Liver

Question 1

What are the exocrine (digestive) functions of the liver?

Answer 1

1 - Synthesis and secretion of bile for digestion and absorption of fats.
2 - Secretes bile into a bicarbonate rich solution that helps neutralise the acid of the duodenum.

Question 2

What are the endocrine functions of the liver?

Answer 2

secretes insulin like growth factor 1 in response to growth hormone. This promotes cell division in a number of tissues including bone.

Question 3

What are the clotting factors of the liver?

Answer 3

1 - Produces many of the plasma clotting factors including prothrombin and fibrinogen.
2 - Bile salts are essential for the absorption of fat soluble vitamin K that is required for the formation of clotting factors in the liver.

Question 4

What role does the liver has with plasma proteins?

Answer 4

The liver synthesizes and secretes proteins including plasma albumin, acute phase proteins, binding proteins for a variety of hormones and lipoproteins.

Question 5

What role does the liver have with metabolism?

Answer 5

1 - Converts plasma glucose to glycogen and triglycerides.
2 - Converts plasma amino acids to fatty acids.
3 - Synthesizes triglycerides and secretes them as lipoproteins.
4 - Produces glucose from glycogen (gluconeogenesis).
5 - Converts fatty acids to ketones during fasting.
6 - Produces urea, the major end product of protein catabolism and releases into the blood.

Question 6

How is the liver involved in cholesterol metabolism?

Answer 6

It synthesizes cholesterol and releases it into the blood and into the bile. It also converts plasma cholesterol into bile salts.

The liver i also a location of iron and vitamin B12 storage.

Question 7

What is the liver divided into?

Answer 7

• 4 lobes; the left, right, caudate (next to inferior vena cava) and quadrate (next to gall bladder).
• The diaphragmatic surface is the superior upper surface.
• The visceral surface faces adjacent abdominal organs - the porta hepatis and gallbladder are located on this surface.

Question 8

Whats the falciform ligament?

Answer 8

It separates the major right and left lobes of the liver. It also attaches the liver to the diaphragmand anterior abdominal wall.

Question 9

Whats the round ligament?

Answer 9

Its a remnant of the umbilical cord found at the lower edge of the falciform ligament.

Question 10

Whats the gall bladder?

Answer 10

An accesory organ to the liver resting in the recess of the inferior visceral surface of the liver.

Question 11

What are the two sources of blood to the liver?

Answer 11

• Hepatic portal vein delivers poorly oxygenated blood from the GI tract.
• Hepatic artery delivers oxygenated blood from the heart.
  These blood vessels divide into two to supply the left and right side of the liver.

Question 12

Describe in more detail the circulation of the liver.

Answer 12

• Oxygenated blood from the aorta enters the hepatic artery (left or right) into the liver delivering 20-25% of the livers blood supply.
• Hepatic portal vein delivers 75-80% of the livers blood supply from the GI tract, Spleen and pancreas - this blood is high in nutrients but low in oxygen.
  In the liver lobules, the two blood sources mix in the central vein, this then drains into the hepatic vein to the inferior vena cava.

Question 13

What’s the functional unit of the Liver?

Answer 13

Lobules - these have a small polyhedral shape made up of cells called hepatocytes. At the edge of each lobule are portal triads formed by the hepatic portal vein, the hepatic artery and the bile duct. Blood flows from the portal triad to the central vein and bile flows toward the portal triad (the bile duct).
Within the liver lobule is a countercurrent flow of blood and bile.

Question 14

What are hepatic sinusoids?

Answer 14

Thin walled leaky capillaries where venous and arterial blood mix as they slowly flow through the hepatic lobe towards the central vein. The hepatic sinusoid is lined with a single layer of fenestrated endothelial cells.
The hepatocytes of the lobules absorb nutrients from blood and produce bile that collects in the small bile canaliculi to the bile duct.

Question 15

What are hepatocytes?

Answer 15

Polarized liver cells that separate sinusoidal blood fron the canalicular bile.
The basal membrane faces the liver sinusoidal endothelial cells while the apical membrane contributes to bile canaliculi jointly with the directly opposing hepatocytes.

Question 16

What is Bile?

Answer 16

An exocrine secretory product of the liver. It contains HCO3-, cholesterol, lecithin, bile pigments and bile salts (important for absorption of water insoluble fats). Biles is stored and concentrated in the gall bladder, it is released during meals, triggered by hormones.

Question 17

Whats the function of the liver sinusoidal endothelial cells?

