Liver physiology

Question 1

What is the largest organ in the body?

Answer 1

Liver which is usually 1.2-1.5kg in weight in an average adult

Question 2

Describe the basic structural features of the liver.

Answer 2

The liver contains both a left and a right lobe and within each of the lobes there are eight segments known as lobules.

Each liver lobule contains a collection of hepatocytes and other cells in a hexagonal shape centred around the central vein.

Question 3

Describe in depth the vasculature of the hepatic lobules.

Answer 3

Each of the eight liver lobules on either lobes of the liver form a hexagonal cylinder shape. Running through the centre of each cylinder is a central vein.
On the edge of each hexagonal cylinder is the portal triad, meaning that each lobule is supplied with a branch of the hepatic artery, a branch of the hepatic portal vein and a bile duct.
Nutrients and oxygen diffuse from the hepatic artery and the hepatic portal vein into blood vessels becoming smaller and smaller which form Sinusoidal capillaries. As the blood vessels approach the inner centre of the lobules these Sinusoidal capillaries converge to form the central vein which transports now the deoxygenated blood back to the heart via the inferior vena cava.

Question 4

How is bile transported through the liver lobules?

Answer 4

Bile canaliculi run between rows and layers of hepatocytes. This is a thin tube that collects the synthesised and secreted bile from hepatocytes. These canaliculi gather at the bile duct as part of the portal triad.

Question 5

Describe the cell type within the liver lobules.

Answer 5

Liver lobules are mainly compromised of the functional unit of the liver, known as hepatocytes.
Resident hepatic macrophages known as Kupffer cells are also found in the liver. As part of the reticuloendothelial system these are involved in phagocytosis of any present foreign bacterium.
Fibroblasts and hepatic stellate cells are also found and support the function of the hepatocytes.

Question 6

Out of the cells found in the liver lobules which are responsible in the progression of liver disease?

Answer 6

Both acute and chronic liver injuries are characterised by a dramatic expansion of the hepatic macrophage population (including Kupffer cells) which produce pro-inflammatory cytokines. There upregulation is seen in fatty liver, as well as hepatitis and cirrhosis.

In chronic liver injury, a type of hepatic macrophage Ly-6C+ triggers hepatic stellate cell activation and promote myofibroblast production of extracellular matrix through releasing pro-fibrotic mediators.

Hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis

Question 7

Describe the blood supply to the liver.

Answer 7

The liver receives oxygenated blood from the heart specifically from the aorta. The aorta branches into left and right hepatic arteries supplying both the left and right lobes of the liver respectively.
The hepatic vein carries deoxygenated blood from the liver to the heart entering through the inferior vena cava.
The additional blood vessels supplying the liver is known as the hepatic portal vein which carries oxygen poor but nutrient rich blood from the GI tract to the liver, ensuring any absorbed contents is not toxic before entering systemic circulation.

Question 8

Aside from blood supply what else is found to drain from the liver?

Answer 8

Bile ducts which are long tube like structures are found in the liver. These bile ducts join to form the common bile duct and eventually the gall bladder which stores bile. This is part of the biliary system.

Question 9

What percentage of the cardiac output does the liver receive?

Answer 9

25% of the resting cardiac output, hence this means that 25% of the total blood is within the liver at one time.

Question 10

Does the hepatic artery or the hepatic portal vein supply more blood to the liver?

Answer 10

Hepatic portal vein supplies 75% of the liver’s total blood whereas the hepatic artery only supplies 25%.

Remember the hepatic artery is oxygen rich whereas the hepatic portal vein is nutrient rich.

Question 11

List the different functions of the liver.

Answer 11

The liver is involved in:
Metabolism
Storage
Detoxification
Transport
Excretion
Catabolism
Synthesis
Immunity
Activation

Question 12

Describe how the liver is involved in carbohydrate storage and metabolism,

Answer 12

Firstly the liver is involved in storage, for example to prevent hyperglycaemia glucose is stored as glycogen which is not as effective due to requiring presence of water so takes up a lot of space and is not as energy dense as fat.
In periods of fasting, glycogenolysis occurs breaking down the stored glycogen to glucose for uptake into the brain.
Gluconeogenesis can also occur during fasting in which glucose is made from fatty acids and amino acids which also occurs in the liver.

Question 13

Describe how the liver is involved in lipid storage and metabolism.

Answer 13

Hepatocytes in the liver are responsible for 85% of our total cholesterol, with the remaining being from dietary sources. Cholesterol is transported around the body in the form of lipoproteins LDL, VDL and HDL also synthesised in the liver.

Question 14

Describe how the liver is involved in protein storage and metabolism.

Answer 14

The liver is responsible for the synthesis of non-essential amino acids. Hepatocytes are responsible for the breakdown of ammonia from amino acids to urea which can then be excreted in the urine.

Question 15

Explain the liver’s role in detoxification and degradation.

Answer 15

Firstly, as previously mentioned, hepatocytes are responsible for the conversion from ammonia to urea, which is the major route of nitrogenous waste through urine and sweat.

However the liver is also responsible for detoxifying drugs and xenobiotics in a two phase metabolism process.

Question 16

Describe phase I and phase II metabolism which occurs in the liver.

Answer 16

Phase I reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. The most abundant enzyme involved in this reaction are the CYP 450 enzymes
Phase II reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation or sulfate.

