Familial Hypercholesterolaemia - Cholesterol kills · Familial hypercholesterolaemia (FH) is an inherited condition that is associated with abnormally high plasma low-density lipoprotein

Familial Hypercholesterolaemia - Cholesterol kills !

Dr Nigel Capps

Consultant Chemical Pathologist

Director of Research & Development, Shrewsbury & Telford Hospital NHS Trust

Co-Director and Joint Cardiovascular Speciality Group Lead, West Midlands (North) Comprehensive Local Research Network

“MAKING THE NHS HEALTH CHECK WORK FOR YOU” 12th Jan 2012

FH – The Facts

• It is common - frequency (hetero) FH ~1/500 ie 110,000 in UK

• It is underdiagnosed < 15,000 known (particularly in < 35 yo)

• It runs in families - autosomal dominant trait

• It increases the risk of heart disease - 50% in men by age 50

• It is treatable – so they need to be found !

1996

Male, age 31

Referred from cardiology – recent MI, high cholesterol

Cholesterol checked by chance 1989/90 – approx 13 mmol/L

Various hospitals – Cholestyramine – up to 8 sachets / day

Early trials of statins – Simvastatin / Lovastatin / Fluvastatin

Father died age 29 –MI, father’s mother early CHD

1 sister – cholesterol “OK”, 3 boys aged 7,5 and 3/12

AdhesionAdhesionMoleculeMolecule

MonocyteMonocyte

IntimaIntima

Vessel LumenVessel Lumen

EndotheliumEndothelium

LDLLDL

LDLLDLMCPMCP--11

MacrophageMacrophage

CytokinesCytokines

Foam Foam CellCell

MODIFIED LDLMODIFIED LDL

IMT “Progression” in FH

De Groot et al Circulation 2004

FH

Control

3.0 4.0 5.0

Children (all male)

Born 1989, at age 10: 7.9 0.7 1.19 6.4 6.6

Born 1990, at age 9: 4.9 0.5 1.51 3.2 3.2

Born 1996, at age 6: 7.5 0.7 1.53 5.7 4.9

Born 2000, at age 6: 5.1 0.8 1.70 3.0 3.0

Now - Atorvastatin 80mg, Ezetimibe 10mg, Colesevelam 625 mg x 6

TC Trig HDLC LDLC TC/HDLC3.5 0.4 1.14 2.2 3.1

Key FH resources

• FH NICE guideline (2008): www.nice.org.uk/cg71

• FH primary care commissioning framework 2009: www.pcc.nhs.uk/familial

• RCP National FH audit (2010): www.rcplondon.ac.uk/resources/audits/FH

• BHF / HEART UK FH booklet (2011): www.bhf.org.uk/publications.aspx

Consider the possibility of familial hypercholesterolaemia (FH) in adults who have raised total cholesterol concentrations (typically greater than 7.5 mmol/l), especially if there is a personal or family history of premature CHD.

Exclude secondary causes of hypercholesterolaemia before considering a diagnosis of FH.

Use the Simon Broome criteria to make a diagnosis of FH.

Absence of clinical signs (for example, tendon xanthomata) does not exclude a diagnosis of FH.

To confirm a diagnosis of FH, take two measurements of LDL cholesterol.

Provide clear and appropriate information about FH, the process of family testing, DNA testing and measuring LDL-C concentration.

DIAGNOSIS

NICE clinical guideline 71. August 2008. FAMILIAL HYPERCHOLESTEROLAEMIA

Simon Broome Diagnostic Criteria for FH

Definite familial hypercholesterolaemia is defined as:

• total cholesterol greater than 6.7 mmol/l or low-density lipoprotein cholesterol (LDL-C) greater than 4.0 mmol/l in a child aged younger than 16 years or total cholesterol greater than 7.5 mmol/l or LDL-C greater than 4.9 mmol/l in an adult (levels either pre-treatment or highest on treatment) plus

• tendon xanthomas in patient, or in first-degree relative (parent, sibling or child), or in second-degree relative (grandparent, uncle or aunt) orDNA-based evidence of an LDL receptor mutation, familial defective apo B- 100, or a PCSK9 mutation.


Simon Broome Diagnostic Criteria for FH

Possible familial hypercholesterolaemia is defined as:

• total cholesterol greater than 6.7 mmol/l or low-density lipoprotein cholesterol (LDL-C) greater than 4.0 mmol/l in a child aged younger than 16 years or total cholesterol greater than 7.5 mmol/l or LDL-C greater than 4.9 mmol/l in an adult (levels either pre-treatment or highest on treatment) plus

• family history of myocardial infarction: younger than 50 years of age in second-degree relative or younger than 60 years of age in first-degree relative or family history of raised total cholesterol: greater than 7.5 mmol/l in adult first- or second-degree relative or greater than 6.7 mmol/l in child or sibling aged younger than 16 years.


Offer a referral to a specialist with expertise in FH to:

All people for confirmation of diagnosis and initiation of cascade testing.

Any child or young person being investigated for FH, or who has a diagnosis of FH – refer to an appropriate child/young person-focused setting.

An adult with FH for consideration for further treatment if they are assessed to be at very high risk of a coronary event, that is, if they have any of the following:

– Established coronary heart disease.– A family history of premature coronary heart disease.– Two or more other cardiovascular risk factors (for example, they are male, they

smoke, or they have hypertension or diabetes).

