FORMATION OF GALLSTONS

FORMATION OF GALLSTONS


PHYSIOLOGY OF GALLBLADDER

• Approximately 600 to 750 mL of bile is produced daily
• During its passage through the bile ductules, canalicular bile is modified by the absorption and secretion of electrolytes and water
• The bile duct epithelium is also capable of water and electrolyte absorption, which may be of primary importance in the storage of bile during fasting in patients who have previously undergone cholecystectomy.
• The gallbladder mucosa has the greatest absorptive capacity per unit of any structure in the body.
• COMPOSITION OF BILE
  Hepatic Bile Gallbladder Bile
  Na (mEq/L) 140–159 220–340
  K (mEq/L) 4–5 6–14
  Ca (mEq/L) 2–5 5–32
  Cl (mEq/L) 62–112 1–10
  Bile salts (mEq/L) 3–55 290–340
  Cholesterol (mg/dL) 60–70 350–930
  pH 7.2–7.7 5.6–7.4
  
  Major solute components of bile by moles percent
  
• Bile acids (80%),
• Lecithin and traces of other phospholipids (16%),
• Unesterified cholesterol (4.0%).
• In the lithogenic state the cholesterol value can be as high as 8 to 10%.
• Conjugated bilirubin, proteins (IgA, metabolites of hormones, and others), electrolytes, mucus, and, often, drugs and their metabolites.
  
  BILE ACIDS

The primary bile acids,

• Cholic acid & chenodeoxycholic acid (CDCA),
• The enzyme cholesterol 7a-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthes.
• Bile acids are conjugated with glycine or taurine and become soluble.

Secondary bile acids,

• Deoxycholate and lithocholate,
• They are formed in the colon as bacterial metabolites of the primary bile acids.
• However, lithocholic acid is much less efficiently absorbed from the colon than deoxycholic acid.
• Another secondary bile acid, found in low concentration, is ursodeoxycholic acid (UDCA), a stereoisomer of CDCA.

Enterohepatic Circulation

• Unconjugated, and to a lesser degree also conjugated, bile acids are absorbed by passive diffusion along the entire gut.
• The active transport of conjugated bile acids occur in the distal ileum
• The reabsorbed bile acids enter the portal bloodstream and are taken up rapidly by hepatocytes, reconjugated, and resecreted into bile (enterohepatic circulation).
  

Types of gall stones

Gallstones are formed by concretion or accretion of normal or abnormal bile constituents.

They are divided into two major types:

• Cholesterol stones account for 80% of the total, with pigment stones comprising the remaining 20%.
• Cholesterol gallstones usually contain >50% cholesterol monohydrate plus an admixture of calcium salts, bile pigments- bilirubin (yellow/red/brown) or Biliverdin (green/blue/black), proteins, and fatty acids.
• Pigment stones are composed primarily of calcium bilirubinate; they contain <20%>
• Pigment stones
  • Black
  • brown
• They differ in colour, shape, size and configuration
• In an individual they are uniform in composition
• In extra gallbladder position they can be
  • primary or
  • secondary

CHOLESTEROL STONES AND BILIARY SLUDGE
The pathogenesis of cholesterol gallstones is clearly multifactorial but essentially involves four factors:

(a) Cholesterol supersaturation in bile,
(b) Crystal nucleation,

(c) Gallbladder dysmotility, and
(d) Gallbladder absorption.


Insolubility of cholesterol

• Cholesterol has many important functions in the body.
• Unfortunately,it can also cause problem.
• Cholesterol is a pearly-white, waxy substance.

Factors of increased biliary cholesterol

• Dietary cholesterol increases biliary cholesterol secretion
• Obesity,
• High-caloric and cholesterol-rich diets, or
• Drugs (e.g., clofibrate) and
• Increased activity of HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis, and
• Increased hepatic uptake of cholesterol from blood may result in increase secretion of cholesterol
• As such cholesterol is insoluble in aqueous medium
• Oversensitive feedback mechanism to turn off Cholesterol-7-a-hydroxylase,
• Excessive cholesterol synthesis in the face of a normal bile acid pool.
• Endogenous and exogenous estrogen's appear to increase cholesterol secretion and decrease bile acid secretion
• When bile salt molecules in water reach concentrations of 2 to 4 mM, they form spherical complexes called micelles;
• Bile acids are amphipathic compounds means have hydrophilic and hydrophobic ends
• In micelles, the negatively charged hydrophilic ends of the molecules face outward, toward the water, and the uncharged hydrophobic regions face the center of the sphere, toward one another.
• Cholesterol molecules are enclosed in the hydrophobic interiors.
• Cholesterol and phospholipids are secreted into bile as unilamellar bilayered vesicles, which are converted into mixed micelles consisting of bile acids, phospholipids, and cholesterol by the action of bile acids.
• If there is an excess of cholesterol in relation to phospholipids and bile acids,
• Unstable cholesterol-rich vesicles remain,
• which aggregate into large multilamellar vesicles
• from which cholesterol monohydrate crystals precipitate
• Several pronucleating factors including mucin glycoproteins, immunoglobulins, and transferrin accelerate the precipitation of cholesterol in bile.

