9.05 Cholestasis / Gallstone

Front 1

What is the total daily bile flow?

Back 1

~600mL

Front 2

What is bile?

Back 2

a bicardonate-rich electrolyte solution containing a sall number of proteins, bile pigments, bile acids and other organic anions, cholesterol and phospholipids

Front 3

What is bile an excretory pathway for?

Back 3

lipid-soluble waste products including cholesterol, bilirubin conjugates and metabolites of foreign compounds, including many drugs and toxins

Front 4

What are bile salts essential for?

Back 4

fat absorption - they micellise fat droplets to facilitate the action of lipase

Front 5

What cells actively secrete bile?

Back 5

hepatocytes

Front 6

What is the role of bile ductules?

Back 6

contribute about 25% of total bile water

Front 7

Is secretion of bile an energy dependent process?

Back 7

yes

Front 8

What is energy required for in the bile secretory process?

Back 8

energy is required for uptake of bile acids, for vescular xport within hepatocytes, cytoskeletal contractions that 'pump' canaliculi, and for canalicular xport of bile acids, organic anions and phospholipid

Front 9

What do the tight junctions between hepatocytes form a diffision barrier between?

Back 9

a barrier between plasma in the perisinusoidal Space of Disse and nascent bile in the canaliculus

Front 10

How do the components of bile (otehr than water and electrolytes) enter bile?

Back 10

through the hepatocyte (transcellular pathway)

Front 11

T/F... hepatocytes must be polarised in order to generate bile

Back 11

T

Front 12

What parts of the cell surface of a hepatocyte gives it its polarity?

Back 12

the sinusoidal and lateral surfaces are equivalent to the basolateral zone of secretory epithelia

the canaliculus is equivalent to the apical pole

Front 13

What are the crevices between neighbouring hepatocytes?

Back 13

bile canaliculi

Front 14

What forms the wall of each canaliculus?

Back 14

the canalicular domain of the hepatocyte plasma membrane

Front 15

What aids the draining of canaliculi into bile ductules?

Back 15

active contraction

Front 16

What are bile ductules?

Back 16

small epithelial-lined canals which modify the composition of bile, particularlyby secretion of bicarbonate

Front 17

What xporter mediates bicarb secretion of bile ductules, where is it located and what hormones regulate it?

Back 17

xporter: Cl-/HCO3- exchanger
apically located
regulated by: secretin, bombesin and VIP

Front 18

How do hepatocytes take up bile acids?

Back 18

by a Na-dependent co-transporter similar to that responsible for bile salt resorption in terminal ileum

The Na is then extruded by the Na/K- ATPase.

Front 19

How are bile acids secreted into bile?

Back 19

by both ATP-dependent and independent mechanism, the latter by a carriermediated process dirven by the electrochemical gradient

However, the major pathway is ATP-dependent, the pump being a member of the ABC family - the bile salt export pump (BSEP)

Front 20

How much of bile flow is independent of bile acid xport in humans?

Back 20

50%

Front 21

What is the crucial element of bile acid-independent bile flow?

Back 21

a second canalicular ATP-dependent transporter, known as the canlicular multispecific organic anion transporter (cMOAT) AKA MRP-2

Front 22

What is MRP-2 responsible for and in what condition is it absent?

Back 22

it's responsible for transport of bilirubin glucaronides, drug and steroid conjugates (particularly glutathione and glutathionyl conjugates)

absent in Dubin-Johnson syndrome, an inherited form of conjugated hyperbilirubinemia

Front 23

What is the MDR-3?

Back 23

the third ABC protein on the canalicular membrane (other two are bile salt export pump (BSEP) and canalicular multispecific organic anion transporter (cMOAT))

MDR-3 is a phospholipid flippase that is critical for the formation of mixed micelles and thus for cholesterol secretion into bile

Front 24

How do gallstones precipitate?

Back 24

from poorly soluble bile constituents

Front 25

What are gallstones promarily composed of?

Back 25

cholesterol, bile pigments orboth

Front 26

What are gallstones an unwanted side effect from?

Back 26

a side affect from normal gall bladder function - to store and concentrate bile

Front 27

What naturally resists cholesterol stone formation?

Back 27

bile salts, phospholipids (especially phosphatidylcholine (lecithin))

Front 28

What are bile salts?

