1. FH Guidelines in Practice : findings from the DH cascade and audit project and the pilot RCP audit
Weirzbicki, et al BMJ 2008, Aug 27;337:1095
Issue date :
August 2008
NICE clinical
guideline 71
Developed by the National
Collaborating
Centre for Primary Car e
Identification and
management of familial
hypercholesterolaemia
Royal College General Practictioners Core Team : Kathy DeMott, Leo Nherera, Meeta Kathoria, Beth Shaw, Gill Richie, Vanessa Nunes, Nancy Turnball
Guideline Development Group (GDG)
GP Chair: Dr Rubin Minhas
Lead Advisor : Prof Steve Humphries
Lipidologists : Prof Andrew Neil, Dr Mary Seed, Dr Ian McDowell
Nurse Specialist/Genetic Counsellor : Ms Melanie Watson
Dietician : Ms Helen Stracey
Epidemiologist : Prof Margaret Thorogood
Paediatrician : Dr Philip Lee
GP : Dr Nadeem Qureshi
Patient Representatives : Dawn Davies, Phil Rowlands
Co-opted Experts : Tony Weirzbicki, Helen Williams, Aileen Parke,
Richard Wray, Mahmoud Barbir, Anneke Lucassen
HEARTUK FH Implementation Group
Dermot Neely, Jonathan Morrell
CVG - Ros Whittall, Tina Hubbard, Sarah Leigh, Royal Free Lipid Clinic - Devi Nair
ICH - Gail Norbury, Alison Taylor, Sian Tabrah, Karen Heath,
FH-Audit – Gaye Hadfield, Brian Starr, Mabella Farrer, Gretta Wood
Simon Broome Study Group - Andrew Neil, Gil Thompson, Nigel Capps, Ian McDowell
John Betteridge, Rossi Naoumova, Mary Seed, Paul Durrington,

2. What genes have mutations  FH
Key NICE priorities
Diagnosis
Use the Simon Broome criteria to diagnose FH
All individuals should be offered a DNA test to confirm the diagnosis and to assist
in Cascade testing of relatives
CHD risk estimation tools such as those based on the Framingham algorithm
should not be used because people with FH are already at a high risk of CHD.
In children at risk of FH because of one affected parent the following diagnostic
tests should be carried out by age of 10 years :
- a DNA test if the family mutation is known
- LDL-C measurement if mutation not known
Key for GPs
NICE evidence-based Guideline  DNA testing is key recommendation
What genes have mutations  FH

3. How is cholesterol removed from blood?
LIVER
Circulates in blood as LDL particle (“Bad Cholesterol”)
“wrapped up” by large protein ApoB
Cholesterol used in
building membranes of
new cells and to
make important hormones
apoB binds
to receptor
Liver has special LDL-grabbing protein
called a “Receptor” – 7 fingered hand

4. How is cholesterol removed from blood?
LIVER
Circulates in blood as LDL particle (“Bad Cholesterol”)
“wrapped up” by large protein ApoB
Cholesterol used in
building membranes of
new cells and to
make important hormones
LDL removed
from Blood
apoB binds
to receptor
Liver has special LDL-grabbing protein
called a “Receptor” – 7 fingered hand
Receptor internalised

5. How is cholesterol removed from blood?
Receptor
recycles
to surface
Recycling controlled
by enzyme PCSK9
LIVER
LDL degraded
and cholesterol
 intestine
LDL removed
from Blood
apoB binds
to receptor
FH - lack of functional receptors, poor LDL binding or high degradation in recycling
Most FH due to LDLR mutations, 5% by APOB, 2% PCSK9

6. DNA tests for FH - GOSH Regional DNA lab since 1997
LDLR - >1000 mutations worldwide! (UK ~200)
often need to screen whole gene - EXPENSIVE
~5% have large deletion – need special method
APOB - Only 1 mutation CHEAP
PCSK9 - Only 1 common mutation CHEAP
Fully accredited / Material archived.
Reports sent to GPs/lipidologists within 6 months.
Established mutation web site (
Over last 2 years 635 proband and 296 relative samples
Can detect a mutation in >70% DFH. Current costs ~£400 and falling. Test of single mutation in relative ~ £100. Cholesterol test ~£10, ECG ~£60

7. What about no mutation patients?
Detection Rate Data
Taylor et al Clin Genet 2009 in press
Completed analysis on 635 proband samples from 6 sites
Some (n=51) did not come with enough information to classify as Definite (n=190) or Possible FH (n=394) – (U-FH)
Conclusions
Prevalence of PFH ~ twice DFH
As seen in Audit
Significantly higher detection rate
in DFH vs PFH
As expected from published data
Sizeable proportion of UFH have
mutation
p <
28.4%
56.3%
25.5%
What about no mutation patients?