Answer 17

They filter between the lumen of the hepatic sinusoid and the hepatocytes allowing transfer of small or soluble substrates between blood and the extracellular space of Disse.

Question 18

What are Kupffer cells?

Answer 18

Tissue macrophages in the liver also known as stellate macrophages. They live in the lumen of the sinusoids of the liver, adherent to endothelial cells. They have an important role in host defence.

Question 19

What are stellate cells?

Answer 19

Found in the sub-endothelial space between the basolateral surface of hepatocytes and anti-luminal side of the sinusoidal endothelial cells.
They have spindle shaped bodies with elongated nuclei.
A single stellate cell usually surrounds more than two sinusoids.
Stellate cells are thought to be involved with fibrosis formation.

Question 20

Whats the circulation of bile in the liver?

Answer 20

Bile canaliculi empties bile into bile ductules, then bile ducts then hepatic ducts. It can then either go directly to the duodenum, or it can be diverted to the cystic duct into the gall bladder. The gall bladder concentrates and stores bile ready for use.

Question 21

The gall bladder is a pear shaped accessory organ of the liver. What are the parts of the gall bladder?

Answer 21

• Fundus: the wide end of the gall bladder that projects from the inferior border of the liver.
• Body: The body contacts the visceral surface of the liver.
• Neck: the narrow and tapered end of the gall bladder makes an s bend into the cystic duct. Internally the mucosa spirals into the spiral fold that keeps the cystic duct open.

Question 22

Whats the cystic duct?

Answer 22

Connects the neck of the gall bladder to the hepatic duct.

Question 23

What are cholangiocytes?

Answer 23

Epithelial cells that line the intra and extra hepatic ducts of the biliary tree. They modify bile to generate ductal bile.

Question 24

What controls the release of bile into the small intestine and is stimulated by hormones in response to eating?

Answer 24

The spincter of oddi.

Question 25

Why is cholesterol important in the body?

Answer 25

Cholesterol is important in the synthesis of cell membranes and contributes to the fluidity of membranes.
Cholesterol is also an important precursor for the synthesis of several molecules including vitamin D, cortisol, aldosterone, progesterone, estrogen, testosterone and bile salts.

Question 26

Describe the production of cholesterol.

Answer 26

80% of cholesterol is produced in the liver, synthesized from Acetyl-Co-A in a multi step pathway.

Question 27

How do statins work?

Answer 27

They inhibit HMG-CoA reductase - an enzyme involved in the production of cholesterol hence lowering cholesterol. However this can intervene with further reaction pathways too.

Question 28

Cholesterol is a lipophilic molecule and therefore does not dissolve well in an aqueous environment. How is it transported around the body?

Answer 28

It’s packaged with phospholipids and apolipoproteins to form a series of different lipoproteins allowing it to be transported in the blood. Lipoproteins contain a lipid core (that contains cholesterol esters and triglycerides) and a hydrophilic outer surface containing phospholipids, free cholesterol and apolipoproteins.
The main cholesterol carrying lipoproteins are LDL’s and HDL’s. High levels of LDL’s are bad for you and have been linked to heart disease.

Question 29

Atherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular disease and stroke. High levels of LDL’s have been linked with atherosclerosis. What can be done to prevent this developing?

Answer 29

Take inhibitors of cholesterol synthesis:

• Statins inhibit HMG CoA reductase in the cholesterol synthesis pathway.
• Newer drugs target LDL levels in the body via PCSK9 inhibitors.

Question 30

How are bile salts produced?

Answer 30

The primary or secondary bile acids are conjugated to amino acids to generate water soluble bile salts. Bile salts have hydrophobic and hydrophilic regions that aggregate to form micelles at a critical concentration - they are important for the emulsification of fats.

Question 31

What are the contents of bile?

Answer 31

Bile salts, lecithin, HCO3-, cholesterol, bile pigments and trace metals.

Question 32

How is the volume of bile increased?

Answer 32

The hepatocytes secrete hepatic bile into the bile canaliculi, epithelial cells that line the bile ducts then secrete a bicarbonate rich fluid to increase the volume of the bile. The liver produces 600 to 1000ml of bile per day that’s discharged into the duodenum or stored in the gall bladder.

Question 33

What are bile acids?

Answer 33

The precursor of bile salts.

• Primary bile acids - cholic acid and chenodeoxycholic acid are synthesized in the hepatocytes from cholesterol.
• Secondary bile acids - deoxycholic and lithocholic acid are formed in the intestine from primary bile acids. by the dehydroxylating action of bacterial flora.

