8Cardio - Familial Hypercholesterolaemia - Type 2 disorders

Question 1

What is the basis for Frederickson’s classification of inherited hyperlipoproteinaemias?

Answer 1

Based on accumulated lipoprotein and its electrophoretic mobility:
Alpha lipoproteins: HDL, migrate fastest
Beta lipoproteins: LDL, migrate slowest
Pre-Beta lipoproteins: VLDL, migrate in between alpha & beta

Question 2

What are the features of a type I dyslipidaemia according to Frederickson’s classification?

Answer 2

Elevated chylomicrons, normal to elevated serum cholesterol, very high serum triglyceride level. However, no atherogenicity is seen.

Question 3

What are the features of a type IIa dylipidaemia according to Frederickson’s classification?

Answer 3

Elevated LDL, high serum cholesterol, normal serum tryiglyceride levels. Very high level of atherogenicity is seen.

Question 4

What are the features of a type IIb dyslipidaemia according to Frederickson’s classification?

Answer 4

Elevated LDL and VLDL, high serum cholesterol, high serum triglyceride levels. Very high levels of atherogenicity is seen.

Question 5

What are the features of a type III dyslipidaemia according to Frederickson’s classification?

Answer 5

Elevated IDL, high serum cholesterol, very high serum triglyceride levels. Very high levels of atherogenicity.

Question 6

What are the features of a type IV dyslipidaemia according to Frederickson’s classification?

Answer 6

Elevated VLDL, normal to elevated serum cholesterol, high serum triglyceride levels. Raised levels of atherogenecity.

Question 7

What are the features of type V dyslipidaemia according to Frederickson’s classification?

Answer 7

Elevated VLDL and chylomicrons, normal to elevated serum cholesterol, very high serum triglyceride levels. Raised level of atherogenecity.

Question 8

What the symptoms of the type II disorder - Familal Hypercholesterolaemia?

Answer 8

FH symptoms (from birth)

1) Raised content of LDL lipoprotein in plasma
2) Raised plasma total cholesterol. All carried on LDL as CE
3) Visible cholesterol (ester) deposits - xanthomas etc.
4) Premature atherosclerosis (vascular disease) causing early death from myocardial infarction - coronary arteries

Question 9

Where may cholesterol deposits form in patients with hypercholesterolaemia?

Answer 9

Cholesterol can be deposited in the form of:
Corneal arcs
Xanthelasmas
Tendon xanthomas

Question 10

What did Goldstein and Brown demonstrate in 1974?

Answer 10

In 1974, Goldstein and Brown showed:
LDL bound with high affinity to normal cells but not to cells from FH patients
Binding of LDL suppressed HMG CoA reductase synthesis in normal cells but not in cells from FH patients
Basis of 1985 Nobel Prize for Medicine

Question 11

What is one of the hallmark diagnostic markers for Familial Hypercholesterolaemia?

Answer 11

Decreased removal of LDL (and IDL) particles from plasma compared to patients with a normal phenotype.

Question 12

How is Familial Hypercholesterolaemia and what are its consequences for homozygotes compared to heterozygote?

Answer 12

Due to a mutation in the LDL receptor gene (over 700 mutations known)
Autosomal dominant
Severe in heterozygotes - frequency 1/500
Very severe in homozygotes - occurrence rare 1/106
Higher in certain populations - Ashkenazi Jews 1/67
Compound heterozygotes
Nottm FH:
1 nonsense mutation = truncated protein
1 point mutation, F to S = altered folding
17mM plasma cholesterol

Question 13

What are the features of the LDL receptor gene?

Answer 13

The LDL receptor gene has:
45kb
18 exons and 17 introns
5.3kb mRNA = 860 aa protein
There are over 700 different LDLR mutations known in FH

Question 14

What are the five different classifications of mutations in the LDL receptor gene?

Answer 14

Class 1 = Null mutants = No synthesis
Class 2 = Transport = No transfer from ER to Golgi
Class 3 = Binding = No binding of LDL
Class 4 = Internalisation = No clustering in coated pits
Class 5 = Recycling = No recycling of LDLR

Question 15

What are the main physical features of the LDL receptor?

Answer 15

N-terminal = ligand binding, followed by EGF precursor homology, followed by O-linked sugars, followed by Membrane-spanning region and a cytoplasmic region at the C-terminus.

Question 16

How does the LDL receptor recognise lipoproteins?

Answer 16

Recognises ApoB100 and ApoE
LDL contains ApoB100
IDL contains ApoB100 and ApoE

Question 17

What will be the effect of a mutations in the LDL receptor which cause LDLR to be absent or inactive?

Answer 17

Absent/inactive LDLR (heterozygotes not be able to compensate) may cause:

1) DECREASED REMOVAL OF LDL AND IDL PARTICLES FROM PLASMA (VIA LIVER)
2) INCREASED FORMATION OF LDL FROM INCREASED IDL
3) MASSIVE INCREASE IN PLASMA LDL AND CHOLESTEROL ESTER, INCREASED RESIDENCE TIME OF LDL IN PLASMA AND INTERSTITIAL FLUID AND INCREASED OXIDATION OF LDL IN ARTERIAL INTIMA
4) ENHANCED METABOLISM OF ox-LDL BY SCAVENGER RECEPTOR PATHWAY
5) UNCONTROLLED CE ENTRY TO ARTERY MACROPHAGES AND SMOOTH MUSCLES CELLS, FOAM CELLS ACCUMULATE IN ARTERIAL INTIMA

OVERALL = LACK OF PROTECTION AGAINST ATHEROSCLEROSIS

Question 18

Why does increased formation of LDL from increased IDL occur?

