familial hypercholesterolaemia
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Familial Hypercholesterolaemia
Jamie Smith
FH is common
• ~ 110,000 in UK• ~ 6,000 in Wales
• <25% diagnosed and treated
Hypercholesterolaemia – Xanthomatosis – Premature CHD
Familial Hypercholesterolaemia (FH)
Typical Family Tree
AgeCholesterol, mmol/L
AgeCholesterol, mmol/L
Lipoprotein Structure
Surface – amphipathicFree cholesterolPhospholipidsApoproteins – amphipathic helix
Core – hydrophobicNeutral lipids-Cholesteryl esters-Triglycerides
Lipoprotein metabolism – endogenous pathway
TGChol
VLDL
TGChol
FA2-MG
LPL
HeartSkeletal muscleAdipose tissueLactating breast
Remnant IDL
B100
CII
Lp surfaceFC, PLapoC
HDL
Lipoprotein metabolism – endogenous pathway
TGChol
VLDL
TGChol
FA2-MG
LPL
HeartSkeletal muscleAdipose tissueLactating breast
Remnant IDL
LDLTG
Chol
Hepatic lipase
B100
LiverPeriphery
CII
The Fate of LDL
LDLR
The Fate of LDL
PCSK9 preventsLDLR recycling
LDLR
FH: LDL-receptor mutations • >1000 mutations in LDL-receptor• Chromosome 19• Heterozygotes 1 in 500• Homozygotes 1 in a million• Founder effects
Michael Brown & Joseph Goldstein
Prognosis in heterozygous FH
Heiberg & Slack BMJ. 1977;ii:493
Prognosis in heterozygous FH
• Cumulative risk of fatal and non-fatal CHD– 50% by age 50yr in men– 30% by age 60yr in women
(Pre-statin)
Slack, Lancet 1969;ii:1380Stone et al. Circulation 1974;49:476
See also Marks et al. Atherosclerosis 2003;168:1Austin et al. Am J Epidemiol 2004;160:407-435 (3 papers)
Prognosis in HeFH has improved since advent of statins
• SMR for CHD fell by 37% (RR 3.4 to 2.1, age 20-79) in 1992-2006 compared with 1980-1991
• Excess mortality from CHD mainly in younger patients (<60 yr)
• All cause mortality (RR 0.67) lower in FH pts without CHD at registration (1992-2006) – predominantly due to less cancer deaths (mainly respiratory and GU)
Neil et al. Eur Heart J 2008;29:2625
Heterozygous FHDiagnosis
• Simon Broome Register criteria– definite FH
• TC > 7.5 or LDL-C > 4.9 mmol/l• (TC > 6.7 or LDL-C > 4.0 for children < 16 yr)• plus Tendon xanthomata in 1st or 2nd degree relative• or LDL-receptor or apoB-100 mutation
– possible FH• Lipids as above plus family history of either MI at <50yr in 2nd
degree or <60yr in 1st degree relative or TC > 7.5 in 1st or 2nd degree relative
Simon Broome Register Group. BMJ 1991;303:893-6.Simon Broome Register Group. Atherosclerosis 1999;142:105-12.
DOH FH Cascade Testing Audit ProjectClassification of FH patients according to
Simon Broome Criteria
July 2007
Peter Lansberg
Stichting Opsporing Familiaire Hypercholesterolemie (StOEH)
National Screening Program Familial
Hypercholesterolemia
Detection of heterozygous FHCascade screening
• 259 FH probands from Central & South Manchester Lipid Clinics
• 121/200 first degree relatives had FH
• Need to screen 60,000 individuals to find same number with non-selective screening
Bhatnagar et al.BMJ 2000;321:1497
Cascade screening reviewedHadfield and Humphries, Curr Opin Lipidol 2005;16:428
Gender and age specific LDL-C criteria graphs for cascade testing
DOH FH Cascade Testing Audit Project
LDL-C levels in mutation positive (red) and mutation negative (blue) relatives
Ages 5-15
Ages 45-54
Umans-Eckenhausen et al. 2001. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357:165-168
Utility of DNA testing• Mutations found in 40-90% of clinical FH depending on degree of
clinical suspicion and methods used• Facilitates diagnosis in children especially• DNA testing gives unequivocal diagnosis• ~25% of individuals in families may be misclassified on cholesterol
testing alone• Patients with clinical FH and a detected mutation are at higher risk
than those in whom no mutation is found. PCSK9 mutations at particularly high risk and those with apoB mutations at lower risk
• Cost– £400 for entire gene screen– £60 for 20 commonest mutations– £60 to test relative in family with known mutation– Gail Norbury ([email protected])
Humphries et al. Curr Opin Lipidol 2008;19:362
Screening for FHConsequences for life insurance
• Netherlands – programme to detect all (~40,000) patients by 2010 (DNA testing)
• FH regarded as serious but treatable• Insurers can use clinical information to
calculate mortality ratings• Risk should be assessed on phenotype
and not on presence or nature of mutation• Accepted at normal rates if LDL-C <4 and
no other CVD risk factors
Homsma et al. Eur J Hum Genet 2008;16:14
FH in children
• US guidelines recommend screening children with family history of hyperlipidaemia or premature CVD at 2-10 yr
• UK MHPRA licensed pravastatin for children 8-13 yr (10-20 mg/d) and 14-18 (10-40 mg/d), and atorvastatin 10-17 (10-20 mg/d)
• Statins safe and effective over 6 weeks to 2 years (meta-analyses of atorva, lova, prava and simva trials)
• Limited data suggest improvement in IMT and endothelial function
• Treating children and adolescents at highest risk (male, family history of event in 3rd or 4th decade) probably justifiable. Statins may be teratogenic
