7.11 Cholecystitis

The electrolyte solution is bicarbonate rich and contains a small number of proteins, bile pigments, bile acids and other organic anions. Lipid components: mixed micelles which are help in aqueous suspension by the detergent

~600mL (0.5-1.0L)

Lipid-soluble waste products including cholesterol, bilirubin conjugates and metabolites of foreign compounds

They are essential for fat absorption. They micellise fat droplets to facilitate the action of lipase

Hepatocytes actively secrete bile; bile ductules playing a smaller role, contributing about 25% of total bile water.

The osmotic gradient generated by secretion of bile acids and other solutes, particularly glutathionyl conjugates. Hydrostatic pressures do not influence bile flow, although reductions of hepatic blood flow can affect the secretion of bile if delivery of oxygen and bile salts is impaired.

-Uptake of bile acids
-Vesicular transport within hepatocytes
-Cytoskeletal contractions that "pump" canaliculi
-For canalicular transport of bile acids, organic anions and phospholipid

Everything except water and electrolytes

The integrity of the tight junctions that form a diffusion barrier between plasma in the perisinusoidal Space of Disse and nascent bile in the canaliculus

The crevice between neighbouring hepatocytes; the walls of each cannaliculus are formed by the canalicular domain of the hepatocyte plasma membrane. Aided by their active contraction, canaliculi drain into bile ductules.

Small epithelial-lined canals which modify the composition of bile, particularly by secretion of bicarbonate

Secretin, bombesin and VIP

By a Na-dependent co-transporter similar to that responsible for bile salt resorption in the terminal ileum. Sodium that enters the cell is subsequently extruded by the Na/K- ATPase

by both ATP-dependent and independent mechanisms, the latter by a carrier-mediated process driven by the electrochemical gradient. However, the major pathway is ATP-dependent, the pump being a member of the ABC family recently identified as the bile salt export pump (BSEP)

a second canalicular ATP-dependent transporter, known as the canalicular multispecific organic anion transporter (cMOAT), now usually referred to as MRP-2. MRP-2 is responsible for transport of bilirubin glucuronides

An inherited form of conjugated hyperbilirubinemia, MRP-2 is absent

A third ABC protein on the canalicular membrane is MDR-3 (mdr2 in mice), a phospholipid flippase that is critical for the formation of mixed micelles and thus for cholesterol secretion into bile.

The precipitation of poorly soluble bile constituents and are composed primarily of cholesterol, bile pigments or both.

Cholesterol stone formation is naturally resisted by bile salts as well as phospholipids , especially phosphatidylcholine (also known as lecithin)

Glycine or taurine conjugates of primary bile acids , including cholate and chendeoxycholate, which are synthesized from cholesterol in hepatocytes or secondary bile acids , including deoxycholate and lithocholate, which are derived by the action of bacterial dehydroxylases on cholate and chendeoxycholate respectively.

Because bile salts are recovered in the ileum and returned to the bile salt pool, both primary and secondary bile salts appear in secreted bile.

There is a continuous flow of bile from the liver to the gall bladder via the hepatic ducts and cystic duct; the choledochal sphincter (Sphincter of Oddi) prevents the entry of bile into the duodenum during this time. The gall bladder accommodates this flow by continuous reabsorption thereby establishing a store of key non-absorbed constituents including bile salts and phospholipids

This process occurs via so-called iso-osmotic reabsorption i.e., the electrolyte composition of the bile does not change significantly during concentration because the absorption of simple electrolytes such as Na + , K + , Cl - , HCO 3 - etc is coupled isosmotically to the reabsorption of water. However, the concentrations of potentially insoluble constituents e.g., cholesterol and biliary pigments also increase during the process of biliary concentration enhancing the risk of supersaturation, crystallization and gallstone formation.

Simple micelles are formed from bile salts alone (typically contain 4-25 bile salt molecules)
Mixed micelles are formed from salts and phospholipids and tend to be larger

he concentration at which micelles form ( the critical micellar concentration or cmc ) is characteristic for each bile acid and is lowered upon conjugation to form bile salts.

Cholesterol stones. Stones of this type are present in greater than 80% of affected individuals. These stones form under conditions where mixed micelles are unable to maintain cholesterol in solution.

Cholesterol stone formation appears to follow an initial process in which tiny crystals form in unstable, cholesterol-laden, phospholipid vesicles. Aggregation of crystals and precipitation of poorly soluble components from the bile onto the growing crystals subsequently sustains the formation of stones.

-Hypersecretion of cholesterol (most important)
-Defects in gall bladder motility
-Inadequate secretion of bile salts and/or phospholipids

Cholesterol hypersecretion leading to supersaturation of the bile.
Cholesterol secretion into the bile is enhanced by increasing age, obesity, exposure to estrogens (including pregnancy) and diets high in animal fat intake. Surprisingly, deoxycholate enrichment of the bile salt pool also appears to promote cholesterol secretion.