Answer 18

Normally 60% of IDL would be uptaken by the liver; only 40% going to LDL.
LDLR cannot take up LDL or IDL and therefore the higher levels of IDL will be converted to LDL (by losing triacylglyceride).

Question 19

What is the importance of lipid oxidation in atherosclerosis?

Answer 19

15 lipoxygenase can oxidise FA in lipoproteins
But longer:
Covalent modification of Arg/Lys on ApoB100, oxLDL
No binding to LDLR
Ox LDL increased binding recognition to scavenger receptor A (on macrophages)
15 LOX knockout mouse - shows atherogenesis in LDLR knockout mice even when fed a high fat diet

Question 20

How does the role of scavenger receptors contribute to the development of atherosclerosis?

Answer 20

Scavenger receptor class A = binds to modified and oxidised LDL.
SR family are high affinity broad specificity receptors = important in uptake via macrophages.
Scavenger receptor allows unrestricted uptake of LDL/oxLDL into foam cells (LDLR regulated by free cholesterol (SREBPs))
Unrestricted uptake of LDL compared to carefully controlled uptake by LDL receptor

Question 21

How does atherosclerosis develop in patients with Familial Hypercholesterolaemia?

Answer 21

In FH, higher LDL concentration, hence more oxidation = FOAM CELL FORMATION faster than Reverse Cholesterol Transport to HDL.
Unrestricted cholesterol entry
LDL uptake via scavenger pathway overwhelms RCT

Question 22

How do heterozygotes for Familial Hypercholesterolaemia compare to other patients in cardiac care (who do not have the condition)?

Answer 22

Heterozygotes for FH typically have much higher serum cholesterol levels than other cardiac care patients and tend to present clinically at a much younger age. In addition, lifestyle factors such as obesity, hypertension and diabetes which are typically seen in other patients in cardiac care are usually absent from people with FH.

Question 23

How is Familial Hypercholesterolaemia diagnosed?

Answer 23

Symptoms (Xanthomas), Family History of early CHD
Plasma “total cholesterol” elavation:
Heterozygotes: (7.5?)9 to 14 mmol/L
Homozygotes: 17 to 25 mmol/L
Normal = 4-5 mM
Genomic DNA = very good IF family mutation is known

Question 24

What are some of the direct methods of treatment for Familial Hypercholesterolaemia?

Answer 24

LDL apheresis or liver transplant.

Question 25

How does LDL apheresis work?

Answer 25

LDL apheresis
Specific removal of LDL from blood/plasma by passing it through LDL-binding affinity chromatography system (anything that recognises ApoB100)
Aim to keep LDL “cholesterol” (LDLC) below 3.9 mmol/L
Only working method for homozygotes - need treatment weekly
LDLC drops to 0.8 mmol/L but by day 7 has risen to 4 mmol/L

Question 26

What evidence is there that liver transplantation can be effective in the treatment of Familial Hypercholesterolaemia?

Answer 26

Liver transplant (rarely)
Eg. 6 yr old homozygote 
Before total cholesterol = 30mM, multiple heart attacks
After total cholesterol = 8mM
SHOWS CRITICAL ROLE OF THE LIVER

Question 27

What is an example of an indirect method of treatment for Familial Hypercholesterolaemia?

Answer 27

STATIN TREATMENT

Question 28

Why does statin treatment only work for heterozygotes and no homozygotes with Familial Hypercholesterolaemia?

Answer 28

Statins increase transcription of the LDLR to reduce plasma LDL levels. If both copies of the LDLR gene are defective, increasing transcription will not enhance LDL re-uptake in the same way it would for heterozygotes.

Question 29

How does statin treatment work?

Answer 29

Oral drugs that block HMGCoA reductase (HMGR)
Statins inhibit (liver) cholesterol synthesis
Lower regulatory pool of cholesterol in liver
Activate production of SREBP
Increase transcription of LDLR gene [& HMGR gene]
Increase amount of active LDLR [& HMGR but it is inhibited]
DECREASE LDL production & increase destruction of LDL
Statins = very good competitive inhibitors of HMG CoA reductase
LDLC falls dose-dependently

Question 30

What supports the lipid hypothesis of atherosclerosis?

Answer 30

The fact that when serum LDL levels rise so to does the incidence of atherosclerosis.

Question 31

What type of statin could be useful in the treatment of homozygotes with Familial Hypercholesterolaemia?

Answer 31

In homozygotes there is evidence that high doses of the more powerful Atorvastatin can reduce LDLC in homozygotes. How?
Probably due to reduced intracellular cholesterol causing a reduction in liver VLDL secretion, and thus reduced LDL production.

Question 32

What other (inferior) treatments are there for heterozygotes (but not homozygotes) with Familial Hypercholesterolaemia?

Answer 32

Other (inferior) treatments for heterozygotes (not homozygotes):
Increase cholesterol loss to bile and reduce enterohepatic circulation:
a) ileal bypass surgery
b) oral drugs - bile acid sequestrants