REFERRAL


Explain cascade testing and discuss implications with the patient.

Use a nationwide, family- based follow – up system to enable comprehensiveidentification of affected people: encourage patients to contact their relatives.

Use a combination of DNA testing and LDLC measurement to identify affectedrelatives of index individuals.

CASCADE TESTING


In children at risk of FH because of one affected parent, the following diagnostictests should be carried out by the age of 10 years or at the earliest opportunity thereafter –

DNA test if the family mutation is known.LDL-C concentration measurement if the family mutation is not known.When excluding a diagnosis of FH a further LDL-C measurement should be repeated after puberty because LDL-C concentrations change during puberty.

DRUG TREATMENTADULTS• If treatment with the maximum tolerated dose of a high-intensity statin and

ezetimibe does not reduce LDL-C concentrations by greater than 50% from baseline, offer a referral to a specialist in FH.

• Advise women to stop taking lipid-modifying drug therapy 3 months before attempting to conceive.

• Prescribe drugs for the treatment of homozygous FH in a specialist centre.


CHILDREN

• Consider lipid-modifying drug therapy by the age of 10 years.

ReviewAt least once a year review all FH patients and include all of the following:

• Symptoms of coronary heart disease.

• Ask whether the person smokes.

• a fasting lipid profile to monitor LDL-C concentration and discuss any changes required to lifestyle or drug therapy to achieve recommended LDL-C.

• Confirm they are taking their medication correctly and enquire about any possible side effects of treatment.

• Record the progress of cascade testing among relatives. This should include at least first- and second-, and when possible, third-degree relatives. If there are still relatives who have not been tested, discuss further action.

• Update family history – note any changes in the coronary heart disease status of relatives. This should include at least first- and second-, and when possible, third-degree relatives.

Consider a baseline electrocardiogram (ECG) for adults with FH.


KEY RECOMMENDATIONS OF 2010 RCP NATIONAL AUDIT OF FH

Commissioning arrangements reviewed urgently, at national and local levels.

Better shared-care arrangements required.

Resources and systems for comprehensive cascade testing – staff and IT, DNA testing.

Additional resources to cope with the care of new FH patients identified.

Because UK FH families are often geographically dispersed, cascade testing wouldbe helped by a funded national register.

Cascade testing alone is likely to find less than 50% of the predicted 100,000 unidentified FH patients in the UK – other methods of finding probands needs exploring.

Current Specialist Lipid Clinicsin West Midlands

Cardiology patients who meet the Simon Broome criteria

Primary care patients who meet the Simon Broome criteria, known

patients and active case finding *

Specialist FH Clinic - sees all cases to confirm diagnosis, offer DNA testing and

initiates treatment30% of adults remain in specialist care for long term management and annual review100% of children remain in specialist care

for long term management and annual review

FH cascade nurse offers testing to all relatives of DNA positive patients with DNA and all relatives of DNA negative patients with cholesterolPositive patients referred back to FH clinic for initial treatment

Joint clinics with paediatrician with special interest in FH

Complex and homozygous paediatric cases referred for management at BCH

Primary care - 70% of adults referred back to Primary Care for long term management * and annual review *

Criteria for patient to move between FH service and primary care and vice versa

(trigger points for referral back to the specialist FH clinic)

Commissioning of Specialised Services in the West Midlands


West Midlands shared care plan for the diagnosis and management of familial hypercholesterolaemia

Date of preparation: Feb 2011, amended April and June 2011. Approved by MTRAC Aug 2011.

A. Introduction

Familial hypercholesterolaemia (FH) is an inherited condition that is associated with abnormally high plasma low-density lipoprotein cholesterol (LDL-C) concentrations, which may lead to early development of atherosclerosis and coronary heart disease (CHD). The disease shows an autosomal dominant pattern of inheritance, so that siblings and children of a person with FH have a 50% chance of inheriting FH.1 It has been estimated that 120,000 people in the UK have FH, but over 85% remain undiagnosed.2 If untreated, the high LDL-C concentration in people with heterozygous FH leads to a greater than 50% risk of CHD in men by age 50 and of at least 30% in women by age 60.1 Homozygous FH is rare, with an incidence of about 1 in a million, and is associated with early death from CHD.1

Treatment with a statin combined with life-style changes has been shown to significantly reduce the risk of CHD-related mortality.2 An audit carried out in 2010 by the Royal College of Physicians found that the standard of care of patients being managed in lipid clinics was good, but that identification of undiagnosed cases was poor, especially the follow-up of families of index cases.2 One recommendation of the audit was the development of shared care arrangements between hospital and primary care, and better links with other specialties including paediatrics.

The aim of this shared care plan is to define thresholds for referral between primary and secondary care for the diagnosis and clinical management of adults, young people and children with FH. Most of the material in this document was based on NICE Clinical Guidance 71, published in 2008.1

This shared care plan also outlines Secondary Care responsibilities regarding cascade testing of family members with FH. Currently cascade testing is not a regionally commissioned service (though available in some areas of the West Midlands). Where not commissioned, it should not be considered a secondary care responsibility.


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Familial Hypercholesterolaemia - Cholesterol kills · Familial hypercholesterolaemia (FH) is an inherited condition that is associated with abnormally high plasma low-density lipoprotein