Lecture 17: Familial Hypercholesterolaemia

Question 1

Understanding Cholesterol: 3

Answer 1

1* Needed to FORM CELL MEMBRANES and HORMONES

2. • Can be OBTAINED from FOOD or SYNTHESISED IN THE LIVER

3* Some saturated fats (e.g. coconut, palm oil) are CHOLESTEROL-FREE CAUSE an INCREASE IN CHOLESTEROL

Question 2

Lipoprotein - diagram on slide 3

Answer 2

Diagram
- has:

1. Phospholipid
2. Free cholesterol
3. Triglyceride
4. Apolipoprotein
5. Cholesteryl ester

Question 3

Relationship of Serum Cholesterol to Mortality: Seven Countries Study

Answer 3

Diagram on slide 4

Deaths are proportional to the increase of high cholesterol diet

Question 4

Atherosclerosis:

Answer 4

The build-up of fats, cholesterol and other substances in and on the artery walls.

A build up of cholesterol plaque in the walls of arteries, causing obstruction of blood flow.

Plaques may rupture, causing acute occlusion of the artery by clot.

Question 5

Lipoprotein Metabolism

3 types - explain them

Answer 5

1. EXOGENOUS PATHWAY – GUT makes lipoproteins to BRING DIETARY FATS TO THE LIVER
2. ENDOGENOUS PATHWAY – LIVER makes lipoproteins to
   TAKE CHOLESTEROL TO PERIPHERAL TISSUES
3. REVERSE CHOLESTEROL TRANSPORT – HDL brings CHOLESTEROL BACK FROM PERIPHERAL TISSUES

Question 6

Lipoprotein Metabolism

Type of lipoprotein and from where to where?

Answer 6

Diagram on slide 7

Question 7

LDL-Receptor Pathway

Answer 7

1. LDL binding
2. Internalisation
3. Lysosomal hydrolysis
4. Regulatory actions

Diagram on slide 8

Cholesterol receptors
1. Decrease HMG CoA reductase
2. Increase ACAT
3. Cholesterol to cholesteryl oleate
4. Decrease in LDL receptors

Question 8

Hypercholesterolaemia

Primary cause? -2

Secondary cause? -4

Answer 8

• Secondary causes:
1. Diet rich in saturated fats
2. Hypothyroidism
3. Nephrotic syndrome
4. Liver disease

• Primary causes include:
1. Familial hypercholesterolaemia (FH)
2. Polygenic hypercholesterolaemia

Question 9

Case 1 of Familial hypercholesterolaemia

Answer 9

41-year-old female of South African descent, strong family
history of hypercholesterolaemia, ischaemic heart disease
and premature cardiovascular death

Familial hypercholesterolaemia
Heterozygous LDLR

TC 10.3 mmol/L (<5.5)
HDL-C 2.5 mmol/L (>1.0)
TG 2.2 mmol/L (<1.7)
LDL-C 6.8 mmol/L (<3.0)
ApoB 1.95 g/L (<1.0)

Question 10

Familial hypercholesterolaemia Characteristics- 6

Answer 10

1. • Autosomal dominant, affecting ~1:250 (formerly 1:500);
   – Afrikaners, 1:60
2. • >80,000 in Australia
3. • <20% FH diagnosed, <10% adequately treated
4. • DEFECT in the LDL-RECEPTOR PATHWAY leads to RAISED TOTAL AND LDL-CHOLESTEROL
5. • Clinical manifestations COOM AFTER age 20, and include
   CORNEAL ARCUS, XANTHELASMA, TENDON XANTHOMAS, followed by
   development of CORONARY ARTERY DISEASE
6. • LIFELONG TREATMENT with CHOLESTEROL -LOWERING THERAPY
   recommended

Question 11

Clinical Manifestations of FH

Answer 11

These physical signs of FH occur when extra cholesterol builds up in different parts of the body:

• Bumps or lumps around your knees, knuckles, or elbows.
• Swollen or painful Achilles tendon.
• Yellowish areas around your eyes.
• Fatty skin deposits called xanthomas over parts of the hands, elbows, knees, ankles and around the cornea of the eye.

