Familial Hypercholesterolaemia

New local pathways

Dr Peter CareyConsultant in Diabetes and Endocrinology

Sunderland Royal Hospital

Lipid Specialists Advisory GroupNorth 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

Soutar, A Nat Clin Pract Cardiovasc Med 2006; 4:214

1

3

2

4

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 B-100, 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

II

I

III

10.3

? chol

Index Case

50 y

25 y? chol

27 y? chol

MI 42 y? chol

First degree relatives 1 in 2 chance of being affected

II

I

III

10.3

? chol

Index Case

67 y

42 y? chol

44 y? chol

MI 42 y? 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

Index Case

APOB R3527QNo CHDTC 4.8

II

I

III

10.3

? chol

Index Case

67 y

42 y 44 y

MI 42 y? chol

Family History Revisited 2007

TC 8.9(mmol/L)

Never on Rx

TC 9.9(mmol/L)

CABG age 44Never on Rx

Index Case

APOB R3527QNo CHDTC 4.8

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 } ~5000 in our region

remain undiagnosed

NICE FH Guideline (CG71 August 2008)

http://www.pcc.nhs.uk/familial

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

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

Statements1. Adults with a baseline Total Chol > 7.5 mmol/L are assessed

for a clinical diagnosis of FH

2. People with a clinical diagnosis of FH are referred for specialist assessment

3. People with a clinical diagnosis are offered DNA testing as part of a specialist assessment

4. Children at risk of FH are offered diagnostic testing before age of 10

5. Relatives of people with a confirmed genetic diagnosis are offered DNA testing through a nationwide systematic cascade process.

6. Adults with FH receive lipid modifying drug treatment to reduce LDL cholesterol by >50% from baseline

7. Children with FH are assessed for lipid modifying drug treatment by the age of 10

8. People with FH are offered a structured review at least annually

FH: can we deliver the new NICE Quality Standard?

Hilton Newcastle Gateshead HotelBottle Bank, Gateshead,

Newcastle upon Tyne NE8 2AR

Tuesday 15th October 2013

Northern Lipid Forumin association with

Regional FH Cascade Testing Program

• 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)

The North East FHG Consortium

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 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

The North East Lipid Clinics Network

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

Patient Class No Families Relatives tested

No Relatives Mutation+ve/-ve (% +ve)

DFH 47 138 75/63 (54.3%)

PFH 47 146 84/62 (57.5)

UFH 6 12 7/4 (63.6)

Total 100 296* 166/130 (56.1)

Data from DH cascade project

545 591* 211/380 (35.7)

DoH FH DNA Cascade Testing Pilot Study

Outcome of cascade testing by Simon Broome Classification

Taylor A et al., Clinical Genetics 2010;77:572

First degree relatives 56% positive on genetic cascade testingbut only 36% positive on LDL-C testing – 1 in 3 positives misclassified

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

First line DNA diagnosis, second line LDL-C for cascade testing

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.