A. Epidemiology

1. Definitions
   1. Cholelithiasis - stones in the gall bladder
   2. Choledocholithiasis - gallstone(s) in the common bile duct
   3. Cholecystitis - inflammation of the gallbladder (usually with stones)
   4. Acalculous Cholecystitis - inflammation of gallbladder due to "sludge" (without stones)
   5. Cholangitis - inflammation of the bile ducts
2. ~10% of adults overall have gallstones (cholelithiasis)
3. Age usually >40 with increased incidence with advancing age
4. Female to Male ratio is ~2:1 across all races
5. Mexican Americans > Non-Hispanic White > African Americans
6. Certain Indian tribes (such as Pima) have very high rates (25% of men, 65% of women)
7. ~70% of patients with asympatomic gallstones will remain asymptomatic
8. Symptoms occur in ~1-4% per year; ~10% in 5 years and 20% in 20 years
9. Thus, asympatomic gallstones may be followed in "low risk" persons
10. Symptomatic gallstones are treated; >500,000 cholecystectomies performed annually

B. Types of Gallstones
[Figure] "The Biliary Tract"

1. Two Main Types
   1. Cholesterol Stones: >75% of stones in developed countries
   2. Pigmented Stones (2 types): black and brown stones
2. Cholesterol Stones
   1. Cholesterol is >80% of stone constituents
   2. Formation depends on gall bladder concentrations of cholesterol, lecithin, and bile salts
   3. Larger stones (>5mm) associated with cholecystitis
   4. Smaller stones (<5mm) or >20 stones associated with pancreatitis
3. Pigment stones
   1. Black stones
   2. polymers of bilirubin with large amounts of mucin glycoproteins
      1. more common in patients with cirrhosis or chronic hemolytic conditions
      2. that is, found in conditions where bilirubin excretion is increased
   3. Brown Stones
   4. calcium salts of unconjugated bilirubin, with variable cholesterol and proteins
      1. primary bile duct stones
      2. usually associated with infection
      3. associated with decreased biliary IgA
   5. prevalence increased in Asians
4. Calcification of Stones
   1. About 15% of stones are calcified (seen on plain radiographs)
   2. Of these, about 65% are pigment stones, usually with calcium throughout
   3. Calcification of cholesterol stones typically occurs only at the rim
   4. Biliary calcium elevations increased risk of gallstone formation
   5. Biliary calcium elevation particularly prominent in Crohn's Disease
5. Biliary Sludge
   1. Composed of thickened gallbladder mucoprotein with tiny cholesterol crystals
   2. May be precursor of gallstones (nucleation sites)
   3. Typically causes biliary pain, cholecystitis (acalculous), or acute pancreatitis
   4. Pregnancy, prolonged total parenteral nutrition (TPN), rapid weight loss, starvation
   5. Ceftriaxone may precipitate in gallbladder as sludge; stone formation may be enhanced

C. Risk Factors

1. Major risk factors are age, female gender, race, family history
2. Dietary factors: high calorie, low fiber, low cis-unsaturated fats, highly refined carbohydrates
3. Lifestyle factors
   1. Low physical activity: sedentary lifestyle (~1.4X increased risk versus active) [2]
   2. Prolonged fasting (starvation)
   3. Rapid weight loss
   4. Recreational physical activity associated with 30-40% reduced cholecystectomy rates [2]
4. Elevated Estrogen Levels
   1. Reproductive factors: pregnancy, parity
   2. Oral contraceptives (OCP)
   3. Estrogen replacement (± progesterone) associated with 1.6-2X increased risk of any kind of gallbladder disease in women [3,8]
   4. Estrogen reduces HMG CoA reductase activity and bile acid production
   5. Bile acids are responsible for cholesterol solubilization
   6. Obesity as well as rapid weight loss are risk factors
5. Low caffeine intake (high intake reduces gallstones) [5]
6. Serum Lipid Levels
   1. Total cholesterol not a risk factor
   2. Elevated triglycerides clearly linked to gallstone formation
   3. Low HDL may be associated with gallstone disease
   4. High intake of poly- and monounsaturated fats reduced gallstone risk in men [4]
7. Elevated Triglyceride Levels
   1. High estrogen levels
   2. Gall bladder stasis
8. Gall Bladder Stasis
   1. Total parenteral nutrition (TPN)
   2. Octreotide (somatostatin analog)
   3. Truncal Vagotomy
   4. Prolonged starvation
   5. Post-operative cholestasis
9. Pigment Stones (15%)
   1. High red blood cell turnover
   2. Hemolytic Anemias - sickle cell, thalassemia, hereditary spherocytosis, elliptocytosis
   3. Hepatic dysfunction (jaundice)
   4. These frequently calcify and are therefore seen on plain abdominal radiographs