Question 12

Risk of CHD is increased in FH

Answer 12

Men - symptoms and affected after age of 30

Women - symptoms and affected after the age of 40

CHD develops ~20 years earlier than background population

Diagram on slide 13

Question 13

FH exposes people to very high cholesterol from birth,… therefore

Answer 13

FH exposes people to very high cholesterol from birth,

‘who therefore reach a threshold for CHD earlier in life’

Cumulative exposure to cholesterol by age:
FH vs unaffected (healthy) individuals

Diagram on slide 14

Question 14

Dutch Lipid Network - FH Criteria

Answer 14

Table on slide 15

Definite FH: >8 points
Probable FH: 6–8 points
Possible FH: 3–5 points
Unlikely FH: <3 points

CAD = coronary artery disease
LDL-C = LDL-cholesterol
Tx = tendon xanthoma

Question 15

Understanding Autosomal Dominant Hypercholesterolaemia Genes…

Answer 15

• FH is typically caused by mutations in LDLR, APOB, or PCSK9

1. APOB - acts as ligand, binding LDL
   particle to receptor
2. PCSK9 enzyme
   - degrades LDL receptors
3. LDL receptor - on hepatocyte, binds to apoB on LDL
   particle, inducing endocytosis of LDL
   LDL receptor

Diagram on everything works in cell — slide 16

Question 16

FH - Genetics

Caused by: 4

Lab molecular studies: 2

Answer 16

• Autosomal dominant, caused by pathogenic variants
in LDLR, APOB, PCSK9
1 – >2000 described in LDLR (~90%)
2 – Several mutations in APOB (~10%)
3 – Very rare mutations in PCSK9 (~1%)

• Laboratory approach to molecular testing
1 – Sequencing (Sanger or next-generation)
2 – MLPA (deletion/duplication analysis) of LDLR

Question 17

Percentage of FH index cases found to carry a mutation, classified by Dutch Lipid Clinic Score

Answer 17

Table on slide 18

Question 18

Polygenic hypercholesterolaemia:

Answer 18

Having a greater-than-average
number of common, cholesterol-raising genetic variants that, together,
have a large effect on the plasma concentration of LDL-cholesterol

Question 19

hypercholesterolaemia

Answer 19

Diagram on slide 19

Question 20

Why do FH genetic testing? - 5

Answer 20

1. • Assists with diagnosis
2. • For the same level of LDL-C, mutation-positive FH patients have more coronary artery disease
3. • May assist with treatment choice and motivating patients to
   take cholesterol-lowering therapy
4. • Cascade screening using genetic testing is cost-effective
5. • Early identification of relatives with FH avoids death of young productive people and MI rehab

Question 21

Screening for FH using LDL-C
FH
4.44 + 1.43mmol/l
FH vs. Not FH LDL levels, Ages 5-15

Age 45-54

Answer 21

Graph on slide 22 and slide 23

Question 22

Treatment in FH - 6

Answer 22

1. • Treatment is aimed at lowering plasma LDL-cholesterol
2. • Diet and correction of other risk factors
3. • Statin ± other drugs e.g. ezetimibe
4. • Many patients not able to tolerate statins and/or not able to reach LDL targets
5. • PCSK9 inhibitors
6. • Severe FH – LDL apheresis

Diagram on slide 24

Question 23

Homozygous FH - 4

Answer 23

1. • Very rare
2. • LDL-cholesterol 15-25 mmol/L
3. • Coronary atherosclerosis in childhood
4. • Difficult to treat

Question 24

Case 2

Answer 24

• 34-year-old female referred to Lipid Clinic by her cardiologist

• On high dose statin and ezetimibe and aspirin

• No cardiovascular symptoms

• Lipid profile
– TC 18.0 mmol/L (<5.5)
– HDL-C 1.1 mmol/L (>1.0)
– TG 0.7 mmol/L (<1.7)
– LDL-C 16.6 mmol/L (>3.0)

Question 25

Lipoprotein Apheresis

Answer 25

Pre-apheresis
• TC 11.2 mmol/L
• HDL-C 0.8 mmol/L
• TG 1.4 mmol/L
• LDL-C 9.8 mmol/L
• ApoB 2.52 g/L

Post apheresis
• TC 2.7 mmol/L
• HDL-C 0.5 mmol/L
• TG 0.4 mmol/L
• LDL-C 2.0 mmol/L
• ApoB 0.59 g/L

