3. Banker 31
• Asymptomatic
• Non-smoker
• 124/62
• Father died MI 49,
paternal uncle angina 52,
paternal grandfather
sudden death 54
• 2 sons aged 6 and 3
• 2 brothers and 1 sister
TC 9.8 HDL 1.4 TG 1.1
4.
5. Prevalence of 10
Dyslipidaemias
Hypercholesterolaemia
Polygenic (common, 1 in 50)
Heterozygous FH (HeFH) (approx. 1 in 500)
Homozygous FH (HoFH) (approx. 1 in 1,000,000)
Hypertriglyceridaemia
Familial lipoprotein lipase deficiency (approx. 1 in 1,000,000)
Familial apolipoprotein CII deficiency (approx. 1 in 1,000,000)
Familial hypertriglyceridaemia (approx. 1 in 100)
Combined Hyperlipidaemia
Familial combined hyperlipidaemia (approx. 1 in 100)
Familial type III hyperlipidaemia (approx. 1 in 5,000)
6. It is Common - Frequency FH ~1/500 120,000 in UK
It is underdiagnosed < 15,000 known, particularly in the < 35 years
group (600/14,000 children)
How Common is FH ?
Same as childhood diabetes
0
20000
40000
60000
80000
100000
120000
140000
2000 2004 2008 2012 2016 2020
NumberFHknown
Survey UK Lipid Clinics
Missing >85%
of predicted
Marks, et al 2004
HEARTUK 2008
Neil, et al BMJ 2000
8. 0
50
100
150
200
250
300
350
0 15 25 35 45 55 65 75
Age (years)
LDL-CBurden(mmol/l-yrs)
FH Non FH
LDL- C Burden in FH patients
By 45yrs FH patient has accumulated LDL-C exposure of non- FH 70yr
old, explaining high CHD risk and need for aggressive lipid-lowering
FH patients have high LDL-C from Birth high LDL-C BURDEN
Like smoking
pack-years
LDL - Burden =
LDL-C level x
years exposure
Starr et al 2008
9. Can LDL-C be lowered in FH
patients?
Low potency (cheap) Simvastatin 40 is inadequate for >95% FH patients
Combination therapy may be needed to achieve target
0%
5%
10%
15%
20%
25%
30%
35%
40%
<2 2-2.9 3-3.9 4-4.9 5-5.9 6-6.9 7-7.9 8-8.9 9-9.9 10-10.9 ≥ 11
LDL (mmol/l)
Pre-treatment LDL Post-treatment LDL
6.7 mmol/l
3.3 mmol/l
Overall
~ 50% reduction
n = 249
Hadfield et al 2007
But 34% > 4.0mmol/l
and 12% > 5.0mmol/l
10. Statins reduce CHD in FH
Simon Broome UK-FH Register papers, BMJ 1991, Athero 1999,
8.1 = >23 yrs reduction
in life expectancy
~ 9 years gained by statins
3.7
8 .1
8.1
3.7
0 1 2 3 4 5 6 7 8 9 10
Standardised Mortality Ratio
Post
Statin
1992–1999
Pre Statin
1988–1992
> 2 fold
20-59 year olds
11. Current Life Expectancy in
treated FH patients Neil et al E Heart J 2008
1.03
1.98
3.88
5.15
0 1 2 3 4 5 6
SMR
Secondary
1980-91 (25)
1992-06
(108)
Based on 2766 (1456 M/1310 F) DFH + PFH patients. 190 CHD and 90 cancer deaths (37727 person years follow-up)
Primary
1980-91 (12)
1992-06 (45)
- 25%
CHD Mortality in those with/without CHD
- 48%
- 34%
0.94
1.36
0.63
0.96
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2
SMR
Cancer
1980-91 (14)
1992-06 (76)
Total
1980-91 (55)
1992-06
(315)
Cancer and Total Mortality
- 29%
Age 20-79 years
17. Simon Broome criteria
Definite FH:
TC > 6.7 mmol/l or LDL-C >4.0 mmol/l (child <16y)
or TC > 7.5 mmol/l or LDL-C >4.9 mmol/l (adult)
(levels either pre-treatment or highest on treatment)
plus
tendon xanthomas in patient, or in 10
relative (parent, sibling,
child), or in 20
relative (grandparent, uncle, aunt)
or
DNA-based evidence of an LDL receptor mutation, familial
defective apo B-100, or a PCSK9 mutation.
Possible FH is defined as above lipids plus one of:
family history of myocardial infarction: below age of 50 years
in 20
relative or below age 60 years in 10
relative
or
family history of raised TC >7.5 mmol/l in adult 10
or 20
relative or > 6.7 mmol/l in child or sibling <16y
19. The LDL receptor
Brown and Goldstein
identified autosomal
dominant LDLR defect in FH
fibroblasts in 1974
20. The LDL-receptor pathway
Soutar, A Nat Clin Pract Cardiovasc Med 2006; 4:214
LDL receptor defect.80-95% of cases
PCSK9 defect. Gain and loss of function mutations. 2%
ApoB3500 defects (binding ligand). 3-10%. Less severe phenotype
Autosomal recessive hypercholesterolaemia. Rare
21. Leigh et al Annals Hum Genet 2008
0
5
10
15
20
25
P 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Exons of LDLR
NumberMutations(%)
W-Wide UK
UCL 2008 Database of published
LDLR mutations
W-Wide n = 949
UK n = 208
*
* p = 0.01
Single base changes
+ small dels
1066 different causes of FH reported world-wide www.ucl.ac.uk/ldlr
23. • Use the Simon Broome criteria to diagnose FH
• All individuals should be offered a DNA test to confirm the diagnosis and
to assist in cascade testing of relatives
• CHD risk estimation tools such as those based on the Framingham
algorithm should not be used because people with FH are already at a high
risk of CHD.
• In children at risk of FH because of one affected parent the following
diagnostic tests should be carried out by age of 10 years :
- a DNA test if the family mutation is known
- LDL-C measurement if mutation not known
Key priorities
Diagnosis
24. Key priorities
• Cascade testing - combination of DNA testing and LDL-C levels is
recommended to identify affected relatives of those with a clinical FH.
• The use of a nationwide, family-based, follow-up system is
recommended to enable comprehensive identification of people affected
by FH.
• Adults - Prescribe a high-intensity statin to achieve a reduction in
LDL-C of > 50% from baseline (ie, before treatment).
• Children/young people – Should be seen by a specialist in an
appropriate setting, and using clinical judgement, statin therapy
considered by age 10
• All people with FH should be offered an annual regular structured
reviewIdentifying people with FH using cascade testing
Ongoing assessment and monitoring
Management
27. HEART UK
FH Guideline Implementation Team
• Identify challenges and risks in the
implementation of the NICE FH Guideline
• Propose solutions and incorporate them into
a FH Guideline Implementation toolkit
• Support commissioning and delivery of
services
28. HEART UK FH GIT
• Raising profile NICE FH Guideline
• www.heartuk.org.uk/fhgit
• Influencing commissioning pathway
• DH, primary care commissioning, RCGP, CV
networks and SHAs
• Support from BHF, PCCS and BCS
• Identify service gaps (RCP audit)
• Liaison with NICE
• Toolkit development
29. HEART UK FH GIT
• Anniversary campaign
• SHA events
• Consensus meeting
• Finalise and launch toolkit
• Patient campaign
• Lobbying (parliamentary and SHAs)
• GP survey
• FOI requests to PCTs
• Supporting commissioning bids