Gallbladder dysmotility

• Defects in gallbladder motility increase the residence time of bile in the gallbladder thereby playing a role in stone formation.
• Progressive enlargement of individual crystals or stones by deposition of additional insoluble precipitate at the bile-stone interface,
• Fusion of individual crystals or stones to form a larger conglomerate.
  
  
  Gallbladder sludge
• A thickened gallbladder mucoprotein with tiny entrapped cholesterol crystals, is thought to be the usual precursor of gallstones.
• Sludge may also occur in asymptomatic patients with prolonged fasting and can be seen on standard ultrasonography of the gallbladder.
• Sludge can sometimes cause biliary pain, cholecystitis, or acute pancreatitis,
• But may also resolve without treatment.
• The antibiotic ceftriaxone can precipitate in the gallbladder and bile ducts as sludge.
  
  GROWTH OF GALLSTONE
• The crystal acquires additional cholesterol to form a visible stone.
• Cholesterol stones often contain alternating layers of cholesterol crystals and mucoprotein.
• Pure cholesterol crystals are quite soft. Protein adds strength to the stone.
• This stage of stone formation is largely influenced by gallbladder stasis.
• Gallstones forming in patients with high spinal cord injury or treated with the somatostatin analog Octreotide have been largely associated with impaired gallbladder motility.
  
  
  Impaired bile salt return
• Seen with ileal disease (Crohn's),
• Ileal resection or bypass.
• Drugs that bind bile acids in the gut,
• such as cholestyramine could also theoretically cause this problem, but new synthesis of bile acids by the liver usually suffices to compensate for the losses.
  
  Some important observation in stone pathogenesis
  
• Increase in cholesterol or decrease in bile acid
• Saturated insoluble cholesterol formation
• Nucleation
  • Increased cholesterol stimulates mucin secretion
  • That results in the formation of cholesterol crystals
• Growth – gall bladder stasis
• Bacteria, fungi or parasite may be detected in the centre of stone
• Increase in billary calcium – promotes crystal aggregation
  • But calcium in diet has protective role
• Biliary prostaglandins
• Reflux of pancreatic fluid
  
  
  Pigment stones

Black pigment stones
• Bilirubin -color: yellow/red/brown.
• Biliverdin -color: green/blue/blackSource: oxidation of bilirubin

• Consist of polymers of bilirubin, with large amounts of mucoprotein.
• Usually contain less amount of cholesterol.
• Contain 30-60% unconjugated bilirubin by weight.
• 50% are radiopaque, 50% are radiolucent (stones that are more than 4% calcium by weight are radiopaque).
• They are the result of precipitation of calcium with the anions, bilirubin, carbonate, phosphate, or palmitate.
  
• Pigment gallstones are classified as either black or brown pigment stones.
• Black pigment stones are typically tarry and frequently are associated with hemolytic conditions or cirrhosis.
• In hemolytic states, the bilirubin load and concentration of unconjugated bilirubin increases.
• These stones are usually not associated with infected bile.
• They are located almost exclusively in the gallbladder.
  
  Brown Pigment Stones
  
• Earthy in texture
• Typically found in the bile ducts, especially in Asian populations.
• Brown stones often contain more cholesterol and calcium palmitate than black stones
• Occur as primary common duct stones
• In patients, associated with disorders of biliary motility and bacterial infection.
• In these settings, bacteria-producing slime and bacteria containing the enzyme glucuronidase cause enzymatic hydrolysis of soluble conjugated bilirubin glucuronide to form free bilirubin, which then precipitates with calcium.
  
  
  Summary of Pathogenesis of Pigment stones
• Pure pigment stone
  • High unconjugated bilirubin
• Haemolytic
• Cirrhosis – hyperslpenism, decreased conjugation
• Mixed pigment stones
  • Biliary drainage disorder with infection
  • Bacteria deconjugates conjugated bilirubin to unconjugated bilirubin
  • Resulting in insoluble unconjugated bilirubin which combines with calcium-Ca bilirubinate
  • TPN-Stasis of bile – infection
  • Biliary sludge – formed of calcium bilirubinate crystals