Arambepola Atherosclerosis 2007;195:339Avis et al. ATVB 2007;27:1803Daniels et al. Pediatrics 2008;122:198
Audit of FH diagnosis and management in Torbay 2009
• Used notes of diagnosed FH patients• Filled out ‘questionnaires’ on various aspects of
management of the condition• Collated results in a database and analysed the data• Set audit standards according to what results should be
reached using NICE guidelines on FH• Patient demographics:
– Total of 24 patients– 10 females, 14 males– Age range: 14 to 70– Average age: 47
11 (46%)
8 (34%)
1 (4%)
1 (4%)
1 (4%)1 (4%)
1 (4%)
Number of patients with co-morbidities
No co-morbidities
Hypertension
Coronary disease
CVD
Hypertension and Coronary disease
Coronary and CVD
Hypertension, coronary disease and CVD
Results
1st degree 2nd degree 3rd degree0
5
10
15
20
15
20
Number of patients with biological relatives of different degrees screened for FH
Nu
mb
er
of
pa
tie
nts
0
2
4
6
8
10
12
A graph showing the spread of cholesterol levels for baseline and latest measurements
Baseline valuesLatest values
Ch
ole
ster
ol
(mm
ol/
L)
No treatment
Medium intensity statin(Simvastatin)
High intensity statin
Ezetimibe
Medium intensity statinand ezetimibe
High intensity statinand ezetimibe
0 1 2 3 4 5 6 7 8 9 10
2
4
9
1
1
7
Lipid lowering treatment
Number of patients
No nutritional advice offered
Nutritional advice of-fered by a non-dieti-
cian
Nutritional advice of-fered by a dietician
Number of patients offered nutritional advice
33%5 out of 24
21%8 out of 24
46%11 out of 24
Audit standardsCriterion Current achievement Standard
Assessment of heart disease in family history 96% 100%
LDL-C concentration measurements 92% 100%
Cascade testing of 1st degree biological relatives 65% 70%
Reduction of LDL greater than 50% from baseline 12% 70%
Patient offered nutritional advice 54% 100%
Patient offered nutritional advice by dietician 21% 80%
Advice on exercise levels 33% 100%
Advice on stopping smoking (if the patient smoked) 50% 100%
How should we implement NICE guidance on FH locally?
Case of SM
58 yr old female
FH diagnosed in 1980s
Cholesterol 16 mmol/L, normal HDL, Trigs
No CVD but hypertension (BP 170/90) and obesity (BMI 35)
Ongoing problems with suspected tendonitis associated with xanthomas
Problems tolerating lipid-lowering meds
Cholestyramine – GI problems
Statins
Nicotinic acid
ezetimibe
Re-tried with rosuva 5mg od
Chol 9.4 LDL 7.35 HDL 1.4 trig 1.43
Family history
Mother – raised chol and CHD in 60s with CABG
Died aged 89 of stroke
2 brothers with possible FH – neither has CHD
3 children – 33 yr old daughter with chol 6.8, 31yr and 24yr old sons – chol unknown (although tested in childhood)
The Wales FH Cascade Testing Initiative
Dr Ian McDowell
???FH
Hospital(eg Cardiology)
??FHGeneral Practice
Lipid Clinic
Genotyping
Treat hyperlipidaemia
Continuing carePrimary care (most)
Continuing careSecondary care(some)
Continuing carePaediatrics (some)
Family Cascade Programme · Full Pedigree
· Family registration · Family Tracing · Test 1st degree relatives
FH diagnosedReferred to lipid clinic
FH excludedin relative
Consultation to advise on FH
treatment options
Discharged from cascade programme:
Clinical and lipid assessment Provisional diagnosis of FH using SB criteria Genotype
positive
Cascade fromrelatives
FH FH X
Document family history
Patient Pathway with Cascade Testing
FH genetic
counsellor
(S)
FH genetic
counsellor
(N)
FH nurse
(M&SW)
FH nurse(SE)
FH nurse(N)
FH Project ManagerSenior Nurse
manager
FH professional steering groupClinical DirectorAll Wales Genetic
Service
Welsh Assembly Government
Cardiff and Vale NHS Trust Cardiac Networks for Wales
AWGS Lead genetic counsellor
Data base & project administrator
Scoring Criteria for patients with possible Familial Hypercholesterolaemia Please note these criteria only apply for index cases, not family members of known genotype positive patients.
Points
Family History First degree relative (FDR) known with premature (<60yrs) CHD
(coronary heart disease)FDR known with LDL-C > 5mmol/lFDR with tendon xanthomata and/or corneal arcus (< 45yrs)FDR (<18yrs) with LDL-C > 3.5mmol/l
1122
PhysicalExamination
Tendon xanthomataCorneal arcus (< 45yrs)
64
LipidLoweringTreatment
Is patient on lipid lowering treatment? YES / NOoIf NO, go to Untreated LDL- Cholesterol ConcentrationsoIf YES, give details ……………………………………
If untreated LDL-C values are unobtainable see attached sheet (Correction Factor Table) and calculate estimated value.
Untreated or corrected
LDL- Cholesterol
Concentrations(mmol/l)
LDL-C > 8.5 LDL-C 6.5 – 8.4 LDL-C 5.0 – 6.4 LDL-C 4.0 – 4.9
8531
Fasting Triglycerides(mmol/l)
Tg 2.5 – 3.5Tg 3.5 – 5Tg > 5
minus 2minus 3minus 4
Proband eligibility for FH genotyping is based on total points scoreOnly one score from each box >8 usually eligible for genotyping 6-8 eligible if funding available 5 or less usually not unless exceptional circumstancesForms which are unclear, incomplete or not eligible for genotyping will be returned to the requesting clinician and the sample stored for X months for possible future use.
