 1 cm are carcinomas ^[2]
  • Diagnosis: Ultrasound (transabdominal or endoscopic)
    • Parietal echogenic tumor, easily mistaken for a gallstone
    • No change in position of pathology during movement or acoustic shadow (in contrast to a gallstone)

The differential diagnoses listed here are not exhaustive.

Approach ^[15][16][2]

• All patients
  • Provide supportive care.
  • Identify and treat concurrent choledocholithiasis (see “Diagnosis of choledocholithiasis”).
• Asymptomatic cholelithiasis
  • Expectant management (see ''Nonsurgical alternatives'' below for details) ^[15]
  • Consider elective cholecystectomy in patients at high risk of developing complications or gallbladder cancer.
• Symptomatic uncomplicated cholelithiasis
  • Elective cholecystectomy is the mainstay of treatment.
  • Acute presentation with biliary colic: elective cholecystectomy
  • Surgery not feasible: Consider conservative management with oral bile acid dissolution therapy and/or extracorporeal shockwave lithotripsy.
• Symptomatic complicated cholelithiasis: See “Acute cholecystitis”, “Choledocholithiasis”, and “Acute cholangitis.”

Treatment of biliary colic ^[15][17]

Initial supportive therapy of acute biliary disease

• Bowel rest: NPO
  • In biliary colic: until the pain subsides (typically within a few hours) ^[15]
  • In other acute biliary conditions: The duration of NPO depends on the need for urgent interventional therapy
• Analgesics ^[2]
  • NSAIDs: preferred first-line analgesics ^[18][2][19]
    • Ketorolac
    • Diclofenac
    • Ibuprofen
  • Opioids: for severe pain that does not improve with NSAIDs or in patients with contraindications to NSAIDs ^[2][20]
    • Morphine
    • Buprenorphine ^[21][2]
    • Meperidine ^[22][23]
    • See also “Pain management.”
• Spasmolytics (e.g., dicyclomine ): consider as adjuvant therapy with analgesics in patients with severe pain ^[15][2]
• In patients with protracted vomiting consider the following:
  • IV fluid therapy
  • Antiemetics
  • Nasogastric tube insertion with suction

Important considerations ^[17]

• Consider inpatient management in patients with intractable pain or if there is concern for complications.
• Most patients may be discharged from the ER once pain has settled if there is no evidence of complications.
• Advise patients to avoid foods with a high fat content.
• Schedule an elective cholecystectomy.

Surgical management

• Procedure: elective laparoscopic cholecystectomy
• Indications
  • Symptomatic cholelithiasis
  • Asymptomatic cholelithiasis with any of the following:
    • Increased risk of gallbladder cancer (e.g., gallbladder polyps, porcelain gallbladder, gallstones ≥ 3 cm) ^[2][24][15]
    • Increased risk of developing complications (e.g., immunocompromised patients, multiple gallstones) ^[15][16]
    • Increased risk of becoming symptomatic (e.g., hemolytic anemia, patients undergoing gastric bypass surgery) ^[15][25][26]
• Contraindication: suspected gallbladder cancer (see ''Treatment'' in “Biliary cancer”) ^[27][16]
• Preoperative precautions: Assess for predictors of choledocholithiasis in all symptomatic patients (see ''Diagnosis of choledocholithiasis”). ^[28]
• Timing: : as early as possible in uncomplicated symptomatic cholelithiasis ^[2][29][30]
• Complications: See “Cholecystectomy” section for details.

Cholecystectomy is usually not indicated in asymptomatic cholelithiasis!

Nonsurgical alternatives ^[2]

Indications

• Patients at high risk of complications due to surgery or anesthesia (e.g., recent myocardial infarction)
• Patients unwilling to undergo surgery

Options

• Expectant management ^[15]
  • Lifestyle modifications :
    • Low-fat diet (especially low in saturated fats) ^[31]
    • Avoid lithogenic drugs, such as estrogen, fibrates. ^[32]
    • Exercise regularly.
  • Follow-up if symptoms recur
• Oral bile acid dissolution therapy
  • May be useful in dissolving pure cholesterol stones (i.e., radiolucent stones) that are < 0.5 cm ^[15]
  • Ursodeoxycholic acid
  • Duration of therapy: 6–24 months ^[15][31]
  • Advantage: symptomatic improvement even if stones are not completely dissolved ^[31]
  • Disadvantages
    • Ineffective in mixed stones
    • High recurrence rates ^[2]
    • Long duration of therapy
    • Requires repeat imaging to track treatment response
• Extracorporeal shock wave lithotripsy (ESWL)
  • Advantages
    • Useful in mixed stones
    • Short duration of therapy
  • Disadvantages
    • May need to be combined with endoscopic sphincterotomy for stone clearance
    • Does not prevent recurrence ^[2]
    • Injury to adjacent solid organs (rare)

Definition

• Surgical removal of the gallbladder

Indications ^[2][33]

• Symptomatic cholelithiasis
• Asymptomatic cholelithiasis with any of the following:
  • Increased risk of gallbladder cancer ^[2][24][15]
  • Increased risk of developing complications ^[15][16]
  • Increased risk of becoming symptomatic ^[15][25][26]
• Acute calculous cholecystitis
• Acalculous cholecystitis

Contraindications ^[33]

• Absolute: none; risks are primarily related to anesthesia
• Relative
  • Hemodynamic or respiratory instability
  • Uncorrected coagulopathy or bleeding diathesis
  • History of extensive abdominal surgery
  • Cirrhosis
  • Portal hypertension
  • Morbid obesity
  • Acute phase of cholangitis

Surgical risk scores

• NSQIP
• ASA-PS

Timing

Timing of cholecystectomy depends on the indication and individual surgical risks.