Accelerated crystallization.
Crystallization is enhanced by stasis associated with impairment of normal gall bladder motility e.g., during pregnancy or in the context of obesity. Crystallization is also enhanced in the presence of elevated concentrations of several pro-crystallizing proteins including Ig G (associated with recruitment of plasma cells to the gall bladder wall) and mucous glycoproteins.

Because bile salts are recovered in the ileum and returned to the bile salt pool, both primary and secondary bile salts appear in secreted bile.

There is a continuous flow of bile from the liver to the gall bladder via the hepatic ducts and cystic duct; the choledochal sphincter (Sphincter of Oddi) prevents the entry of bile into the duodenum during this time. The gall bladder accommodates this flow by continuous reabsorption thereby establishing a store of key non-absorbed constituents including bile salts and phospholipids

This process occurs via so-called iso-osmotic reabsorption i.e., the electrolyte composition of the bile does not change significantly during concentration because the absorption of simple electrolytes such as Na + , K + , Cl - , HCO 3 - etc is coupled isosmotically to the reabsorption of water. However, the concentrations of potentially insoluble constituents e.g., cholesterol and biliary pigments also increase during the process of biliary concentration enhancing the risk of supersaturation, crystallization and gallstone formation.

Simple micelles are formed from bile salts alone (typically contain 4-25 bile salt molecules)
Mixed micelles are formed from salts and phospholipids and tend to be larger

he concentration at which micelles form ( the critical micellar concentration or cmc ) is characteristic for each bile acid and is lowered upon conjugation to form bile salts.

Cholesterol stones. Stones of this type are present in greater than 80% of affected individuals. These stones form under conditions where mixed micelles are unable to maintain cholesterol in solution.

Cholesterol stone formation appears to follow an initial process in which tiny crystals form in unstable, cholesterol-laden, phospholipid vesicles. Aggregation of crystals and precipitation of poorly soluble components from the bile onto the growing crystals subsequently sustains the formation of stones.

-Hypersecretion of cholesterol (most important)
-Defects in gall bladder motility
-Inadequate secretion of bile salts and/or phospholipids

Cholesterol hypersecretion leading to supersaturation of the bile.
Cholesterol secretion into the bile is enhanced by increasing age, obesity, exposure to estrogens (including pregnancy) and diets high in animal fat intake. Surprisingly, deoxycholate enrichment of the bile salt pool also appears to promote cholesterol secretion.

Accelerated crystallization.
Crystallization is enhanced by stasis associated with impairment of normal gall bladder motility e.g., during pregnancy or in the context of obesity. Crystallization is also enhanced in the presence of elevated concentrations of several pro-crystallizing proteins including Ig G (associated with recruitment of plasma cells to the gall bladder wall) and mucous glycoproteins.

Conversion of crystals to stones

They typically arise under circumstances in which there is enhanced red cell destruction (especially extravascular haemolysis) and thus enhanced bilirubin production.

UDP-glucuronic acid + bilirubin -> bilirubin monoglucuronide + UDP

2 Bilirubin monoglucuronide -> bilirubin diglucuronide + bilirubin

Its solubility may be impaired if there is significant secretion of unconjugated bilirubin e.g., if the supply of UDP-glucuronic acid is overwhelmed or if bacterial colonization of the biliary tree has occurred resulting in the deconjugation and release of poorly soluble unconjugated bilirubin. Other bilirubin metabolites may also participate in pigment stone formation.

The C fibres conducting the deep pain are connected to both somatic motor as well as the autonomic nervous system. Hence deep somatic pain is associated with reflex contraction or spasm of the overlying skeletal muscle as well as autonomic symptoms such as sweating, nausea and changes in blood pressure. Hence irritation of parietal peritoneum is associated with sweating, vomiting, hypotension and guarding and rigidity of the overlying abdominal wall muscles.

No.

he receptors are located within the capsule of solid organs or submucous and myenteric plexus of the hollow organs and are sensitive to distension. They are more sparsely distributed and the fibres are extensively connected to the sympathetic and parasympathetic system

This type of pain is always dull, poorly localised, unpleasant and associated with nausea, vomiting and autonomic symptoms like sweating and changes in blood pressure. Reflex spasmodic contractions of the local visceral smooth muscles results in the colicky pain. When a viscus is inflamed or hyperaemic, relatively minor stimuli can cause severe pain.

Referred pain and is referred to a somatic structure that developed from the same embryonic segment or dermatome as the structure in which the pain originates eg. pain in the tip of the scapula following irritation or the parietal peritoneum covering the central portion of the diaphragm as seen in cholecystitis