Cholelithiasis

Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). The diagnosis is established by ultrasound. Management options include supportive care to prevent and control associated symptoms. When indicated, cholecystectomy is the definitive treatment. Gallstones may lead to complications such as choledocholithiasis (a stone trapped in the common bile duct), cholecystitis (inflammation of the gallbladder), or cholangitis (biliary sepsis). These conditions require urgent medical attention.

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Overview

Definition

Cholelithiasis is the presence of gallstones in the gallbladder.

Epidemiology

  • Prevalence in the United States: 6% of men and 9% of women
  • Women > men (3:1), but this ratio decreases with age
  • Most commonly seen at > 40 years of age
  • Highest prevalence in Native Americans and Mexican Americans

Opened gallbladder with gallstones

Image: “Opened gall bladder containing numerous gallstones” by Emmanuelm. License: CC BY 3.0

Etiology

Cholesterol stones (80%)

  • Precipitates of mostly cholesterol with bile salts, calcium, and mucin
  • Risk factors:
    • Obesity
    • Rapid weight loss (often after bariatric surgery)
    • Diabetes
    • Dyslipidemia
    • Genetic predisposition
    • Pregnancy (impaired gallbladder emptying caused by progesterone)
    • Medications (hormone therapy, oral contraceptives, ceftriaxone, fibrates, somatostatin analogs)
    • Prolonged fasting
    • Parenteral nutrition
    • Spinal cord injury

Pigment stones (10%)

  • Caused by excess bilirubin 
  • Black stones consist of mostly calcium bilirubinate.
  • Risk factors:
    • Cirrhosis
    • Crohn’s disease/ileal resection
    • Hemolytic anemias (hereditary spherocytosis, thalassemias, sickle cell disease)
    • Advanced age

Brown stones (“mixed”; 10%)

  • Bacterial infection or parasitic infestation
  • Often form in bile ducts
  • Most common in Asian populations

Mnemonic

Risk factors for cholesterol stones: 4 Fs

  1. Fat
  2. Female
  3. Forties
  4. Fertile

Pathophysiology and Clinical Presentation

Pathophysiology

  • Cholesterol stones (3 mechanisms overlap):
    • Cholesterol supersaturation of bile
      • Hypersecretion of cholesterol (80% from dietary origin)
      • Decreased concentration of phospholipids and bile salts (that solubilize cholesterol) → cholesterol precipitation
    • Gallbladder hypomotility (stasis)
      • Associated with certain conditions: diabetes, pregnancy, parenteral nutrition
      • Cholesterol microcrystals are not flushed out effectively → gallbladder sludge
    • Nucleation
      • Mucin (secreted by biliary epithelium) promotes crystallization of cholesterol in the sludge.
      • Gallstones form and grow larger, further promoted by gallbladder stasis.
  • Black pigment stones: 
    • Overproduction of bilirubin (hemolysis increases unconjugated bilirubin)
    • Decrease in hepatic cycling of bilirubin (cirrhosis)
  • Mixed/brown pigment stones: 
    • Related to infections (bacterial or parasitic infestation, e.g., clonorchiasis)
    • Often form in bile ducts
    • Lytic enzymes from bacteria/parasites hydrolyze bile lecithin → fatty acids, which bind calcium 
    • Calcium salts + bilirubin + cholesterol → brown stones
  • Variant pathology: “porcelain” gallbladder
    • Not a gallstone but often found in conjunction with gallstones
    • Calcifications in the gallbladder wall, with mechanism felt to be the same as gallstones
    • Increased risk of gallbladder cancer

Overlapping mechanisms that produce gallstones: cholesterol supersaturation, gallbladder hypomotility, and accelerated nucleation

Image by Lecturio.

Clinical presentation

  • Asymptomatic (80%): Gallstones are found on imaging incidentally.
  • Biliary colic:
    • Gallstone moves and transiently obstructs the cystic duct.
    • Constant, dull right upper quadrant (RUQ) pain:
      • Lasting < 6 hours
      • Postprandial or nocturnal 
      • May radiate to the epigastrium, right shoulder, and back
    • Nausea, vomiting
    • No peritoneal signs

Diagnosis

  • History:
    • RUQ pain
      • Postprandial
      • Nocturnal 
    • Nausea, vomiting, bloating, early satiety
    • Risk factors
  • Physical exam:
    • May have no significant findings
    • Mild RUQ tenderness, no peritoneal signs
  • Laboratory studies: complete blood count and liver function tests (LFTs) are often normal.
  • Imaging:
    • RUQ ultrasound (US)
      • First test to perform for RUQ pain
      • 95% specific for detecting stones
      • Shows gallstones with posterior acoustic shadow, possible sludge 
    • Endoscopic ultrasound (EUS)
      • If regular ultrasound is equivocal or if concurrent stone in the common bile duct (CBD) is suspected
      • Can detect very small stones
    • Magnetic resonance cholangiopancreatography (MRCP)
      • If the ultrasound is equivocal
      • If CBD stone is also suspected

