1. Jonathan Morrell Hastings
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 TC 9.8 HDL 1.4 TG 1.1 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. Same as childhood diabetes
How Common is FH ?
It is Common - Frequency FH ~1/ ,000 in UK
It is underdiagnosed < 15,000 known, particularly in the < 35 years group (600/14,000 children)
Same as childhood diabetes
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 ♀ <30 5 30-39 22 2 40-49
30-39 22 2
40-49 48 7
50-59 80 51
60-69
100 75
Slack, Lancet.1969;1380-2

8. Like smoking pack-years
LDL- C Burden in FH patients
Starr et al 2008
FH patients have high LDL-C from Birth  high LDL-C BURDEN
LDL - Burden =
LDL-C level x
years exposure
Like smoking pack-years
By 45yrs FH patient has accumulated LDL-C exposure of non- FH 70yr old, explaining high CHD risk and need for aggressive lipid-lowering

9. Can LDL-C be lowered in FH patients?
Hadfield et al 2007
3.3 mmol/l
Overall
~ 50% reduction
6.7 mmol/l
But 34% > 4.0mmol/l
and 12% > 5.0mmol/l
n = 249
Low potency (cheap) Simvastatin 40 is inadequate for >95% FH patients
Combination therapy may be needed to achieve target

10. ~ 9 years gained by statins
Statins reduce CHD in FH
Simon Broome UK-FH Register papers, BMJ 1991, Athero 1999,
Post Statin
1992–1999
Pre Statin
1988–1992
> 2 fold
20-59 year olds
8.1 = >23 yrs reduction
in life expectancy
~ 9 years gained by statins

11. Current Life Expectancy in treated FH patients
Neil et al E Heart J 2008
Age years
CHD Mortality in those with/without CHD
Cancer
(14)
(76)
Total
(55)
(315)
Cancer and Total Mortality
Secondary
(25)
(108)
- 25%
- 34%
Primary
(12)
(45)
- 48%
- 29%
Based on 2766 (1456 M/1310 F) DFH + PFH patients. 190 CHD and 90 cancer deaths (37727 person years follow-up)

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
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
UK NEQAS (Birmingham) Roadshows - UK NEQAS on the Web
UK NEQAS (Birmingham) Roadshows - UK NEQAS on the Web
14 April 2017
14 April 2017
20 Relatives of FH Proband LDL Cholesterol Distribution
Copyright UK NEQAS (Birmingham) - NB! Not all of the slides presented appear in this handout
Copyright UK NEQAS (Birmingham) - NB! Not all of the slides presented appear in this handout 18 18

19. The LDL receptor Brown and Goldstein identified autosomal
dominant LDLR defect in FH
fibroblasts in 1974

20. The LDL-receptor pathway
ApoB3500 defects (binding ligand). 3-10%. Less severe phenotype
LDL receptor defect.80-95% of cases
Autosomal recessive hypercholesterolaemia. Rare
PCSK9 defect. Gain and loss of function mutations. 2%
Soutar, A Nat Clin Pract Cardiovasc Med 2006; 4:214

21. UCL 2008 Database of published LDLR mutations
Leigh et al Annals Hum Genet 2008
1066 different causes of FH reported world-wide
Single base changes
+ small dels
W-Wide n = 949
UK n = 208 *
* p = 0.01

22. NICE FH Guidelines

23. Key priorities Diagnosis 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

24. Key priorities Management Ongoing assessment and monitoring
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 review
Ongoing assessment and monitoring
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.
Identifying people with FH using cascade testing

25. Pathway implementation
Scotland
Wales
Northern Ireland
England

26. A guideline not a directive
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
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