The document summarizes key elements of the NICE FH Guideline and the work of the HEART UK FH GIT. The NICE guideline recommends using the Simon Broome criteria to diagnose FH and offering all individuals a DNA test to confirm diagnosis and assist with cascade testing of relatives. It also provides guidance on treatment and monitoring for both adults and children with FH. The HEART UK FH GIT works to raise awareness of the NICE guideline, support its implementation through a toolkit, and influence commissioning of FH services to address gaps in care.

1. Key elements of the NICE FH Guideline
and the work of the HEART UK FH GIT
Jonathan Morrell
Hastings

2. National Health Checks 2009

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

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

7. FH – natural history
Age
(years)
♂
% CHD
♀
% CHD
<30 5 0
30-39 22 2
40-49 48 7
50-59 80 51
60-69 100 75
Slack, Lancet.1969;1380-2

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

12. How should we identify
people with FH?

13. Clinical signs
Eliza Parachute 1851

14. Xanthelasma

15. Corneal Arcus Lipidus

16. Tendon Xanthomas in HeFH

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

18. 20
Relatives of FH Proband
LDL Cholesterol Distribution

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

22. NICE FH Guidelines

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

25. Pathway implementation
• Scotland
• Wales
• Northern Ireland
• England

26. NICE FH Guidelines
A guideline not a
directive

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