Question 26

Family Cascade Screening

Answer 26

Pedigrees on slide 28

Question 27

World map of Familial hypercholesterolemia

Answer 27

Slide 29 map and diagram

Question 28

FH in Western Australia : 5

Answer 28

1. • ~10,000 people with FH in WA
2. • FHWA - a cascade screening program run by the RPH
3. Lipid Disorders Clinic, designed to detect new cases of FH in families by screening relatives of index cases
   with FH
4. • Early detection and treatment of individuals with FH can delay or prevent the onset of coronary heart disease
5. • National FH Registry

Question 29

FH Cascade Screening -2

Answer 29

1. Index cases have initial consult
   (phenotypic and genotypic assessment)
   – Ongoing medical care through their GP
   where appropriate
2. Participants consenting to cascade
   screening are given the option of
   informing their relatives themselves or
   having FH nurses contact their relatives on
   their behalf

Question 30

FH Cascade Screening

Answer 30

Diagram on slide 31

Question 31

Detecting FH - 6

Answer 31

1. For cascade screening to be successful, we need to find new FH index patients
2. They can be detected by:
3. Cardiology
4. GPs
5. The pathology lab
6. Paediatrics

Question 32

Child-Parent Screening for FH - 4

Answer 32

1. • A study in the UK showed that screening for FH could be done in 1-2-year-olds at immunisation visits (n=10,095); see Wald et al, New Engl J Med 2017
2. • The method screens the child at an age when the measurement of cholesterol is most discriminatory for FH
3. • Genetic testing also performed
4. • If a child with FH is identified, the parent with FH may then be identified
   – For every 1000 children screened, 8 people (4 children and 4 parents) with FH can be identified

Question 33

Child-Parent Screening for FH – WA Pilot Study -6

Answer 33

1. 448 children of 1-2 years of age were screened by capillary
   blood sample, with FH genetic testing performed if total
   cholesterol >95th centile
2. 32 (7.1%) had total cholesterol >5.3 mmol/L
   – …..3. 3 had a pathogenic variant (2 in LDLR, 1 in APOB)
   – …..4. Reverse cascade screening identified a further 5 individuals with FH
3. 8 new FH diagnosed from screening 448
4. This approach was considered acceptable to the parents who
   participated, and is potentially a highly cost-effective detection strategy for FH

Question 34

FH Genetic Testing in Australia

Answer 34

‘FH genetic testing was listed on the Medicare’

• Benefits Schedule in May 2020
  73352 Characterisation of germline variants causing familial
  hypercholesterolaemia (which must include the LDLR, PCSK9 and APOB
  genes), requested by a specialist or consultant physician, for a patient:
  (a) for whom no familial mutation has been identified; and
  (b) who has any of the following:
  (i) a Dutch Lipid Clinic Network score of at least 6;
  (ii) an LDL-cholesterol level of at least 6.5 mmol/L in the absence of
  secondary causes;
  (iii) an LDL-cholesterol level of between 5.0 and 6.5 mmol/L with
  signs of premature or accelerated atherogenesis
  Applicable only once per lifetime
  1,200.00
  73353 Detection of a familial mutation for a patient who has a first- or
  second-degree relative with a documented pathogenic germline gene
  variant for familial hypercholesterolaemia
  Applicable only once per lifetime

Question 35

LDL Genetic Risk Scores - 2

Answer 35

• Not yet in clinical use

• SNP panels vary between labs as well as whether they are simple SNP tallies or weighted scores, as well as what cut-off
is used to designate ‘polygenic’ hypercholesterolaemia

Question 36

Polygenic Hypercholesterolaemia

Answer 36

Red = clinically FH but no
monogenic mutation

Blue = normal population

Diagram on slide 37

Question 37

Summary - 4

Answer 37

1 • ‘Elevated LDL-C is associated with increased risk for CVD’

2. • Familial hypercholesterolaemia is a common ‘monogenic cause of premature CVD’
3. • Genetic testing for FH aids in screening of family members to identify those with FH and, with treatment, prevent CVD

4 • However, FH is under-diagnosed (and under-treated), and the challenge remains to identify FH index cases to facilitate cascade screening