Familial hypercholesterolaemia

Familial Hypercholesterolaemia
Jamie Smith

FH is common
~ 110,000 in UK
~ 6,000 in Wales
<25% diagnosed and treated

Familial Hypercholesterolaemia (FH)
Hypercholesterolaemia – Xanthomatosis – Premature CHD

Typical Family Tree
Age
Cholesterol, mmol/L
Age
Cholesterol, mmol/L

The Primary Hyperlipidaemias
Familial Hypercholesterolaemia (FH) – single gene abnormalities which alter LDL-R function (Soutar and Naoumova, Nature Clin Pract Cardiovasc Med 2007;4:214)
Autosomal Dominant Hypercholesterolaemia (ADH)
LDL-receptor mutations (“Classical FH”)
Familial Defective apolipoprotein B (FDB)
PCSK9 mutations (FH3)
Autosomal Recessive Hypercholesterolaemia (ARH)
[Phytosterolaemia (Sitosterolaemia)]
Familial Combined Hyperlipidaemia (FCH)
Familial Dysbetalipoproteinaemia (type III)
Chylomicronaemia

Lipoprotein Structure
Surface – amphipathic
Free cholesterol
Phospholipids
Apoproteins – amphipathic helix
Core – hydrophobic
Neutral lipids
-Cholesteryl esters
-Triglycerides

Lipoprotein metabolism – endogenous pathway
Heart
Skeletal muscle
Adipose tissue
Lactating breast
B100
TG
Chol
FA
2-MG
CII
VLDL
LPL
TG
Chol
Lp surface
FC, PL
apoC
Remnant
IDL
HDL

Lipoprotein metabolism – endogenous pathway
Heart
Skeletal muscle
Adipose tissue
Lactating breast
B100
TG
Chol
FA
2-MG
CII
VLDL
LPL
TG
Chol
Remnant
IDL
Hepatic lipase
TG
Chol
LDL
Liver
Periphery

The Fate of LDL
LDLR

The Fate of LDL
LDLR
PCSK9 prevents
LDLR recycling

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:1380
Stone et al. Circulation 1974;49:476
See also Marks et al. Atherosclerosis 2003;168:1
Austin 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 Project
Classification of FH patients according to Simon Broome Criteria
July 2007

National Screening Program Familial
Hypercholesterolemia
Peter Lansberg
StichtingOpsporingFamiliaire Hypercholesterolemie (StOEH)

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
Cascade screening reviewed
Hadfield and Humphries, Curr Opin Lipidol 2005;16:428
Bhatnagar et al.
BMJ 2000;321:1497

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 (norbug@gosh.nhs.uk)
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;195:339
Avis et al. ATVB 2007;27:1803
Daniels 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

Results

Audit standards

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)

Repeat fasting and check TFTs for hypothyroidism
Are there any secondary causes of hypercholesterolaemia?
(see table)
YES
NO
Manage secondary causes and reassess
Repeat fasting LDL-C is > 4.9 mmol/l?
YES
NO
Is there a personal or family history of premature CHD*or
tendon xanthoma
Manage CVD risk as per guidelines for primary and secondary prevention and type 2 diabetes
*Premature CHD:
<60 years in 1st degree relative and <50 years in 2nd degree relative
NO
YES
REFER TO LIPID CLINIC
Total cholesterol > 7.5 mmol/l and/or LDL–C (fasting) > 4.9 mmol/l
Some causes of secondary hypercholesterolaemia:
Cause Cholesterol
hypothyroid ++
CKD +
Nephrotic synd ++
Hepatic cholestasis ++/+++
Pregnancy +/-
Anorexia +
Long term steroids +
antipsychotics +/+++
Ciclosporin +

The Wales FH Cascade Testing Initiative
Dr Ian McDowell

Dutch database
Dutch national screening programme for FH
Over 45,000 family members
18,000 diagnosed with FH.
Database: Pass Clinical
Wales clinical pilot of database
commenced 2009

Key Features
Pedigree drawing function
Workflow management
Templates and archiving
Multisite working
Audit and research

???FH
Family Cascade Programme
Full Pedigree
Family registration
Family Tracing
Test 1st degree relatives
??FH
Hospital
(eg Cardiology)
General
Practice
Lipid Clinic
Cascade from
relatives
Clinical and lipid assessment Provisional diagnosis of FH using SB criteria
Genotype positive
FH 
FH X
Document family history
FH diagnosed
Referred to lipid clinic
FH excluded
in relative
Consultation to advise on FH treatment options
Genotyping
Treat hyperlipidaemia
Discharged from cascade programme:
Continuing care
Primary care (most)
Continuing care
Secondary care(some)
Continuing care
Paediatrics (some)
Patient Pathway with Cascade Testing

Welsh Assembly Government
Cardiff and Vale NHS Trust
Cardiac Networks for Wales
Clinical Director
All Wales Genetic Service
FH professional steering group
Senior Nurse manager
AWGS Lead genetic counsellor
FH Project Manager
Data base & project administrator
FH genetic counsellor
(S)
FH genetic counsellor
(N)
FH nurse
(M&SW)
FH nurse
(SE)
FH nurse
(N)

Familial hypercholesterolaemia

by PeninsulaEndocrine on Aug 12, 2011

Accessibility

Categories

Tags

Upload Details

Usage Rights

2 Embeds 6

Statistics

Familial hypercholesterolaemia — Presentation Transcript

http://peninsulaendocrine.blogspot.com	5
http://peninsulaendocrine.blogspot.co.uk	1