Question 34

Describe in more detail how the bile acids are derived.

Answer 34

Starting from cholesterol which breaks down into primary bile acids cholic acid (stored in gall bladder) and chenodeoxycholic acid. These can then produce secondary bile acids which get released into the duodenum: cholic acid produces deoxycholic acid and chenodeoxycholic acid produces lithocholic acid.

Question 35

Whats enterohepatic circulation?

Answer 35

95% of bile salts that enter the intestine are recycled back to the liver via the hepatic portal vein. The bile salts are re-absorbed by a sodium dependent pathway in the ileum.
Uptake of bile salts from the portal blood into hepatocytes occurs via active transport pathways.
The recycling from the GI tract to the liver is known as the enterohepatic circulation

Question 36

How is the release of bile into the small intestine controlled?

Answer 36

The sphincter of oddi is a ring of smooth muscle found where the common bile enters the small intestine.
After consuming fatty acids, the small intestine will produce the peptide hormone cholecystokinin (CCK) - this relaxes the sphincter and contracts the gall bladder allowing bile to be released.

Question 37

What does the gall bladder do to bile?

Answer 37

It concentrates the bile by removal of salts and water - it can increase the concentration of bile salts up to 20 fold.

Question 38

What are bile pigments?

Answer 38

The breakdown product of the heme portion of haemoglobin from erythrocytes broken down in the liver and spleen. Bile contains roughly 0.2% bile pigments, responsible for the green/yellow colour. The major pigment is bilirubin.

Question 39

What plasma proteins does the liver secrete?

Answer 39

• Albumin: a plasma protein that transports lipids and steroid hormones.
• Globulins: alpha and beta globulins also transport lipids and steroid hormones.
• Clotting factors: these are mainly produced in the liver like prothrombin and fibrinogen.

Question 40

What are insulin like growth factors?

Answer 40

An important mediator of Growth Hormone action - the liver synthesizes IGF1 and IGF2 in response to growth hormone. It is structurally similar to proinsulin and has potent growth promoting effects.
- IGF2 is important in fetal and neonatal growth.
IGF1 levels are low in infancy, peak during puberty and decline in adulthood.

Question 41

Drugs are often metabolised in the liver in two stages, what are these 2 stages?

Answer 41

1 - The drug undergoes a reaction to form a derivative.
2 - The derivative undergoes conjugation to form a conjugate. This usually produces a pharmacologically inactive or less lipid soluble product that is eliminated in urine or bile.

Question 42

In phase 1 of the reactions, the cytochrome P450 enzymes are important. How does this impact drug metabolism?

Answer 42

• Population variation in P450 enzymes are important in terms of therapeutics.
• Dietary substances can inhibit (grapefruit juice) or induce (brussel sprouts) P450 enzymes hence impacting drug metabolism.

Question 43

How does clopidogrel work?

Answer 43

Clopidogrel is an anti-thrombotic agent that inhibits platelet activation (involved in blood clotting). It is a pro-drug that requires oxidation - it undergoes a 2 step metabolism using hepatic P450 enzymes to generate the active thiol metabolite which reacts with platelets by binding selectively and irreversibly to P2Y12 receptor on platelet membranes.
The majority of clopidogrel is also inactivated by blood esterases so only 15% is metabolised by the liver.
A 2 step metabolism phase leads to a delayed onset of action.

Question 44

What can be associated with a reduced response to clopidogrel treatment?

Answer 44

Genetic mutations in the P450 enzymes.

Question 45

Paracetamol is an analgesic anti-pyretic drug with a peak plasma concentration at 30-60 minutes. How does it get inactivated?

Answer 45

Paracetamol gets inactivated in the liver by conjugation to glucouronide or sulphate.

Question 46

What is paracetamol toxicity?

Answer 46

When you consume a toxic does of paracetamol (2 to 3 time s max therapeutic dose) you get hepatoxicity and potentially renal toxicity. This is because the normal conjugation pathways become saturated and the drug is metabolised by mixed function oxidases to form N-acetyl-p-benzoquinone imine (NAPBQI) - this is very toxic to cells.

Question 47

What are kupffer cells (other than macrophages of the liver found in hepatic sinusoid)?

Answer 47

The first line of defence against particulates and immunoreactive material passing from the gastointestinal tract via the portal circulation and may be considered as a final component in gut barrier function. They efficiently phagocytise pathogens entering from the blood circulation.

Question 48

What does over activation of kupffer cells lead to?

Answer 48

Inflammation of the liver - hepatitis.