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Familial hypercholesterolaemia
(FH)
Dr Callum Livingstone
Consultant Chemical Pathologist
Royal Surrey County Hospital
Low density lipoprotein (LDL)
LDL receptor
Familial hypercholesterolaemia (FH)
• Defective LDL-receptor gene
• AD inheritance
• Prevalence 1/500 (heterozygous), F = M
Clinical features
• Hypercholesterolaemia
• Premature CHD and PVD
• Family history of CHD
• Tendon xanthomata
• Aortic stenosis
FH is a monogenic disorder !
Tendon xanthomata
Corneal arcus
Diagnostic criteria (Simon Broome)
Definite FH
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Serum cholesterol
>6.7mmol/L in children
>7.5mmol/L in adults
plus
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Tendon xanthomata in the patient or first or second degree relative
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or genetic defect confirmed on testing
Possible FH
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Cholesterol concentrations as above
plus
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Family history of MI below 50 years in a second degree relative or
60 years in a first degree relative
or
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Family history of hypercholesterolaemia in a first or second degree
relative
NICE, 2008
Diagnostic criteria for relatives
NICE, 2008
CHD risk calculation
Framingham underestimates CHD risk in FH
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Male 35 years
TC 8.0 mmol/L
‘Possible’ FH by S/B criteria
HDLC 2.0 mmol/L
TC:HDLC 4.0
Non-diabetic
Non-smoker
BP 120/80 mmHg
Factors influencing phenotype
• Genetic
– Specific mutations leading to FH phenotype (>800)
– Factors influencing lipoprotein metabolism
– Gender
• Metabolic
– Hormonal
– Body weight
– Other vascular risk factors
• Environmental
– Diet
– Behavioural factors
– Lipid lowering treatment
Assessment of the
hyperlipidaemic patient
• Clinical examination
– vascular risk factors
– seek stigmata of hyperlipidaemia
– seek evidence of vascular disease
• Exclude secondary causes
• Assess vascular risk
Cardiovascular risk factors
Non-modifiable
Modifiable
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Family history
Previous MI
Age
Gender
Smoking
Hypertension
Diabetes
Raised LDLC
Low HDLC
Sedentary lifestyle
Obesity
Hyperfibrinogenaemia
Raised haematocrit
Hyperhomocysteinaemia
Secondary causes of hyperlipidaemia
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Hypothyroidism
Nephrotic syndrome
Renal failure
Cholestasis
Alcohol excess
Diabetes
Drugs
- TSH
- urinalysis
- UE
- LFTs,
- GGT, MCV
- glucose, HbA1c
Management of FH
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Treat other vascular risk factors
Give lifestyle advice
Treat lipids to target
Arrange regular follow-up
Screen relatives
Genetic testing
Lipid lowering treatment
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Statins
Cholesterol uptake inhibitors (Ezetimibe)
Resins
Fibrates
Nicotinic acid derivatives (Tredaptive)
Combination therapy
Adverse effects of statins
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Myositis
Deranged LFTs
GI symptoms
Sleep disturbance
Hair loss
Headache
( CK)
( ALT)
Screening for FH
• Population screening
• Screening in the clinical setting
• Screening relatives (cascade testing)
Homozygous FH
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Prevalence 1/106 (1/4 x 5002)
No functioning LDL receptor
Xanthomata early and atypical sites
CHD in childhood
Statins poorly effective
Need LDL apheresis
Possible future treatment with ApoB100 antisense
oligonucleotides
Calculation of [LDLC]
c[LDLC ]= [total chol] – [HDLC] – [trig]/2.2
Beware of spurious results !
References
• Identification and management
cholesterolaemia. NICE, 2008
of
familial
hyper
• Wierzbicki AS et al. Familial hypercholesterolaemia:
summary of NICE guidance. BMJ 2008; 337: 509-510.
• Bhatnagar D. Diagnosis and screening for familial
hypercholesterolaemia: finding the patients, finding the
genes. Ann Clin Biochem 2006; 43: 441-456.