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Familial Hypercholesterolaemia
New local pathways
Dr Peter Carey
Consultant in Diabetes and Endocrinology
Sunderland Royal Hospital
Lipid Specialists Advisory Group
North East Cardiovascular Network
Familial Hypercholesterolaemia
• In 1939 first description of tendon xanthoma and
angina as an inherited condition in the Archives of
Internal Medicine.
• In the early 1970s Goldstein and Brown
demonstrated that individuals with homozygous FH
were unable to provide feedback inhibiton of HMG
CoA reductase.
• In 1974/5 they were able to show that this was due to
the absence of LDL-R.
What is Familial
Hypercholesterolaemia?
• A monogenic inherited disorder caused by a
single mutation in one of three genes (LDLR,
APOB or PCSK9)
• These genes are responsible for the removal of
excess LDL cholesterol from the blood.
• Affected individuals will have elevated LDL
cholesterol concentrations from birth which are
high enough to result in accelerated
atherosclerosis.
Genetic Defects
• Approximately 1400 unique mutations have been
identified.
• The vast majority (93%) occur in the LDL receptor
gene.
• This has made it a challenge to use genetic
testing to identify the defect.
• However, comprehensive genetic analysis is
becoming more affordable with technological
advances.
FH – a monogenic disorder of the
LDL-receptor pathway
2
1
4
3
Soutar, A Nat Clin Pract Cardiovasc Med 2006; 4:214
Simon Broome diagnostic criteria for Probands
1.
Total Chol > 7.5mmol/l or LDL > 4.9mmol/l in an adult or
Total Chol > 6.7mmol/l or LDL > 4.0mmol/l in a child < 16 yrs
(levels either pre-treatment or highest on treatment)
Definite Familial Hypercholesterolaemia is defined as 1 plus 2 or 3:
2. Tendon xanthomas in patient, 1st degree relative (parent, sibling, child), or
2nd degree relative (grandparent, uncle, aunt)
3. DNA-based evidence of an LDL receptor mutation, Familial Defective Apo B100, or a PCSK9 mutation.
Possible Familial Hypercholesterolaemia is defined as 1 plus 4 or 5:
4. Family history of MI: < 50 yrs in 2nd degree relative or < 60 yrs in 1st degree
relative
5. Family history of raised Total Chol: > 7.5mmol/l in adult 1st or 2nd degree
relative or > 6.7mmol/l in child or sibling aged < 16 years.
Tendon Xanthoma
Corneal Arcus Lipidus
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
Vermissen J et al ; BMJ (2008) 337: 2423
National Health Checks Program
Of those >40 years, approximately 4% have total cholesterol >7.5mmol/L,
of whom 1 in 20 will have undiagnosed FH
and 3-5 relatives with undiagnosed FH
Family History 1990
MI 42 y
? chol
I
Index Case
50 y
II
10.3
? chol
III
25 y
? chol
First degree relatives
27 y
? chol
1 in 2 chance of being affected
Family History Revisited 2007
MI 42 y
? chol
I
Index Case
67 y
II
III
10.3
42 y
? chol
44 y
? chol
Index
Case
APOB
R3527Q
No CHD
TC 4.8
? chol
First degree relatives
1 in 2 chance of being affected
Second degree relatives 1 in 4 chance of being affected
Family History Revisited 2007
MI 42 y
? chol
I
Index Case
67 y
II
III
10.3
42 y
TC 8.9
(mmol/L)
44 y
TC 9.9
(mmol/L)
Never on Rx CABG age 44
Never on Rx
Index
Case
APOB
R3527Q
No CHD
TC 4.8
? chol
National Health Checks Program
Of those >40 years, approximately 4% have total cholesterol >7.5mmol/L,
of whom 1 in 20 will have undiagnosed FH
~5000 in our region
and 3-5 relatives with undiagnosed FH
remain undiagnosed
}
NICE FH Guideline (CG71 August 2008)
Primary Care Service Framework
for Familial Hypercholesterolaemia
“Although the NICE guideline was
published in 2008, few commissioners
have taken action and FH remains
something of a Cinderella condition. ”
19 February 2010
http://www.pcc.nhs.uk/familial
NICE Quality Standards (QS41)
• Standard 41 – Familial hypercholesterolaemia
was published in August 2013.
• 8 quality statements regarding the diagnosis and
management of people of all ages with familial
hypercholesterolaemia
• Derived from CG71, designed to drive measurable
quality improvements
Statements
1.
2.
3.
4.
5.
6.
7.
8.
