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 Soutar, A Nat Clin Pract Cardiovasc Med 2006; 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 < 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 R3527Q No CHD TC 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 44 Never on Rx Index Case APOB R3527Q No CHD TC 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)

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 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.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 Hotel Bottle Bank, Gateshead, Newcastle upon Tyne NE8 2AR Tuesday 15th October 2013 Northern Lipid Forum in 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 FATS 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 ClassNo Families Relatives tested No Relatives Mutation+ve/-ve (% +ve) DFH /63 (54.3%) PFH /62 (57.5) UFH6127/4 (63.6) Total * 166/130 (56.1) Data from DH cascade project * 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 testing but 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:

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.