D. Pathogenesis of Cholesterol Gallstones

1. Composition
   1. Cholesterol 70% (note cholesterol is minimally soluble in aqueous phase)
   2. Organic matrix of glycoproteins, calcium salts, bile pigments
   3. Cholesterol is solubilized by miscless of bile salts and phospholipids
   4. Phosphatidylcholine is main phospholipid constituent
2. Formation of Stones
   1. Usually form in presence of supersaturated cholesterol
   2. Monohydrate cholesterol crystals can precipitate from supersaturated solution
   3. These crystals become entrapped in gallbladder mucin gel with bilirubinate
   4. Ultimately, these entrapped crystal-gels agglomerate forming stones
3. Major Requirements for Stone Formation
   1. Elevated cholesterol in biliary fluid
   2. Sluggish gallbladder emptying
   3. Reduced biliary water levels (normally 90% of bile is water)
   4. Slowed intestinal transit, leading to increased bile salt formation
   5. Bile salts are reabsorbed in the terminal ileum back into the blood
   6. Chronic intestinal infection may help nucleate microscopic stones

E. Symptoms of Gallstones

1. Asymptomatic
2. Pain - may be nonspecific abdominal pain
   1. Often begins in epigastrium, full, dull pain in central upper abdomen
   2. Typically does not radiate to the back
   3. Right Upper Quadrant (RUQ) pain - intermittent "biliary colic"
   4. Positive Murphey Sign - abrupt cessation ofinhalation on palpation of RUQ
3. Pruritis - frequent complication of cholestasis
4. If infection (cholecystitis) occurs, may progress with fever, chills, malaise, rupture
5. Intermittent choledocolithiasis can occur
6. Pancreatitis - severe knife-like abdominal pain to back

F. Diagnosis of Gallstones

1. Abdominal radiograph detects only 15% of gallstones (but will detect 85% of renal stones)
2. Ultrasound
   1. Imaging modality of choice if gallstones not seen on abdominal radiograph
   2. Detects 85-90% of gallstones; specificity ~95%
   3. Good visualization of ducts - assess for dilation
   4. Assessment of gall bladder wall thickness
   5. For cholecystitis, ultrasound sensitivity ~95%, specificity ~80%
3. Radionucleotide Scan
   1. 99Tc-HIDA scan (or DesIDA) removed by liver and secreted to gall bladder
   2. Addition of morphine sulfate increases pressures in biliary tree
   3. This improves filling of the gall bladder and increases sensitivity
   4. Absorbed by liver, secreted into common bile duct
   5. Should visualize gall bladder unless obstructed
   6. There are a number of causes of non-visualization:
   7. Acute Cholecystitis
      1. Poor liver uptake, function
      2. Carcinoma, Adenoma (more distal to cystic duct)
      3. Abscess in region
   8. Previous cholecystectomy
      1. Eating Prior to study (Gall bladder contracted)
      2. Patients on hyperalimentation (poor emptying of Gall bladder)
   9. Highly sensitive (97%) and specific (~90%) for acute cholecystitis
4. Computerized Tomographic (CT) Scan
   1. Tertiary modality for stone visualization: only images ~50% of stones
   2. Good visualization of entire liver and pancreas also
5. Endoscopic Retrograde Cholangiopancreatography (ERCP)
   1. Evaluate (and possibly treat) common bile duct stones (choledocholithiasis)
   2. May be used to remove stones
   3. Sphincterotomy - standard of care for common bile duct stones
   4. May be most effective for specific diagnosis and treatment of common duct stones
   5. Pancreatis or cholangitis occur in ~4% of patients
6. Endoscopic ultrasonography can be used for diagnosis (>90% sensitivity and specificity)
7. Laparoscopic common bile duct exploration is well tolerated and as safe as ERCP [6]