Adults with a baseline Total Chol > 7.5 mmol/L are assessed
for a clinical diagnosis of FH
People with a clinical diagnosis of FH are referred for
specialist assessment
People with a clinical diagnosis are offered DNA testing as
part of a specialist assessment
Children at risk of FH are offered diagnostic testing before
age of 10
Relatives of people with a confirmed genetic diagnosis are
offered DNA testing through a nationwide systematic cascade
process.
Adults with FH receive lipid modifying drug treatment to
reduce LDL cholesterol by >50% from baseline
Children with FH are assessed for lipid modifying drug
treatment by the age of 10
People with FH are offered a structured review at least
annually
Northern Lipid Forum
in association with
FH: can we deliver the new
NICE Quality Standard?
Hilton Newcastle Gateshead Hotel
Bottle Bank, Gateshead,
Newcastle upon Tyne NE8 2AR
Tuesday 15th October 2013
Regional FH Cascade Testing Program
The North East FHG Consortium
•
•
•
•
•
•
•
•
North East Cardiovascular Network LSAG (10 clinics)
Northern CCG Forum (13 CCGs)
Northern Regional Genetics Service (genetic diagnosis)
NewGene Ltd (DNA analysis by chip and/or sequence)
Academic Health Sciences Network (AHSN) (DNA project)
Newcastle NIHR Diagnostic Evidence Co-operative (DEC)
AstraZeneca Ltd (PASS software licences)
City Hospitals Sunderland (BHF FH nurses host Trust)
Total cholesterol > 7.5 mmol/l and/or
LDL cholesterol > 4.9 mmol/l
FATS7 2014 Appendix 2
Total cholesterol > 7.5 mmol/l and/or
LDL cholesterol > 4.9 mmol/l (contd)
The North East Lipid Clinics Network
The lipid clinics will:
Confirm the clinical diagnosis of FH or other disorder
Provide lifestyle and dietetic advice
Start and/or titrate lipid lowering drug treatment.
Provide information
Identify and arrange investigation if required
Use DLNC score to prioritise patients for genetic
testing
Recommend if family cascade screening is appropriate
Arrange follow up and an annual structured review
DoH FH DNA Cascade Testing Pilot Study
Newcastle patients - Mutation Status by Simon Broome Diagnosis
Definite FH 77% positive, Possible FH 38% positive
Overall, mutations were detected in 75/145 (52%)
FH Phenotype Score for Identification of Proband
– part of the solution?
Second Degree Relatives of FH Proband
- the LDL Cholesterol Overlap
Second degree relatives 1 in 4 chance of being affected
LDL-C Diagnostic Tables for 1º relatives
Age 
DoH FH DNA Cascade Testing Pilot Study
Outcome of cascade testing by Simon Broome Classification
Patient Class
No Families
Relatives
tested
No Relatives
Mutation+ve/-ve (% +ve)
DFH
PFH
UFH
Total
47
47
6
100
138
146
12
296*
75/63 (54.3%)
84/62 (57.5)
7/4 (63.6)
166/130 (56.1)
Data from DH
cascade project
545
591*
211/380 (35.7)
First degree relatives 56% positive on genetic cascade testing
but only 36% positive on LDL-C testing – 1 in 3 positives misclassified
Taylor A et al., Clinical Genetics 2010;77:572
Not FH - what else could it be?
Inherited dyslipidaemias and premature CHD
% of total CHD
Combined Hyperlipidaemia (FCH)
19%
Hyper Lipo(a) (normolipidaemia)
19% (13)
Dyslipidaemia (high TG, low HDL)
15%
Hypoalphalipoproteinaemia (FHA)
4%
Hypercholesterolaemia (FH)
3%
Hypertriglyceridaemia
1%
>50% of premature CHD have a familial lipoprotein disorder
Genest JJ et al., Circulation (1992) 85: 2025-33
FH Genetic Cascade Testing (GCT) Pathway
If Clinical Diagnosis of FH in Proband with DLNC ≥ 6
1. DNA diagnosis and Family Cascade Testing offered
2. Proband contacted on receipt of genotyping results
3. Proband M+ offered appointment with FH Genetic nurse
4. Family pedigree recorded in PASS and used to identify
relatives to be contacted (direct or indirect as preferred)
5. Relatives offered an appointment for Genetic Cascade
Testing M+ test and fasting lipid profile in adults
6. If proband test negative (M-) lipid profiles in other family
members advised when appropriate
7. Letter to GP recommending Lipid Clinic referral for M+
relatives or M- relatives with LDL-C in red/grey zone.
First line DNA diagnosis, second line LDL-C for cascade testing