Physiology of the Liver

Question 1

Describe blood supply to the liver.

Answer 1

• Around 250-500 ml/min of oxygenated, nutrient-poor blood flows via hepatic artery
• Majority is oxygen-poor and nutrient-rich via hepatic portal vein (1000-1300 ml/min)
• Hepatic portal system - low pressure system (around 9 mmHg)
• Venous system pools and drains into hepatic vein and eventually IVC - pressure in hepatic vein is 0 mmHg

Question 2

Why does the liver act as a blood reservoir?

Answer 2

Liver is expandable
- Normal volume around 450 ml (around 10% of total blood volume)

Question 3

What can cause build up of blood in the liver?

Answer 3

• Anything causing pressure to rise in right atrium of heart

Question 4

Describe the liver lobules.

Answer 4

• Hexagonal functional units of liver
• Central vein at centre of lobule
• At each corner of lobule is portal triad - branch of hepatic portal vein, hepatic artery and bile duct
• Blood exits portal vein and hepatic artery into sinusoid and drains into central vein

Question 5

Describe the sinusoids.

Answer 5

• Fenestrations found in the linings - some around 1um in diameter - large enough for proteins to pass through
• Some substances pass into hepatocytes lining sinusoid

Question 6

Describe the relationship between the hepatic vein and the central vein.

Answer 6

• Hepatocytes produce substances e.g albumin - pass into sinusoid and into central vein
• Each central vein coalesces to form hepatic vein

Question 7

Describe the role of the hepatocytes.

Answer 7

• Metabolise substances from sinusoids and secrete products/synthesise substances and secrete back into sinusoid - drains back into central vein
• Bile synthesis - secrete into biliary caniculi - drain in opposite direction

Question 8

Describe stellate cells

Answer 8

• Found in space underneath endothelial cells
• Functions as store for vitamin A
• May act as APCs

Question 9

How do stellate cells change during liver diseases?

Answer 9

• Loss of lipid droplets
• More prominent RER and Golgi apparatus
• Migrate out of space of Disse and increase metalloprotease production - remodel ECM and increase fibrosis

Question 10

Describe detoxification

Answer 10

• PHASE 1 - Involves enzymes involved in oxidation, reduction and hydrolysis e.g cytochrome P450 enzymes and dehydrogenases.
• Most metabolites from Phase 1 are highly active
• PHASE 2 - Conjugation to other molecules - become more water soluble - cannot cross membranes. More easily excreted

Question 11

Define xenobiotics

Answer 11

Any substance foreign to the body

Question 12

Describe paracetamol detoxification.

Answer 12

• Doesn’t undergo Phase 1 Metabolism
• 45-55% metabolised by glucuronosyltransferase
• 20-30% by sulfotransferase
• Less than 15% - hydrolysis by cytochrome P450 - produces hepatotoxic product NAPQI - conjugated by gultathione S-transferase

Question 13

Why do paracetamol overdoses cause liver damage?

Answer 13

• NAPQI concentrations saturate glutathione S-transferase

Question 14

Describe protein metabolism.

Answer 14

• Deamination - catalysed by deaminases. Requires addition of water. Formation of ammonia.
• Ammonia enters urea cycle and converts to urea for excretion, or transamination where amine group produces non-essential amino acids
• Remaining product - gluconeogenesis

Question 15

Describe plasma protein production and a factor that affects them.

Answer 15

• 90% of production occurs in hepatocytes e.g clotting factors, carrier proteins, hormones
• LIVER DISEASE e.g cirrhosis

Question 16

Describe red blood cell breakdown.

Answer 16

• Done by macrophages called Kupffer cells - broken down into globin and haem groups
• Globin broken down by peptidases into amino acids
• Haem groups broken down into iron - transferred to bone marrow via transferring to make new RBCs
• Rest broken down into biliverdin, then unconjugated bilirubin and then conjugated

Question 17

Describe conjugated bilirubin.

Answer 17

• Excreted into bile ducts and through intestines
• If built up, results in jaundice and results from increased RBC breakdown, bile duct blockage and liver cell damage

Question 18

Describe glucose metabolism. PART 1

Answer 18

• In liver, enters through GLUT2 channel (not insulin dependent)
• Insulin potentiates inward flow of glucose - activates hepatic glucokinase - glucose phosphorylated to G6P
• Enters glycolysis to produce ATP

Question 19

Describe glucose metabolism. PART 2

Answer 19

• Insulin activates glycogen synthase - stimulates glycogenesis, and stimulates glycerol and fatty acid production - triglyceride formation
• Glucagon binds to glucagon receptor (GPCR) - activates intracellular glycogen phosphorylase - glycogen broken down into G1P and then G6P

Question 20

Describe glucose metabolism. PART 3

Answer 20

• Glucagon prevents FFAs becoming triglycerides and direct them to beta-oxidation - enter mitochondria and form ketone bodies
• Ketone bodies only used as energy in muscle, brain and heart

Question 21

Describe bile formation. PART 1

Answer 21

• Bile acids made from conversion of cholesterol to cholic and chenodeoxycholic acid (primary bile acids)
• These travel down biliary tree. Half stored in gall bladder - remainder enters small intestine and travels to ileum
• In ileum - bacteria breaks these down into deoxycholic and lithocholic acid (secondary bile acids)

Question 22

Describe bile formation. PART 2

Answer 22

• In liver, secondary bile acids conjugated with glycine or taurine to produce bile salts - aids in digestion of lipids
• Bile salts stored in gallbladder and released in response to fatty meal or enter small intestine
• In small intestine, bacteria can remove glycine and taurine - turned back into secondary bile acids for reabsorption

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Question 23

Describe the fate of the bile acids.

Answer 23

• 5% lost in faeces
• Majority reabsorbed in hepatic portal vein - secretion and reabsorption circuit known as enterohepatic circulation

Question 24

Describe liver regeneration

Answer 24

• Removal of around 70% of liver results in regeneration to original size
• Considered in liver transplants