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.”

• 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 ^[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 (e.g., after bariatric surgery)
• 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 ^[2][3][4]

• 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 ^[2][3][4][5]

• 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)
• Nonspecific symtoms
  • Nausea, vomiting, early satiety
  • Bloating, dyspepsia
• Complications of cholelithiasis can be the first manifestation of gallstone disease.

Only a minority of patients with gallstones are symptomatic!

Approach ^[2]

See “Cholelithiasis in pregnancy” for considerations in pregnant individuals.

• Asymptomatic cholelithiasis : No diagnostic workup is required.
• Suspected symptomatic cholelithiasis
  • Obtain imaging for cholelithiasis: biliary point-of-care ultrasound (POCUS) or transabdominal RUQ ultrasound
  • Rule out complications of cholelithiasis (e.g., acute cholecystitis or choledocholithiasis).
  • If the diagnosis remains 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

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

RUQ ultrasound

If appropriately trained, consider performing a biliary POCUS.

• Indication: best initial test in suspected symptomatic cholelithiasis ^[6][7]
• Characteristic findings ^[6]
  • Cholelithiasis ^[8]
    • Intraluminal highly echogenic foci
    • Strong posterior acoustic shadowing
    • Rolling stone sign: movement of the echogenic foci with the changing of patient posture
  • 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
• Accuracy: operator- and technique-dependent ^[12]
  • RUQ ultrasound performed by a radiologist: ≥ 95% sensitivity and specificity for cholelithiasis
  • Biliary POCUS performed by emergency providers: ∼ 90% sensitivity and specificity for cholelithiasis

If appropriately trained, consider performing a biliary POCUS to rule in cholelithiasis. If the study is negative, further investigations (e.g., laboratory studies, RUQ ultrasound performed by a radiologist, additional imaging) may be necessary. ^[12]

Additional imaging studies

Additional imaging may be required if complications of cholelithiasis (e.g., acute cholecystitis, acute cholangitis, choledocholithiasis, biliary pancreatitis) cannot be ruled out, or to evaluate for other causes of abdominal pain.

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)
• Supportive findings: well-defined hypointense (on T2) filling defect(s) within the gallbladder lumen ^[13]

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). ^[14][15]
  • Cannot detect the more common radiolucent pure cholesterol stones

Abdominal x-ray

• Indication: usually not indicated in the evaluation of cholelithiasis, but may be performed as part of the workup of acute abdominal pain
• Findings: gallstones with an outer radiopaque rim and radiolucent center ^[16]
• 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.

Differential diagnosis of RUQ pain

• Abdominal (See also “Acute abdominal pain” and “Differential diagnosis of abdominal pain.”)
  • 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
  • Acute coronary syndrome (See also “Chest pain.”)
• See also “Differential diagnosis of acute abdomen.”

Differential diagnoses of intraluminal gallbladder wall pathology

• Cholangiocarcinoma
• Gallbladder polyp

The differential diagnoses listed here are not exhaustive.

Approach ^{[2][17][18][19]}

See “Cholelithiasis in pregnancy” for considerations in pregnant individuals.

• Asymptomatic cholelithiasis
  • Expectant management is typically sufficient.
  • Consider the need for prophylactic cholecystectomy: See “Indications” in “Surgical Management.”
  • Patients with gallstones found incidentally during an ED visit can be referred back to their primary care physician for shared decision-making regarding surgical consult.
• Symptomatic uncomplicated cholelithiasis
  • Treatment of biliary colic
    • Provide initial supportive therapy for acute biliary disease.
    • Counsel on lifestyle modifications to prevent further attacks (see “Nonoperative management of cholelithiasis” for details.)
  • Outpatient referral to general surgery for an elective cholecystectomy to prevent recurrence.
  • Consider surgical consult and admission if the pain is intractable.
• Symptomatic complicated cholelithiasis
  • Admit for further management and consult general surgery and/or gastroenterology.
  • See “Acute cholecystitis,” “Acute cholangitis,” “Choledocholithiasis,” and “Biliary pancreatitis.”

Initial supportive therapy of acute biliary disease ^[17][19]

• Bowel rest: NPO
  • In biliary colic: until the pain subsides (typically within a few hours) ^[17]
  • In other acute biliary conditions: The duration of NPO depends on the need for urgent interventional therapy
• Analgesics ^[2]
  • NSAIDs: preferred first-line analgesics ^[2][20][21]
    • Ketorolac
    • Diclofenac
    • Ibuprofen
  • Opioids: for severe pain that does not improve with NSAIDs or in patients with contraindications to NSAIDs ^[2][22]
    • Morphine
    • Buprenorphine ^[2][23]
    • Meperidine ^[24][25]
    • See also “Pain management.”
• Spasmolytics (e.g., dicyclomine ): consider as adjuvant therapy with analgesics in patients with severe pain ^[2][17]
• Treatment for protracted vomiting
  • IV fluid therapy
  • Antiemetics
  • Consider NG tube insertion with suction.

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][17][26]
    • Increased risk of developing complications (e.g., immunocompromised patients, multiple gallstones) ^[17][18]
    • Increased risk of becoming symptomatic (e.g., hemolytic anemia, patients undergoing gastric bypass surgery) ^[17][27][28]
• Contraindication: suspected gallbladder cancer (see ''Treatment'' in “Biliary cancer”) ^[18][29]
• Preoperative precautions: Assess for predictors of choledocholithiasis in all symptomatic patients (see ''Diagnosis of choledocholithiasis”). ^[30]
• Timing: as early as possible in uncomplicated symptomatic cholelithiasis ^[2][31][32]
• Complications: See “Complications of cholecystectomy”.

