eur heart j 2013; 34: 3478-3490.. heterozygous familial hypercholesterolaemia (fh) nordestgaard et...

Eur Heart J 2013; 34: 3478-3490.

Heterozygous familial

hypercholesterolaemia (FH)

Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490

Pathophysiology & genetics


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.



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


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.



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


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.



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.



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.



Whom to screen:

how to find index cases?


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


Death 76 yrs No CHD LDL 3.8 mmol/L

Age 78 yrs CHD 58 yrs LDL 7.4 mmol/L


Age 47 yrs No CHD LDL 2.4 mmol/L


Index case: start of cascade screening

Age 18 yrs LDL 2.2 mmol/L



FH FH

FH

FH

Man Woman

Family pedigree


DUTCH FH CRITERIA

Clinical diagnosis versus

mutation diagnosis


Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia.



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


Pedigree of a family with familial hypercholesterolaemia.



Death 76 yrs No CHD LDL 3.8 mmol/L





Index case: start of cascade screening




FH FH

FH

FH

Man Woman

Family pedigree


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


LDL lowering treatment


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


Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < 0.001 for difference).



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


Summary of diagnostic and treatment strategies.



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.

eur heart j 2013; 34: 3478-3490.. heterozygous familial hypercholesterolaemia (fh) nordestgaard et...

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