Block A Workshop - Familial Hypercholesterolaemia

Question 1

What is familial hypercholesterolaemia?

Answer 1

Too much cholesterol (LDL) / lipids in the blood caused by genetic factors
(Slide 2)

Question 2

What are atheroma / atheromatous plaques?

Answer 2

Deposits laid down on vascular walls during atherosclerosis that are made of macrophages, debris and cholesterol and are covered with a fibrous cap
(Slide 3)

Question 3

What is atherosclerosis?

Answer 3

A condition in which arteries become narrowed and hardened due to the accumulation of plaque (atheroma) on their inner walls - caused by injury to the endothelium (the inner lining of arteries)
(Slide 3)

Question 4

What happens when atheroma / atheromatous plaques burst?

Answer 4

The material released can block capillaries and cause ischaemia and possibly an infarction on the brain or heart
(Slide 3)

Question 5

What is an infarction?

Answer 5

The death of a tissue due to a lack of blood flow to it

Note: Myocardial infarction = heart attack
(Slide 3)

Question 6

State 5 symptoms of a heart attack.

Answer 6

Answers Include:
Chest pain - (pressure, heaviness tightness or squeezing across chest)

Pain in other areas (can feel like it’s spreading from the chest - into arms etc)

Light-headedness / Dizziness
Sweating

Shortness of breath

Nausea or vomiting

Feeling of anxiety

Coughing / Wheezing

Note: Chest pain is usually severe but in some cases can only be minor.
(Slide 4)

Question 7

State 5 risk factors for Atherosclerotic cardiovascular disease (ASCVD) / coronary heart disease (CHD).

Answer 7

High blood pressure
High Cholesterol
High triglycerides
Smoking / tobacco
Insulin resistance, obesity or diabetes
Inflammation from diseases (such as arthritis) or other unknown causes
Depression
(Slide 5)

Question 8

What are 3 physiological functions of cholesterol?

Answer 8

Vital component of cell membranes
Essential in the production of bile acids
Acts as a precursor of steroid hormones and vitamin D
(Slide 6)

Question 9

What are dietary triglycerides and cholesterol packaged together with?

Answer 9

Apo proteins
(Slide 7)

Question 10

Where are dietary triglycerides and cholesterol packaged together with apo proteins?

Answer 10

In the liver
(Slide 7)

Question 11

What are dietary triglycerides and cholesterol packed together with apoproteins then released into circulation as?

Answer 11

Very low-density lipoproteins (VLDL)
(Slide 7)

Question 12

What does cholesterol form a complex with?

Answer 12

Lipoproteins (to form chylomicrons, VLDL, LDL, IDL and HDL)

Question 13

Can VLDL and LDL be good?

Answer 13

Yes, small amounts of these are normal and are even good as they’re needed to transport cholesterol. Too much leads to issues though.

Question 14

Does HDL or LDL contain a higher percentage of cholesterol?

Answer 14

LDL contains more; HDL contains less and contains more protein, making it more dense.

Question 15

Does VLDL, LDL, or HDL contain the highest percentage of triglycerides?

Answer 15

VLDL contains more, with VLDL becoming LDL and then HDL as triglycerides are transported to the bodies cells
(Slide 8)

Question 16

Explain how VLDL, IDL, and LDL are produced, LDL and HDL’s role in cholesterol transportation, and chylomicron’s role in triglyceride transportation.

Answer 16

1. Chylomicrons carry triglycerides from the small intestine to the body’s cells
2. Chylomicron remnants (have fewer triglycerides) travel to the liver for disassembly
3. VLDL is produced by the liver (via breakdown of chylomicrons) and then brings more triglycerides to the body’s cells
4. VLDL becomes IDL (Intermediate-density lipoprotein) and then cholesterol-rich LDL as triglycerides are removed
5. LDL delivers cholesterol to the body’s cells (good in low amounts but can cause atherosclerosis in high amounts)
6. HDL picks up excess cholesterol and delivers it to the liver for use or disposal
   (Slide 8)

Question 17

VLDL can become IDL and then LDL, but can LDL be converted to HDL?

Answer 17

No

Question 18

Where is HDL primarily synthesised?

Answer 18

The liver

Question 19

State 6 causes of high cholesterol.

Answer 19

Diet
Genetics (Familial Hypercholesterolaemia)
Regular Smoking
Physical Inactivity
Some medications
Having other chronic diseases
(Slide 9)

Question 20

What is the rate-limiting step in cholesterol production?

Answer 20

The conversion of HMG-CoA into mevalonate (mevalonic acid)
(Slide 10)

Question 21

What enzyme catalyses the conversion of HMG-CoA to mevalonate (mevalonic acid)?

Answer 21

HMG-CoA Reductase
(Slide 10)

Question 22

What are the class of drugs that inhibit HMG-CoA Reductase called?

Answer 22

Statins
(Slide 11)

Question 23

What level of LDL is diagnostic for familial hypercholesterolaemia?

Answer 23

Above 190 mg/dl
(Slide 12)

Question 24

Familial hypercholesterolaemia is autosomally dominant; what does this mean?

Answer 24

That the gene that causes the condition is located on a non-sex chromosome (known as an autosome), and that 1 bad copy from a parent is enough to cause the condition

Question 25

Does having 2 bad copies of the gene that causes familial hypercholesterolaemia make the condition worse?

Answer 25

Yes, it results in an even more elevated level of cholesterol, leading to an increased risk of a heart attack from childhood

Question 26

Does removing (and re-adding) LDL affect HMG-CoA reductase activity—and what does this mean?

Answer 26

No, removing and re-adding LDL doesn't affect HMG-CoA reductase activity. This means the Michaelis constant of the familial hypercholesterolaemia and the wild-type enzymes are the same, meaning the condition does not directly affect activity and must affect something else to do with how the enzyme acts (Slides 13 and 14)

Question 27

What is the Michaelis constant?

Answer 27

The concentration of a substrate at which an enzyme reaction reaches half of its maximum rate. It is a measure of the enzyme's affinity for the substrate, with a low Michaelis constant indicating a high affinity. (Slide 14)

Question 28

What are most cases of familial hypercholesterolaemia caused by?

Answer 28

A mutation in the LDL receptor gene, leading to fibroblasts not recognising LDL, and fewer LDL being removed from the bloodstream (Slides 15 and 16)

Question 29

How is LDL cleared from the bloodstream normally?

Answer 29

1. LDL binds to LDL receptors on the surface of fibroblasts 2. LDL is then internalised via endocytosis 3. After internalisation, the LDL particle is transported to lysosomes where it is broken down, releasing cholesterol into the cell 4. Cholesterol levels in the cell regulates the activity of HMG-CoA; when there is enough cholesterol, its activity decreases, resulting in less cholesterol being synthesised (Slide 16)