8. No mutation patients?
Technical reasons – No method detects all mutations. Sequencing
may give more complete coverage.
Genetic heterogeneity – May be 4th or 5th gene to be found.
Over-Diagnosis – Many patients do not have “true” FH. Family
history of hypercholesterolaemia and early CHD not very specific.
Detection Rate compares favourably with the 20-30% seen in
BRCAI/2 in familial breast cancer- also fewer “unclassified” variants
Need for pre-test counseling about detection rate
and that non-detection of a mutation does not mean not FH!

9. FH DIAGNOSIS IN FAMILY Y
Chol/TG
mmol/l
MI age
35yrs
4.4
8.1
Does Dad have FH?
Can we find the genetic cause?
Can we use this information to see if either son has FH?
4.1 7y
5.4 5y
Make a detailed family tree

10. Used DNA techniques to Screen LDLR gene. * Carrier LDLR mutation
CONFIRMING FH DIAGNOSIS IN FAMILY Y 1 *
Used DNA techniques to Screen LDLR gene.
DNA change Pro664Leu
* Carrier LDLR mutation 2
MI 59
Is this true FH ? or is
it something else
“Familial Combined”
Chol/TG
mmol/l
7.7/3.5
72y
7.8/1.9
68y 3 4 5
4.4
8.1/1.7
6.7/2.5
8.7/1.6
5.6
Confirm FH,
Encourage
maintenance
of good diet etc
Reassure
4.1 7y
5.4 5y FH
Carriers ?
Using DNA assay
None carry mutation
4.5 9y
5.7 6y
Average for Children ~4.9. FH > 6.7

11. Open symbol Normal Chol.
GENETIC DIAGNOSIS IN FH FAMILY M 1 2 *
Open symbol Normal Chol.
Filled symbol
High Chol.
* Carrier of P644L
MI at 29yrs
5.6
43y
9.0
37y *
Dietary advice
statin later
Reassure others N 5 ?
Birth 3 4 FH
carrier?
4.4 7y
3.1 5y
30th %ile

12. DNA improves Cost effectiveness of CT
Efficiency of CT based on assumption that 50% of 1st degree relatives will be FH
A Mutation identifies best families for cascade testing - Humphries et al 2006
Mutation +ve probands % relatives will be FH
Mutation -ve families only 25-30% have high cholesterol,
Those with a detected mutation have higher rate of CHD – Humphries et al 2006
CT acceptable and feasible in UK Manchester/Oxford, DH Project, Hadfield et al 2008
DNA - CT programme running in Netherlands for >10 years - Uman-Eckens et al 2002
Is Cost Effective in terms of cost per Life years gained Marks et al Humphries BMJ 2000
Allows unambiguous diagnosis in relatives and for further cascading

13. DNA test avoids false –ve diagnosis
The Overlap Problem
Collaboration with John Kastelein et al Amsterdam
Data on 2469 non-carriers
and 825 carriers of family mutation.
Analyse by age
2.2mmol/l
Data from Starr et al 2008
4.6mmol/l
Gets worse
with age! FH
False +ve = 8%
False –ve = 15%
3.2mmol/l
mmol/l
DNA test avoids false –ve diagnosis

14. DNA testing for identification of relatives
Starr et al Clin Chem Lab Med 2008
5-15 years
45-54 years
2.2 mMol/l
3.1 mMol/l
4.6 mMol/l
4.6 mMol/l SB SB
4.2mmol/l
False +ve = 8%, False –ve = 15%
False +ve = 16%, False –ve = 46%
As mean LDL-C rises with age in non-FH, overlap increases.
DNA testing gives an unambiguous result

15. Cascade Method uses Trained and supported “Genetic Nurses”
LDL-C Diagnostic Tables for 1º relatives
SB LDL-Cut-offs too high for Relatives
Appropriate specificity and sensitivity
for 1/500
In 10 relatives probability = ½
NICE recommends to use diagnostic
chart from Starr et al 2008
Considerable “grey aea” – have to
retest and follow up
Key
Likely FH
Uncertain
Unlikely FH
Cascade Method uses Trained and supported “Genetic Nurses”
Age 

16. Method used for Cascading
Hadfield et al Ann Clin Chem 2008
A clinical diagnosis of FH is confirmed and a DNA test offered
Index case invited to discuss family tracing with FH nurse
Family pedigree is drawn and used to identify first degree relatives who should be offered testing
Relatives are contacted directly by nurse or via index case
Relatives are offered a point-of-care test at the clinic or at home (or are advised to visit their GP for a test)
All relatives offered a DNA AND lipid test.
When FH suspected GP asked to refer the patient to lipid clinic.
Fact File
GP to 32 year old sister of FH patient “You’re a young woman you don’t want to be taking tablets for the rest of your life”. Her cholesterol was 9.
Need GPs to identify and refer suspect FH and to support CT in relatives.