Cholecystectomy is usually not indicated in asymptomatic cholelithiasis.

Nonoperative management of cholelithiasis ^[2]

Indications

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

Expectant management ^[17]

• Lifestyle modifications :
  • Low-fat diet (especially low in saturated fats) ^[33]
  • Avoid lithogenic drugs, such as estrogen, fibrates. ^[34]
  • 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 ^[17]
• Ursodeoxycholic acid (off-label)
• Duration of therapy: 6–24 months ^[17][33]
• Advantage: symptomatic improvement even if stones are not completely dissolved ^[33]
• 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)

ESWL is also used in the treatment of nephrolithiasis.

• Definition: : a noninvasive method of stone fragmentation using an acoustic pulse in the treatment of gallstones and pancreatic stones
• Indication: typically used for solitary stones that can be localized well on imaging (radiolucent)
• Procedure
  • Stones are localized using x-ray or ultrasound.
  • A lithotriptor generates shock waves that are focused on the stone, fragmenting it in the process.
  • Passage of stone fragments
    • Biliary stones: through the biliary system into the duodenum.
    • Pancreatic stones: through the pancreatic duct into the duodenum
• Advantage: is noninvasive: and can be performed on an outpatient basis ^[2]
• Disadvantages
  • Commonly causes biliary colic
  • Lower success rate in the presence of multiple stones
  • Risk of injury to adjacent solid organs (rare)
• Prognosis: high recurrence rate (between 40 and 60% within 5 years) ^[35][36]

ESWL is contraindicated in pregnancy. ^[37]

• Keep patient NPO.
• Provide initial supportive therapy for acute biliary disease (e.g., analgesia, IV fluids, antiemetics).
• Obtain RUQ ultrasound or perform biliary POCUS if available.
• Identify and manage complications of cholelithiasis (e.g., acute cholecystitis, acute cholangitis, choledocholithiasis, biliary pancreatitis).
• Refer to general surgery for an elective cholecystectomy to prevent recurrence.

Cholelithiasis in pregnancy ^[38][39]

• Cholelithiasis affects 12% of pregnant individuals. ^[40][41]
• Incidentally detected cholelithiasis in asymptomatic individuals does not require further evaluation or management.
• Symptomatic cholelithiasis manifests similarly in pregnant and nonpregnant individuals.
• Additional differential diagnoses of cholelithiasis to consider in pregnant individuals include:
  • HELLP syndrome (hemolysis, elevated liver enzymes, low platelets)
  • Acute fatty liver of pregnancy
  • Intrahepatic cholestasis of pregnancy

Diagnostics ^[38][39]

The diagnostic approach for cholelithiasis during pregnancy is similar to that for nonpregnant individuals, with the following additional considerations for imaging modalities.

• Preferred initial imaging modality: RUQ ultrasonography
• Diagnostic uncertainty: MRI without contrast ^[41][42][43]
• Suspected choledocholithiasis: MRCP or endoscopic ultrasound (in consultation with a specialist) ^[38]

ALP levels can be elevated in pregnant individuals who do not have biliary disease because of placental ALP production. ^[44]

Management of symptomatic cholelithiasis in pregnancy ^[39][44]

• Admit to the hospital for monitoring. ^[39]
• Provide initial supportive management of acute biliary disease as in nonpregnant patients, but avoid NSAIDs.
• Consult surgery for consideration of operative versus nonoperative management of cholelithiasis; use shared-decision making. ^[45]
  • Laparoscopic cholecystectomy may be preferred over conservative management. ^[38][39][45]
  • Consider corticosteroids to induce fetal lung maturity if indicated. ^[46]
  • Assess for risk factors for venous thromboembolism and provide appropriate VTE prophylaxis. ^[46]
• For management of complications, see also “Acute pancreatitis during pregnancy” and “Acute cholecystitis in pregnancy.”

Do not delay emergency surgery (e.g., for complicated cholelithiasis) during pregnancy, regardless of the trimester. ^[45][46]

ERCP during pregnancy may be considered for the management of cholelithiasis complications (e.g., acute biliary pancreatitis, choledocholithiasis) if the benefits outweigh the risks of post-ERCP pancreatitis and fetal radiation exposure. ^[38]

General

• Cholecystitis
  • Acute cholecystitis (most common)
  • Chronic cholecystitis
  • Porcelain gallbladder
• Choledocholithiasis
• Acute cholangitis
• Acute biliary pancreatitis
• Biliary-enteric fistula: Cholecystoenteric/choledochoenteric fistula (rare) , which can cause gallstone ileus (rare) ^[47][48]

Complications due to gallstone impaction at the gallbladder neck or infundibulum

Mirizzi syndrome ^[49][50]

• 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 ^[49][51]
• Clinical features: similar to choledocholithiasis
• Diagnostics: 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. ^[52]
  • Open cholecystectomy may be preferred if diagnosed preoperatively. ^[50]
• 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) ^[47][55]

• Definition: marked distention 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 ^[47]
  • 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 distention of the gallbladder
• Clinical features: asymptomatic mass in the RUQ; no signs of infection
• Diagnostics: (preferably ultrasound or CT); show 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.