• Symptomatic uncomplicated cholelithiasis: electively, but as early as possible ^[2][29][30]
• Uncomplicated choledocholithiasis: within 72 hours of ERCP-guided stone clearance ^[34][2]
• Complicated cholelithiasis or choledocholithiasis: depends on the severity of complication and the patient's anesthesia risks
• Mild biliary pancreatitis: during the same hospital admission ^[35][36][37]
• Acute cholecystitis (see ''Treatment'' in “Acute cholecystitis” for details) ^[38][39]
  • Low-risk mild acute cholecystitis: early cholecystectomy
  • High-risk or severe acute cholecystitis: interval cholecystectomy
• Acute cholangitis: ∼ 6 weeks after successful ERCP-guided stone clearance ^[40]

Approach ^[33]

• Laparoscopic cholecystectomy
  • Current standard of care for most indications of cholecystectomy ^[41]
• Open cholecystectomy
  • Typically performed using a right subcostal incision
  • Not routinely performed
  • Indications include:
    • Unsuccessful laparoscopic cholecystectomy
    • Gallbladder cancer
    • As part of a bigger operative procedure that requires an open surgery

Complications ^[33][42][2]

Intraoperative and early postoperative complications

• Hemorrhage
• Transmural bowel injury
• Surgical site infection
• Postcholecystectomy bile leak ^[43][44][45]
  • Etiology
    • Inadequately ligated cystic duct (most common)
    • Leak from small biliary ductules from the dissected gallbladder bed
    • Injury to bile duct
  • Clinical features
    • Intraoperatively: golden yellow bile in the operative field
    • Postoperatively
      • Fever, abdominal pain, persistent paralytic ileus
      • Biliary peritonitis
      • Subhepatic collection → biloma or abscess
  • Treatment
    • Intraoperative diagnosis: repair of injured bile duct and/or placement of drain in the gallbladder fossa
    • Postoperative diagnosis: ERCP and stenting or surgical repair, depending on the severity

Delayed complications

• Incisional hernia (at trocar site)
• Biliary stricture
• Biliary-enteric fistula
• Postcholecystectomy diarrhea
  • Definition: chronic diarrhea after removal of the gallbladder ^[46][33]
  • Pathophysiology: Removal of the gallbladder → no reservoir of bile → entry of excess bile acids into the colon → osmotic diarrhea ^[47][48]
    • May also be functional or due to other undiagnosed causes of diarrhea
  • Diagnostics: SeHCAT test ^[33]
  • Treatment: Preferred first-line agent is cholestyramine. ^[46]
• Postcholecystectomy syndrome: persistent RUQ pain or new symptoms following gallbladder removal ^[33]
  • Incidence: 10–15% of patients ^[33]
  • Clinical features
    • Gastritis, dyspepsia, GERD
    • Postcholecystectomy diarrhea and bloating
    • Jaundice and upper abdominal pain
  • Diagnostics: LFT and transabdominal ultrasound are preferred initial tests
  • Treatment: Treat the underlying cause

General

• Cholecystitis
  • Acute cholecystitis (most common)
  • Chronic cholecystitis
  • Porcelain gallbladder
• Choledocholithiasis
• Cholangitis
• Acute biliary pancreatitis
• Biliary-enteric fistula: Cholecystoenteric/choledochoenteric fistula (rare) , which can cause gallstone ileus (rare) ^[49][50]

Complications due to gallstone impaction at the gallbladder neck or infundibulum

• Mirizzi syndrome ^[33][51]
  • Definition: extrinsic compression of the common bile duct (or any extrahepatic bile duct) by gallstone(s) impacted in the cystic duct or the infundibulum of the gallbladder ^[52][33]
  • Clinical features: similar to choledocholithiasis
  • Imaging findings (preferably ERCP/MRCP)
    • Narrowing of the common hepatic duct
    • Stone within the cystic duct
    • Dilation of the intrahepatic biliary tree
  • Treatment
    • ERCP-guided CBD stent placement may be considered preoperatively to allow for biliary drainage. ^[35]
    • Open cholecystectomy may be preferred if diagnosed preoperatively. ^[51]
  • Complications ^[53][54]
    • Cholecystocholedochal fistula: an abnormal communication between the gallbladder and the common bile duct
    • Cholecystoenteric/choledochoenteric fistula (biliary-enteric fistula): an abnormal communication between the gallbladder or the CBD with the adjacent bowel
    • Gallstone ileus: due to biliary-enteric fistula
• Gallbladder mucocele (gallbladder hydrops) ^[55][49]
  • Definition: marked distension of the gallbladder with sterile mucinous content due to chronic biliary outflow obstruction
  • Etiology ^[55]
    • Impacted gallstone at the gallbladder neck (most common)
    • Resolved acute cholecystitis ^[49]
    • Tumors at the gallbladder neck or CBD (e.g., GB polyps, cholangiocarcinoma, carcinoma of pancreatic head)
    • Acute inflammatory conditions (e.g., Kawasaki disease)
    • Extrinsic compression of the biliary outflow tract (e.g., lymphadenopathy, adhesions, strictures)
  • Pathophysiology: chronic biliary outflow obstruction → resorption of bile and secretion of mucin by biliary mucosa → collection of mucinous secretion within the gallbladder with no outflow → gross distension of the gallbladder
  • Clinical features: asymptomatic mass in the RUQ; no signs of infection
  • Imaging (preferably ultrasound or CT): grossly distended fluid-filled gall bladder without signs of inflammation ^[55]
  • Treatment
    • In children with no evidence of cholecystitis: trial of conservative management ^[56]
    • In adults: laparoscopic cholecystectomy ^[55]

We list the most important complications. The selection is not exhaustive.