G. Treatment of Gallstones [7]

1. Who to treat
   1. Symptomatic stones
   2. Possible: Chronic hemolytic anemia: sickle cell diseasee, other chronic hemolytic anemia
   3. Children with stones
   4. High Risk for GB Cancer: Native Americans and patients with calcified Gallbladders
   5. Diabetics should NOT undergo elective cholecystectomy for asymptomatic stones
2. Types of therapy
   1. Oral dissolution therapy - Ursodeoxycholic Acid (Ursodiol); see below
   2. Lithotripsy (shock wave) - for patients with small stones and functional gall bladder
   3. Laparoscopic Cholecystectomy - primary mode of therapy in most patients
   4. Open Cholecystectomy
   5. ERCP - generally for diagnosis and/or treatment of common duct stone
   6. ERCP may be complicated by pancreatitis or cholangitis
3. Cholecystectomy [9,10]
   1. Laparoscope may be used for both acute cholecystitis and asymptomatic conditions
   2. Low incidence of complications or progression compared with open cholecystectomy
   3. Intraoperative cholangiography associated with 70% reduction in common bile duct injuries in for both open and laparoscopic procedures [9]
   4. Laparoscopic procedure reduces hospital stay and recovery time; no mortality effect [10]
   5. Difficult to remove common duct stones laparoscopically
4. Sphincterotomy [11]
   1. Treatment of choice for choledocholithiasis
   2. Overall 97% stone extraction rate
   3. After endoscopic sphincterotomy, cholecystectomy should be performed
   4. Sphincterotomy overall morbidity 5.8%, mortality 0.2%

H. Ursodiol Therapy

1. Mechanism
   1. Bile salt in gall bladder permits re-solubulization of cholesterol crystals
   2. Works from outside of stone to inside
   3. Not effective in large stone (>20mm) or calcified or pigment stones
   4. Relatively slow acting
2. Indications for Ursodiol Therapy
   1. Primary therapy for symptomatic gallstones is laparoscopic cholecystectomy
   2. Infrequent attacks and small gallstones are candidates for ursodiol
   3. High risk operative candidates
   4. For prevention of formation in rapid weight reduction programs
   5. Must have radiolucent stones and patent cystic duct
   6. Maintenance therapy should be used in elderly and high risk surgical patients
3. Dosage and Side Effects
   1. 8-10mg/kg qd (one to two doses) appears to be optimal
   2. Lower doses (3-5mg/kg) may be effective; >10mg/kg no added benefit
   3. Maintenance therapy at 300mg/d ~50% effective in preventing attacks
   4. For prevention of stones in rapid weight reduction programs, 600mg/d adequate
4. Efficacy
   1. ~37% for stone dissolution after 6 months
   2. Mean rate of dissolution was ~1mm/month
   3. Dissolution must be documented by ultrasound

I. Other Cholestatic Diseases

1. Post-Operative Cholestasis
   1. Presents with jaundice and hyperbilirubinemia (>10mg/dL; primarily direct)
   2. Mild alkaline phosphatase and amylase increase
   3. Etiology likely multifactorial including high bilirubin loads, gall bladder stasis
   4. Treatment - mainly supportive care, cholestyramine, naloxone for pruritis
   5. Cholecystokinin or amino acids iv to improve gall bladder emptying
2. Biliary Tract Emergencies
   1. Acute Cholecystitis
   2. Ascending Cholangitis
   3. Acute Pancreatitis
   4. These occur due to obstruction in biliary tree, usually from gallstones

J. Acute Cholecystitis [12]

1. Etiology
   1. Caused by obstruction of cystic duct usually due to gallstones (~90%)
   2. Gallstones are typically large (>5mm)
   3. Acalculous (sludging, tumor) cholecystitis occurs in ~10% of cases
   4. Organ becomes necrotic and can perforate
2. Bacterial overgrowth occurs in static compartment
   1. Usually enteric bacteria: E. coli, Klebsiella pneumonia, S. fecalis and faecium
   2. May have mixed infections, especially older patients
   3. Typically called "ascending cholangitis"
   4. Organ may perforate (emphysematous cholecystitis) [14]
   5. Infection with gas forming organisms such as Clostridia can also cause gas gangrene
   6. ~45% of patients with occluded cystic ducts will have secondary bacterial infection
3. Symptoms
   1. Classical triad of RUQ pain, leukocytosis, fever (originally with cholangitis)
   2. Pain may have begun in epigastric region (visceral component)
   3. May progress to "Reynold's Pentad" = Triad + Sepsis and change in mental status
   4. Pain generally due to vascular compromise
   5. Cystic duct obstruction leads to stasis, distension, then vascular compromise
4. Physical Examination [13]
   1. May be suggestive, but of overall limited value to confirm diagnosis
   2. RUQ or epigastric tenderness
   3. Positive Murphy sign - pain and arrested inspiration when examiner's fingers hooked under right costal margin during deep inspiration
   4. Radiographic evaluation, usually ultrasound, is required for diagnosis
5. Laboratory
   1. Alkaline phosphatase increase with mild transaminase elevation
   2. Highly elevated transaminases (>200-400) suggest ascending cholangitis
   3. Leukocytosis with left shift (band forms)
   4. Bilirubin rarely elevated unless common bile duct occluded due to edema or stone
   5. Blood cultures must be obtained
   6. Duration of antibiotic treatment is increased if positive blood cultures
6. Diagnosis and Therapy

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