Back 28

glycine or taurine conjugates of primary bile acids, including deoxycholate and lithocholate, which are deived by the action of bacterial dehydroxylases on cholate and chedeoxycholate respectively

Front 29

Why do primary and secondary bile salts appear in secreted bile?

Back 29

because bile salts are recovered in the ileum and returned to the bile salt pool

Front 30

What is the function of cholecystokinin (CCK)?

Back 30

coordinates activation of gall bladder emptying and pancreatic enzyme secretion

Front 31

What happens to bile during fasting?

Back 31

continuously flows from the lover 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 at this time

Front 32

What process allows for bile constituents to become concentrated in the gall bladder during fasting?

Back 32

iso-osmotic reabsorption, ie. the electrolyte composition of the bile does not change significantly during concentration because the absorption of simple electrolytes such as Na+, K+, Cl-, HOC3- etc is coupled isomotically to the reabsorption of water

Front 33

What is the risk of potentially insoluble constituents becoming concentrated (ie. during fasting)?

Back 33

enhanced risk of supersaturation, crystallisation and gallstone formation

Front 34

What keeps biliary contents in a soluble state in spite of the concentration of bile in the gall bladder?

Back 34

the formation of micelles

Front 35

What are micelles?

Back 35

lobular clusters of bile salts and phospholipids that are arranged with their chargedhead-groups facing thebulk aqueous phase and their hydrophobic tails facing inwards into the centre of the micellar structure.

Front 36

What are simple micelles?

Back 36

micelles formed from bile salts alone. They contain 4-25 bile salt molecules

Front 37

What are mixed micelles?

Back 37

micelles made from a mix of bile salts and phospholipids. They are larger than simple micelles

Front 38

What important molecules pack readily into micelles to be solubilised?

Back 38

cholesterol

Front 39

What is the critical micellar concentration (cmc)?

Back 39

the concentration at which micelles form and is characteristic for each bile acid and is lowered upon conjugation to form bile salts

Front 40

What is the most common type of gallstone composed of?

Back 40

cholesterol (present in 80% of affected individuals)

Front 41

How do cholesterol gallstones form?

Back 41

under conditions where mixed micelles are unable to maintain cholesterol in solution

first, tiny crystals form in unstable, cholesterol-laden, phospholipid vesicles.

then, appregation of crystals and precipitation of poorly soluble components from the bile onto the growing crystals subsequently sustains the formation of stones

Front 42

What factors promote cholesterol stone formation?

Back 42

hypersecretion of cholesterol (this is the most important factor)
defects in fall bladder motility
inadequate secretion of bile salts and/or phospholipids

Front 43

What are the three stages of cholesterol stone formation?

Back 43

1. Cholesterol hypersecretion leading to supersaturation of the bile
2. Accelerated cyrstallisation
3. conversion crystals to stones

Front 44

What factors promote cholesterol secretion into the bile?

Back 44

increasing age, obesity, exposure to estrogens (incl pregnancy) and diets high in animal fat secretion. Also deoxycholate enrichment of the bile salt pool.

Front 45

What factors promote crystallisation of cholesterol?

Back 45

enhanced stasis associated with impairment of normal gall bladder motility, e.g. during pregnancy or in the context of obesity. Also increased in presence of elevated concs of several pro-crystallising proteins incl Ig G (assoc with recruitment of plasma cells to the gall bladder wall) and mucous glycoproteins

Front 46

How do pigment stones arise?

Back 46

in circumstances in which there is enhanced red call destruction (especially extravascular hemolysis) and thus enhanced bilirubin production. Bilirubin is normally maintained in soluble form by conjugation to glucuronic acid, a key hepatocyte process.

Upon conjugation, bilirubin diglucuronide is secreted into the bile. Its solubility may be impaired if there is significant secretion of unconjugated bilirubin. Other bilirubin metabolites may also participate in pigment stone formation

Front 47

What are the intracellular reactions that sustain the conversion of bilirubin to its soluble form- glucuronic acid?

Back 47

UDP-glucuronic acid + bilirubin -> bilirubin monoglucuronide + UDP ...(1)

2 Bilirubin monoglucronide -> bilirubin diglucuronide + bilirubin ...(2)

Front 48

What circumstances might make bilirubin less soluble?

Back 48

when there is sig secretion of unconjugated bilirubin, ie. if the supply of UDP-glucuronic acid si overwhelmed or if bacterial colonisation of the biliary tree has occurred resulting in the deconjugation and release of poorly soluble unconjugated bilirubin.