Physiology and Pharmacology of the Liver

Question 1

What is the liver’s blood supply?

Answer 1

75% hepatic portal vein

25% hepatic artery

Question 2

Describe the passage of blood through the liver

Answer 2

Enters via the hepatic portal vein and the hepatic artery. Goes through venules and arterioles, then mixes in the liver sinusoids (fenestrated capillaries).
It then drains to the central vein of the liver lobule, then into branches of hepatic veins, then drains into a hepatic vein.

Question 3

What shape is each liver lobule?

Answer 3

Hexagonal in cross section

Question 4

What is at the centre of each liver lobule?

Answer 4

A branch of hepatic vein at its centre (central vein)

Question 5

What is at each corner of the lover lobules?

Answer 5

A portal triad:
A branch of hepatic portal vein
A branch of hepatic artery
A bile duct

Question 6

How are hepatocytes arranged in the lobules?

Answer 6

In cords, arranged as hepatic plates

Question 7

Which direction does blood flow through the sinusoid?

Answer 7

Inwardly, towards the central vein

Question 8

What does bile flow through? Which direction does it flow in?

Answer 8

It flows outwardly to the bile duct through canaliculi

Question 9

How are hepatocytes arranged between the sinusoids?

What do the basolateral membranes of these cells face?

Answer 9

In plates, 2 cells thick.
The basolateral membranes face a pericellular space between these cells and the endothelial cells that line the sinusoids, called the space of Disse.

Question 10

What does the apical membrane of the hepatocytes between the sinusoids create?

Answer 10

The apical membrane is grooved

Forms the canaliculi for bile

Question 11

What do sinusoidal spaces contain?

Answer 11

Endothelial cells that form a fenestrated structure
Kuppfer cells: macrophages resident to the sinusoidal vascular space- these removed particulate matter and senescent erythrocytes
Stellate (Ito) cells within the space of Disse: important for storage of Vitamin A, may play a role in fibrosis and cirrhosis

Question 12

How much bile is produced per day?

Answer 12

It is produced continuously, 0.6-1.2 litres per day

Question 13

Where is bile between meals?

Answer 13

It is stored and concentrated in the gall bladder

Question 14

What happens to bile during a meal?

Answer 14

Chyme in the duodenum stimulates gall bladder smooth muscle to contract via CCK and vagal impulses.
The sphincter of oddi opens (via CCK)
Bile spurts into the duodenum via cystic and common bile ducts (mixed with bile from the liver)

Question 15

What secretions make up bile?

Answer 15

Secretion of hepatocytes
Secretion of cholangiocytes
The secretions mix in the ducts

Question 16

What does hepatic bile consist of?

Answer 16

Primary bile acids: mainly cholic and chenodeoxycolic acids.
These form bile salts with Na+ and K+. Many are conjugated to glycine or taurine. Some are conjugated to sulphate or glucuonate.

Water and electrolytes including Na, K, Ca, Cl and HCO3 ions.

Lipids and phospholipids e.g. lecithin

Cholesterol

IgA

Bilirubin

Question 17

What may excess cholesterol relative to bile acids and lecithin precipitate into?

Answer 17

Microcrystals that aggregate into gallstone (cholithiasis)

Question 18

What can be used to dissolve non-calcified cholesterol gallstones?

Answer 18

Ursodeoxycholic acid

Question 19

What percentage of the volume of bile does secretion from bile duct cells (cholangiocytes) contribute to?

Answer 19

25%

Question 20

What does the secretion from cholangiocytes comprise of?

Answer 20

Similar composition to alkaline pancreatic juice

aqueous, alkaline, Na+, K+, Cl-, HCO3-rich

Question 21

What happens to the flow rate of secretion from cholangiocytes during meals?

Answer 21

During meals flow rate increases in response to secretin released from duodenal S cells

HCO3-/Cl- exchange occurs across the duct cell apical membrane – reduced at high flow rate - therefore HCO3- content increases

Question 22

What proportion of the bile salts that enter the duodenum is lost in the faeces?
What happens to the rest?

Answer 22

5%

Most is reabsorbed by active transport in the terminal ileum and undergoes enterohepatic recycling

Question 23

Name 2 resins that bind bile salts to prevent reabsorption of cholesterol and lower plasma cholesterol?

Answer 23

Colestyramine

colestipol

Question 24

How are bile salts transported from the ileum to the into the enterocytes?

Answer 24

The Na+/bile salt transporter ASBT

Question 25

What mediates the basolateral transport of bile salts into the portal circulation from the enterocytes?

Answer 25

Organic solute transporter ost-alpha/ost-beta

Question 26

Which transporter transports bile salts back into the liver from the portal circulation?

Answer 26

mainly NTPC, Na-taurocholate cotransporting polypeptide

Question 27

What is the starting point for bile salt synthesis?
How many reactions are involved in the pathway?
Which enzyme mediates it first?

Answer 27

Synthesis is from cholesterol in a series of 14 reactions, first mediated by cholesterol 7-alpha-hydroxylase (CYP7alpha1) to form the primary bile salts.

Question 28

What is the rate of synthesis of bile salts dependent on?

Answer 28

the hepatic portal blood concentration of the salts:
Low concentrate stimulates synthesis
High concentration inhibits synthesis

Question 29

What does CCK cause to happen?

Answer 29

causes gall bladder contraction and relaxation of the sphincter of Oddi

Question 30

What does secretin cause to happen?

Answer 30

causes aqueous alkaline bile secretion

Question 31

What does vagal activity cause?

Answer 31

produces a mild secretory response in the cephalic phase of digestion

Question 32

What is the most common pathology of the biliary tract?

Answer 32

cholelithiasis

Question 33

How is cholelithiasis treated?

Answer 33

Surgery is the usual option, but ursodeoxycholic acid may be useful

Question 34

What analgesics may be used to relieve the pain in biliary colic?

Answer 34

Morphine – but constricts the sphincter of Oddi; buprenorphine and pethidine are alternatives

Question 35

What may be used for relief of biliary spasm?

Answer 35

Atropine, or glyceryltrinitrate (GTN)

Question 36

What does drug metabolism in the liver act to do?

Answer 36

Convert parent drugs to more polar metabolites that are not readily reabsorbed in the renal tubules, facilitating excretion
Convert drugs to metabolites that are usually pharmacological less active than the parent compound. Less frequently, metabolites may:
gain activity (e.g. prodrugs)
have unchanged activity
possess a different type of activity

Question 37

What is the main organ of drug metabolism?

Which other parts of the body have metabolic activity of drugs?

Answer 37

The liver

the G.I. tract, lungs and plasma also have activity

Question 38

How many phases are involved in drug metabolism?

What do they each do?

Answer 38

Drug metabolism often proceeds in two, sequential, phases.
Phase 1: Makes drug more polar, adds a chemically reactive group (a ‘handle’) permitting conjugation
Reactions involved are oxidation, reduction and hydrolysis

Phase 2: Adds an endogenous compound increasing polarity, e.g. glucuronyl, sulphate, methyl, acetyl, glycyl or glutathione groups
This is conjugation

Question 39

Do all drugs undergo both phases of drug metabolism?

Answer 39

No- some undergo both phases, some may only undergo Phase 1 orPhase 2 and some are excreted unchanged.