Question 17

What factors influence the rate of drug metabolism?

Answer 17

Age - as we get older the enzymes do not work as well as they previously did, meaning drug metabolism is slower. This can lead to complications as you take more medications are you get older.

Nutrition - nutrients within the diet compete with the CYP 450 enzymes for metabolism altering the rate of drug metabolism.

Genetics - genes alter the polymorphisms present in each of the enzymes which affect how effective these enzymes are able to perform metabolism.

Question 18

Which hormones are modified by the liver?

Answer 18

The liver is responsible for:
- Converting Vitamin D3 to 25-hydroxyvitamin D3 before it is transported to the kidney and undergoes a second hydroxylation step to become the active 1,25-hydroxyvitamin D3.
- Converting the thyroid hormone from T4 to the more potent T3.
- Hepatocytes produce insulin like growth factor which modify the action of growth hormone.

Question 19

Which hormones are degraded by the liver?

Answer 19

Insulin and glucagon
Oestrogens, glucocorticoids, growth hormone and parathyroid hormone
Gastrin and other GI hormones (although kidney is responsible for degrading more of these)

Question 20

Which nutrients are stored in the liver?

Answer 20

Fat
Glycogen
Trace elements - copper and iron

Fat soluble vitamins (such as A, D and K) which are stored for long periods
Water soluble vitamins (Vitamin B) which is stored for short periods except for Vitamin B12 which can be stored for longer periods.

Question 21

What happens to fat storage in liver disease?

Answer 21

In obesity there is a higher proportion of body fat, the amount of fat which is uptaken by the liver is also higher which can lead to fatty liver disease, the earliest stage of liver disease. Whilst this is reversible intervention is required here to prevent progression of liver disease.

Question 22

Which are the hormones that are synthesised in the liver?

Answer 22

Insulin-like growth factor
Thrombopoietin - which stimulates platelets

Question 23

Which are the plasma protein that are synthesised in the liver?

Answer 23

Coagulation factors
Transport for cholesterol (lipoproteins)
Transport for steroid and thyroid hormones
Angiotensinogen which is important in the renin-angiotensin system for salt conservation.

Question 24

Which proteins involved in iron transport and metabolism are synthesised in the liver?

Answer 24

Transferrin (transports iron)
Haptaglobin (binds free haemoglobin)
Hemopexin (binds free heme in the blood)
Hepcidin (inhibits iron uptake in the gut)

Question 25

What are the complications associated with free iron in the blood?

Answer 25

It is a pro-oxidant so can damage vasculature leading to CVD

In times of infection, bacterium love to take up free iron to aid their proliferation. These are released as acute phase proteins (also synthesised in the liver) to minimise free iron in the period during the inflammatory response.

Question 26

What are the acute phase proteins that are synthesised in the liver?

Answer 26

Fibrinogen
C-reactive protein
Haptoglobin
Serum amyloid A
Complement proteins

Question 27

Which bile acids are synthesised in the liver?

Answer 27

Both primary and secondary bile acids.
Primary bile acids include cholic acid and chenodeoxycholic acid.
Secondary bile acids include deoxycholic acid and lithocholic acid.

Question 28

What is bile?

Answer 28

It is an aqueous alkaline fluid which contains bile salts, cholesterol, lecithin and bilirubin.
Bile is stored and concentrated in the gall bladder and in response to a meal enters the duodenum.

Question 29

What are specifically bile salts?

Answer 29

Derived from cholesterol, bile salts alongside lecithin acts as emulsifiers which convert large fat globules to a liquid emulsion of micelles (hydrophobic core with hydrophilic shell). Micelles increase the surface area which enables lipase to act.
Bile salts and lecithin have both a water and lipid soluble portion enabling micelle formation.

Question 30

After bile salts work in the GI tract what happens to them?

Answer 30

95% of bile salts are reabsorbed in the terminal ileum in which they are transported back to the liver by the hepatic portal vein for them to be reused.
The remaining 5% is loss in the faeces this includes a component known as bilirubin which is a breakdown product of heme from red blood cell degradation.

Question 31

Describe the process of heme breakdown.

Answer 31

Macrophages of the reticuloendothelial system including resident macrophages such as the Kupffer cells in the lobules as well as macrophages in the tissue, spleen produce haem-oxygenase I to bilirubin.
The unconjugated bilirubin is transported through the blood complexed to albumin to the liver. There it is taken up via facilitated diffusion by the liver and conjugated with glucuronic acid which secreted in the bile.
In the colon of the intestine, glucuronic acid is removed by bacterium and the resulting bilirubin is converted to urobilinogen.
Some urobilinogen is reabsorbed and enters the hepatic portal vein and enters the enterohepatic urobilinogen cycle. Eventually it is oxidised by intestinal bacterium to brown stercobilin.
The remaining urobilinogen is transported by blood to the kidney where it is converted to urobilin (responsible for giving urine its yellow colour) and is excreted.

Question 32

Describe the immunological function of the liver.

Answer 32

Mainly carried out by the reticuloendothelial system comprised of:
Macrophages (Kupffer cells) which phagocytose and degrade bacterium and other antigens from the GI tract carried from the hepatic portal vein.
There is also the hepatic stellate cells which are antigen presenting cells.
Also other immune cells which are present but others like monocytes and neutrophils which can infiltrate inwards.