17. Detection rate using LDL- cut-offs
DH FH Audit and Cascade project
4.5 per Index Case
Hadfield et al Ann Clin Chem 2009
2.5 per
Index Case
46% under
25 years
66%
60%
36%
High acceptance rate, but low pick up of new FH due to out-of-catchment loss & low sensitivity of LDL-C cut-offs

18. Supports acceptance and utility of DNA based-cascade testing.
Improved detection rate in DNA cascade
Hadfield et al Ann Clin Chem 2009, Taylor et al Clin Genet in press
DH-Cascade based on LDL-C cut-offs
545 index cases  591 relatives tested  211 “FH”
35.7%
1.1 / proband
DH-Cascade based on DNA diagnosis
100 index cases  296 relatives tested  166 Mut+ve
2.9 / proband*
56.1%*
* p < vs LDL-C arm
Supports acceptance and utility of DNA based-cascade testing.

19. NICE Health Economics Modeling of CT
Nehero, Thorogood, Neil, Humphries in prep
Compared CT by
Cost/QALY
£1184
£1463
£1456
£1376
LDL-Cholesterol only
DNA only (only CT from mutation +ve probands)
DNA where mutation plus LDL-C in DFH
DNA where mutation plus LDL-C in DFH + PFH
Compared to LDL-C only, use of DNA where a mutation can be found
plus using LDL for identification of FH relatives in DFH + PFH gave most QALYs,
with an Incremental Cost Effectiveness Ratio of ~£2700/QALY
Compared to the NICE threshold of £20,000 this is
VERY GOOD VALUE !

20. Funding now identified for 2009-2010 national roll out
Audit of FH management in UK
Humphries, Young, Potter et al
On-going through Royal College of Physicians
Obtained 1 yr funding from DH
Established Steering group with reps from Colleges/stakeholders
Developed web-based information capture system using NICE recs
Trialled in 14 lipid clinics throughout England and Wales – 248 notes
Reported in June 2008.
Patient management good
Additional resources will be needed to manage increased numbers
Funding DNA testing not widely available (1/14)
No systematic CT - opportunistic only
Only ad hoc shared care and pediatric arrangements
Key Findings
Funding now identified for national roll out

21. Agreed and stable funding streams from commissioners
What do we need for an integrated effective FH Management Programme ?
Programme must be a UK-wide Network
FH clinics run by Lipidologists
Access to Pediatric input
Trained “Genetic” FH Nurses for Cascade Testing
DNA testing by accredited Genetics Labs
National Register – link families and avoid duplication
Appropriate Computer software and connectivity
Core Data set and agreed Quality Standards
Audit of service  X X  X   
Agreed and stable funding streams from commissioners

22. Challenge for next 10 years is to find the 100,000 FH patients in UK
FH Research - the Time Line
Dequker et al 2004, Medical Archaelogy IMAJ
years
Madonna Lisa Maria di Gherardini
Born Florence 1479
Died age 37 years
Xanthelasma?
Xanthoma?
Challenge for next 10 years is to find the 100,000 FH patients in UK

23. National Register is key NICE recommendation Why a National Register?
Computer and IT needs
Hadfield et al DH report 2007
Key Requirements are:
Draws Pedigree
Collects agreed core (clinical and personal) data set
Maintains high level of data confidentiality and security (encryption)
Manages patient pathway (invite/follow up letters, appointments etc)
Compatibility with healthcare IT structures
Enables connectivity across SHA/Devolved province borders.
National Register is key NICE recommendation
Dutch StOh CT programme have developed a package that achieves this.
Commercially available and supported
Package being trialled in Wales -Ian McDowell et al
Will report on findings in next 6 months
Why a National Register?

24. requires ability to contact
Why is a National Register Needed ?
Hadfield et al 2008
Examined in DH FH project
On ave 34% 10 rels lived outside
catchment area
Highest % in London and SE
Lowest contact success
Efficiency of any CT
requires ability to contact
distant relatives.
DNA testing by postal
mouthwash sample

25. What about Screening children?
Proposed by Wald et al BMJ 2007
Screen all children for high cholesterol at the time of childhood immunisation,
Test the parents of the identified children  one with highest Chol has FH
“elegantly screens for FH in two generations simultaneously… with the potential
of preventing premature CHD in nearly everyone with the disorder.”
No data on acceptability of the test to parents (and therefore take-up rate)
No data on cost of the programme (and therefore cost- effectiveness)
Overlap in Chol levels of FH and non-FH children is >> than used in model
Counter - Hadfield and Humphries BMJ 2007
Currently only CT from known adult index cases is tried and tested and demonstrated to be acceptable and cost effective