Management

Medical management

  • Preventive therapy (to prevent symptoms and more stone formation):
    • Dietary modification (↓ saturated fat intake; ↑ unsaturated fatty acids, vegetable protein, vitamin C)
    • Weight loss
    • Physical activity
  • Medical management:
    • Manage expectantly; surgical referral when symptoms develop
    • Oral litholysis with bile acids (ursodeoxycholic acid); efficacy is limited, need to take over a long period of time (> 6 months)
    • Nonsteroidal anti-inflammatory drugs (NSAIDs), spasmolytics, anti-nausea medications (symptom relief)

Surgical management

  • Cholecystectomy:
    • Definitive treatment when indicated
    • Laparoscopic is the standard of care.
    • Open surgery for difficult cases and contraindications to laparoscopy
  • General indications for surgery:
    • Symptomatic (biliary colic) patients
    • Asymptomatic patients at risk of gallbladder cancer 
      • Porcelain gallbladder
      • Gallstones > 3 cm
      • Gallbladder adenomas
      • Anomalous pancreatic ductal drainage
    • Asymptomatic patients with hemolytic disorders
    • The following asymptomatic patients may benefit from surgery: 
      • Diabetic patients due to high risk for complications
      • Patients undergoing bariatric surgery for weight loss
  • Complications/risks of surgery:
    • CBD injury
    • Biliary leaks
    • Injury to surrounding organs
    • Infection/abscess
    • Postcholecystectomy syndrome (bloating, dyspepsia)

Complications

ConditionPathologyClinical presentationLaboratory studiesDiagnostic imagingManagement
CholecystitisCystic duct obstruction with inflammationConstant RUQ pain (> 6 hours), Murphy’s sign↑ WBCUSUrgent cholecystectomy
CholedocholithiasisGallstone in CBD causing obstruction
  • Primary: formed in the bile duct
  • Secondary: gallstone migration
Postprandial colicky RUQ pain > 6 hours; others: jaundice, acholic stool, dark urine, pruritus↑ bilirubin, ALPUS, MRCPERCP for stone removal → cholecystectomy to prevent recurrence
Acute cholangitisCholedocholithiasis with infection; with biliary sepsis (E. coli, Klebsiella, Pseudomonas, Enterococcus)
  • Charcot’s triad: RUQ pain + fever + jaundice
  • Reynold’s pentad: Charcot’s triad + shock/hypotension + altered mental status
↑ WBC, ↑ bilirubin, ALPUS, MRCPERCP → emergent cholecystectomy
Gallstone pancreatitisSmall stones transiently obstructing pancreatic ductEpigastric pain, nausea/vomiting↑ WBC, ↑ amylase/lipase, ↑ bilirubin, ALPMRCP/ CT scanDelayed cholecystectomy
Gallstone ileusLarge stone (> 2.5 cm) passing into the small bowel through a cholecystoduodenal fistula → obstructionSmall bowel obstruction (diffuse abdominal pain, nausea/vomiting)↑ WBCCT scanSurgery to extract the stone (cholecystectomy not performed in the same setting)
ALP: alkaline phophatase, CBD: common bile duct, CT: computed tomography, ERCP: endoscopic retrograde cholangiopancreatography, MRCP: magnetic resonance cholangiopancreatography, RUQ: right upper quadrant, US: ultrasound, WBC: white blood cells

Differential Diagnosis

  • Peptic ulcer disease: ulceration of gastric or duodenal mucosa. Presents with epigastric pain and nausea/vomiting. Pain is sometimes relieved with eating, unlike in biliary colic. The condition may be associated with hematemesis/melena. Diagnosis is made by upper endoscopy.
  • Gastroenteritis: acute viral infection of the gastrointestinal tract. Commonly presents with diffuse abdominal pain, nausea/vomiting, and diarrhea. The illness is usually self-limited and resolves with supportive treatment.
  • Acute appendicitis: an infection of the appendix. Presents with right lower quadrant (RLQ) pain. Frequently associated with local peritonitis (rebound tenderness and guarding in the RLQ). In some cases (pregnancy, retrocecal appendix), appendicitis may also present with pain in the RUQ.
  • Pancreatitis: inflammation of the pancreas. The condition may present with sudden onset severe epigastric/RUQ pain that is typically sharp, radiates to the back, and is relieved on bending forward. Most commonly associated with gallstones or alcohol abuse.
  • Nephrolithiasis: also known as kidney stones. Presents with sudden onset of severe right or left flank pain. Pain is colicky in nature and is associated with urinary symptoms such as hematuria/dysuria. Imaging shows stones in the urinary tract.

References

  1. Carey M C (1992). Pathogenesis of gallstones. Retrieved 14 Nov 2020 from: https://pubmed.ncbi.nlm.nih.gov/1529152/#
  2. Marschall H.U., Einarsson C. (2007). Gallstone disease. Retrieved 14 Nov 2020 from: https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2007.01783
  3. Zakko, S. (2020). Overview of gallstone disease in adults. In Chopra, S. and Grover, S. (Eds). UpToDate. Retrieved 14 Nov 2020 from: https://www.uptodate.com/contents/overview-of-gallstone-disease-in-adults?search=Cholelithiasis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H58360586

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