eur heart j 2013; 34: 3478-3490.. heterozygous familial hypercholesterolaemia (fh) nordestgaard et...
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Eur Heart J 2013; 34: 3478-3490.
Heterozygous familial
hypercholesterolaemia (FH)
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Pathophysiology & genetics
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Pathophysiology of heterozygous familial hypercholesterolaemia.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Atherosclerosis
Myocardial infarction
Angina pectoris
Elevated LDL cholesterol
Mutations in LDL receptor, apolipoproteinB or PCSK9
Liver with only 50% functional LDL receptors
Coronary heart disease
Heterozygous familial hypercholesterolaemia
Nord
estgaard et al. E
ur H
eart J 2013; 34: 3478-3490
LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
35yrs
53yrs
48yrs
55yr
12.5yrs
Start high dose statin
Start low dose statin
Threshold for CHD
Female sex
Smoking Hypertension
Diabetes Triglycerides
HDL-C Lipoprotein(a)
Without FH
Homozygous FH Heterozygous FH
Age in years
Adapted from Steve Humphries 2013
Coronary disease & death before age 20
Untreated coronary disease before age 55/60
Underdiagnosis &
undertreatment
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Estimated per cent of individuals diagnosed with familial hypercholesterolaemia in different countries/territories, as a fraction of those theoretically predicted based on a frequency of
1/500 in the general population.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Netherlands Norway
Iceland Switzerland
UK Spain
Belgium Slovak Republic
Denmark South Africa Australia Hong Kong
France Taiwan
Italy Oman
USA Canada Japan Chile Brazil
Mexico
Diagnosed FH (estimated), % of estimated number in country0 25 50 75 100
Number of FH (estimated based on 1/500) Diagnosed FH (estimated)71% 43% 19% 13% 12%
6% 4% 4% 4% 3%
1% 1% 1%
<1% <1% <1% <1% <1% <1% <1% <1% <1%
33,300 9,900
600 15,600
123,600 92,200 22,200 10,900 11,100
100,00045,000 14,100
130,900 46,300
121,000 5,700
621,200 68,600
254,800 34,300
381,500 214,900
Numbers from Livingston, Descamps & Humphries
~ 200 countries or territories in the World
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Prevalence of definite or probable familial hypercholesterolaemia according to Dutch Lipid Clinic Network Criteria in the Copenhagen General Population Study by 20-year age groups
and by gender.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Adapted from Benn et al J Clin Endocrin Metab 2012; 97: 3956-3964
Dutch Lipid Clinic Network criteria:Definite or probable FH
Screening 69,000 persons from the
Copenhagen General Population Study
Estimated millions of individuals worldwide with familial hypercholesterolaemia by WHO regions and by income groups.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Risk of coronary heart disease as a function of the Dutch Lipid Clinic Network Criteria for a diagnosis of familial hypercholesterolaemia in individuals on or off statin from the general
population.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Whom to screen:
how to find index cases?
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
We recommend:
children, adults, and families should be screened for FH if
• Family member presents with FH• P-cholesterol in adult ≥8mmol/L (≥310mg/dL) • P-cholesterol in child ≥6mmol/L (≥230mg/dL)• Premature CHD• Tendon xanthomas• Sudden premature cardiac death
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Death 76 yrs No CHD LDL 3.8 mmol/L
Age 78 yrs CHD 58 yrs LDL 7.4 mmol/L
Age 48 yrs CHD 48 yrs LDL 8.3 mmol/L
Age 47 yrs No CHD LDL 2.4 mmol/L
Age 50 yrs No CHD LDL 3.3 mmol/L
Index case: start of cascade screening
Age 18 yrs LDL 2.2 mmol/L
Age 8 yrs LDL 5.6 mmol/L
Age 15 yrs LDL 6.1 mmol/L
FH FH
FH
FH
Man Woman
Family pedigree
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
DUTCH FH CRITERIA
Clinical diagnosis versus
mutation diagnosis
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Clin
ical
dia
gnos
is
Mutation diagnosis
Mutation without clinical diagnosis
Clinical diagnosis without mutation
Patient: treat LDL Family: monitor LDL & consider treatment
Patient: treat LDL Family: mutation test, monitor LDL, & consider treatment
Patient: monitor LDL & consider treatment Family: monitor LDL & consider treatment
Adapted from Luis Masana
Cascade screening preferred method
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Pedigree of a family with familial hypercholesterolaemia.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Death 76 yrs No CHD LDL 3.8 mmol/L
Age 78 yrs CHD 58 yrs LDL 7.4 mmol/L
Age 48 yrs CHD 48 yrs LDL 8.3 mmol/L
Age 47 yrs No CHD LDL 2.4 mmol/L
Age 50 yrs No CHD LDL 3.3 mmol/L
Index case: start of cascade screening
Age 18 yrs LDL 2.2 mmol/L
Age 8 yrs LDL 5.6 mmol/L
Age 15 yrs LDL 6.1 mmol/L
FH FH
FH
FH
Man Woman
Family pedigree
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
LDL cholesterol targets:(heterozygous & homozygous FH)
•<3.5mmol/L(<135mg/dL) for children
•<2.5mmol/L(<100mg/dL) for adults
•<1.8mmol/L(<70mg/dL) for adults with known CHD or diabetes
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
LDL lowering treatment
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Based on a consensus of •opinions of experts •small studies, retrospective studies, and registries
However•effect of LDL cholesterol lowering in individuals without FH based on: randomised trials and meta-analyses
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < 0.001 for difference).
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Cumulative event-free survival (%) in FH
0
100 80 60 40 20
0 Follow-up (years)
5 10
No statin treatment
Statin treatment
Adapted from Vermissen et al. BMJ 2008; 337: a2423
In addition to lifestyle and dietary counselling, treatment priorities are
Children (from age 8-10):1.Statin2.Ezetimibe3.Bile acid binding resin4.Lipoprotein apheresis in homozygotesAdults:1.Maximal potent statin dose2.Ezetimibe3.Bile acid binding resins4.Lipoprotein apheresis in homozygotes & treatment-resistant heterozygotes with CHD
Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Summary of diagnostic and treatment strategies.
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
Disclosures
Supported by unrestricted educational grants to EAS from Amgen, Aegerion, AstraZeneca, Genzyme, Hoffman-La Roche, Kowa Europe, Novartis, and Sanofi-Aventis/Regeneron. These companies were not present at the Consensus Panel meetings, had no role in the design or content of the Consensus Statement, and had no right to approve or disapprove the final document.
Eur Heart J 2013; 34: 3478-3490.