VI. PATHOPHYSIOLOGY A.

THEORETICAL BASED (SOURCE: GASTROINTESTINAL AND LIVER DISEASE BY SLEISENGER AND FORDTRAN) NON-MODIFIABLE FACTORS *Age Increase in age = increase in prevalence of gallstones Women = more estrogen than men Increased progesterone Increased estrogen Gallbladder volume is doubled Receptors that radiate the reabsorption of bile Decreased bile acid pool MODIFIABLE FACTORS Increased activity of 3hydroxyl-3-methylglutaryl coenzyme A reductase Caloric restriction Prolonged fasting Sphincter of Oddi fails to relax *Obesity *Rapid weight loss *Total parenteral nutrition *Drugs

*Gender

*Pregnancy

Estrogen(in men)

*Disease of the ileum

Increased hepatic LDL receptor

Lipid-lowering Fibric acid derivative

Increased clearance of plasma LDL cholesterol Decreased plasma LDL; increased plasma HDL

ceftriaxone

Decreases activity of cholesterol 7αhydroxylase Decreases bile acid contrentations

40% is secreted and unmetabolized into bile

Acetyl CoA cholesterol transferase(ACAT)

Produces cholesterol as fatty acid ester Cholesterol is stored in the liver Primary acid: chenodeoxycholate and cholate

BILE Secondary acid: deoxycholate and lithocholate Tertiary acid: ursodeoxycholate

Low ACAT activity enlarged Cholesterol ester pool

Secreted by ATP-binding cassettes superfamily from hepatocytes into bile ABCG5 with ABCG8 trasports cholesterol Correlates with arachidonic acid Precursor of prostaglandin ABCB11 transports bile acids Secretion of bile salts

Supply of free cholesterol for bile acid formation and lipoprotein assembly Endoplasmic reticulum(synthesizes cholesterol with HMG CoA reductase(ratelimiting enzyme) Increases activities of HMG CoA reductase

ABCB4 transports phospholipids If mutated

Gallbladder Acidifies bile Increase solubility of calcium salts Precipitation less favorable

Stimulates hepatic cholesterol secretion into bile Stimulates mucin secretion Increased rate of cholesterol synthesis Decreased flow of bile into gallbladder Bile becomes more lithogenic Cholesterol is carried in the form of vesicles Unilamellar coalesce into multilamellar Less stable Supersaturated bile Sludge and gallstone formation Biliary sludge stasis Stone Made up of hydrophobic regions that can bind to cholesterol, phospholipid and bilirubin Accelerates nucleation with unconjugated bilirubin