Lecture 17: Familial Hypercholesterolaemia Flashcards by lucy hemp

Understanding Cholesterol: 3

1* Needed to FORM CELL MEMBRANES and HORMONES

- 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

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Lipoprotein - diagram on slide 3

Diagram
- has:

Phospholipid
Free cholesterol
Triglyceride
Apolipoprotein
Cholesteryl ester

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Relationship of Serum Cholesterol to Mortality: Seven Countries Study

Diagram on slide 4

Deaths are proportional to the increase of high cholesterol diet

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Atherosclerosis:

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.

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Lipoprotein Metabolism

3 types - explain them

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

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Lipoprotein Metabolism

Type of lipoprotein and from where to where?

Diagram on slide 7

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LDL-Receptor Pathway

LDL binding
Internalisation
Lysosomal hydrolysis
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

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Hypercholesterolaemia

Primary cause? -2

Secondary cause? -4

• 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

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Case 1 of Familial hypercholesterolaemia

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)

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Familial hypercholesterolaemia Characteristics- 6

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

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Clinical Manifestations of FH

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.

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Risk of CHD is increased in FH

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

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

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

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Dutch Lipid Network - FH Criteria

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

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Understanding Autosomal Dominant Hypercholesterolaemia Genes…

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

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

Diagram on everything works in cell — slide 16

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FH - Genetics

Caused by: 4

Lab molecular studies: 2

• 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

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

Table on slide 18

Polygenic hypercholesterolaemia:

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

hypercholesterolaemia

Diagram on slide 19

Why do FH genetic testing? - 5

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

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

Age 45-54

Graph on slide 22 and slide 23

Treatment in FH - 6

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

Diagram on slide 24

Homozygous FH - 4

• Very rare
• LDL-cholesterol 15-25 mmol/L
• Coronary atherosclerosis in childhood
• Difficult to treat

Case 2

• 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)

Lipoprotein Apheresis

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

Family Cascade Screening

Pedigrees on slide 28

World map of Familial hypercholesterolemia

Slide 29 map and diagram

FH in Western Australia : 5

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

FH Cascade Screening -2

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

FH Cascade Screening

Diagram on slide 31

Detecting FH - 6

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

Child-Parent Screening for FH - 4

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

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

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 5. 8 new FH diagnosed from screening 448 6. This approach was considered acceptable to the parents who participated, and is potentially a highly cost-effective detection strategy for FH

FH Genetic Testing in Australia

‘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

LDL Genetic Risk Scores - 2

• 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

Polygenic Hypercholesterolaemia

Red = clinically FH but no monogenic mutation Blue = normal population Diagram on slide 37

Summary - 4

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