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2. Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Heterozygous familial hypercholesterolaemia (FH)
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3. Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Pathophysiology & genetics
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4. Pathophysiology of heterozygous familial hypercholesterolaemia.
Pathophysiology of heterozygous familial hypercholesterolaemia. LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9.
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5. Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
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
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Heterozygous familial hypercholesterolaemia

6. LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy.
LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy. Data derived from Huijgen et al.20 and Starr et al.21 LDL, low-density lipoprotein; LDL-C, LDL cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease; FH, familial hypercholesterolaemia.
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7. Coronary disease & death before age 20
Untreated coronary disease before age 55/60
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

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Underdiagnosis & undertreatment
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9. 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.
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. As most countries do not have valid nationwide registries for familial hypercholesterolaemia, several values in this figure represent informed estimates from clinicians/scientists with recognized expertise in and knowledge of familial hypercholesterolaemia in their respective countries. Numbers were provided by Michael Livingston, Steve E. Humphries (UK), Olivier S. Descamps (Belgium).
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10. Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
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 country 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, , ,600 92,200 22,200 10,900 11, ,00045,000 14, ,900 46, ,000 5, ,200 68, ,800 34, , ,900
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~ 200 countries or territories in the World
Numbers from Livingston, Descamps & Humphries

11. 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.
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. Based on individuals. This was originally reported as 1/137 but recalculation suggested that the prevalence of definite or probable familial hypercholesterolaemia combined is closer to 1/200 (personal communication Børge G Nordestgaard). FH, familial hypercholesterolaemia. Adapted from Benn et al.10
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12. Dutch Lipid Clinic Network criteria: Definite or probable FH
Screening 69,000 persons from the Copenhagen General Population Study
Adapted from Benn et al J Clin Endocrin Metab 2012; 97:

13. Estimated millions of individuals worldwide with familial hypercholesterolaemia by WHO regions and by income groups.
Estimated millions of individuals worldwide with familial hypercholesterolaemia by WHO regions and by income groups. Estimates are shown for the theoretical frequency of heterozygous familial hypercholesterolaemia of 1/500 in the general population,1 as well as for the directly detected frequency of ∼1/200 in the Danish population,10 a typical country in Northern Europe.
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15. 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.
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. Data are based on individuals from the Copenhagen General Population Study. CI, confidence interval; FH, familial hypercholesterolaemia; CHD, coronary heart disease = ischaemic heart disease. Adapted from Benn et al.10
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Whom to screen:
how to find index cases?
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17. 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
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18. Family pedigree 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
Man
Woman
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19. DUTCH FH CRITERIA

20. Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
Clinical diagnosis versus mutation diagnosis
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21. Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia.
Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia. This figure illustrates the fractions of three different clinical scenarios in a study from Spain,18 and therefore not necessarily the exact proportions for these three groups in other countries. ‘Mutation without clinical diagnosis’ means definite, probable, or possible familial hypercholesterolaemia with a familial hypercholesterolaemia-causing mutation but with less severely elevated LDL cholesterol (i.e. below the diagnostic threshold). LDL, low-density lipoprotein cholesterol; FH, familial hypercholesterolaemia.
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22. Adapted from Luis Masana
Clinical diagnosis
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

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Cascade screening preferred method
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24. Pedigree of a family with familial hypercholesterolaemia.
Pedigree of a family with familial hypercholesterolaemia. Red and green colours indicate family members with and without heterozygous familial hypercholesterolaemia. CHD, coronary heart disease; LDL, low-density lipoprotein; FH, familial hypercholesterolaemia.
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25. Family pedigree 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
Man
Woman
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26. 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
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LDL lowering treatment
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28. 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
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29. Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < for difference).
Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < for difference). Based on 413 and 1537 Dutch subjects with heterozygous familial hypercholesterolaemia on or off statin treatment. CHD, coronary heart disease; FH, familial hypercholesterolaemia. Adapted from Versmissen et al.3
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© The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

30. Adapted from Vermissen et al. BMJ 2008; 337: a2423

31. Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490
In addition to lifestyle and dietary counselling, treatment priorities are
Children (from age 8-10):
Statin
Ezetimibe
Bile acid binding resin
Lipoprotein apheresis in homozygotes
Adults:
Maximal potent statin dose
Bile acid binding resins
Lipoprotein apheresis in homozygotes & treatment-resistant heterozygotes with CHD
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32. Summary of diagnostic and treatment strategies.
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© The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

33. 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.
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