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Guideline Development Group (GDG) GP Chair: Dr Rubin Minhas Lead Advisor : Prof Steve Humphries Lipidologists : Prof Andrew Neil, Dr Mary Seed, Dr Ian.

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Presentation on theme: "Guideline Development Group (GDG) GP Chair: Dr Rubin Minhas Lead Advisor : Prof Steve Humphries Lipidologists : Prof Andrew Neil, Dr Mary Seed, Dr Ian."— Presentation transcript:

1 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 Royal College General Practictioners Core Team : Kathy DeMott, Leo Nherera, Meeta Kathoria, Beth Shaw, Gill Richie, Vanessa Nunes, Nancy Turnball Issue date:August 2008 NICE clinicalguideline 71 Developed by the NationalCollaborating Centre for Primary Care Identification and management of familial hypercholesterolaemia Weirzbicki, et al BMJ 2008, Aug 27;337:1095 FH Guidelines in Practice : findings from the DH cascade and audit project and the pilot RCP audit 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, HEARTUK FH Implementation Group Dermot Neely, Jonathan Morrell

2 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 NICE priorities Key for GPs Diagnosis NICE evidence-based Guideline  DNA testing is key recommendation What genes have mutations  FH

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

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

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

6  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 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 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 p < 0.00001 51 394 190 Some (n=51) did not come with enough information to classify as Definite (n=190) or Possible FH (n=394) – (U-FH) Detection Rate Data Completed analysis on 635 proband samples from 6 sites 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 56.3% 28.4% 25.5% What about no mutation patients? Taylor et al Clin Genet 2009 in press

8 No mutation patients?  Technical reasons – No method detects all mutations. Sequencing may give more complete coverage.  Genetic heterogeneity – May be 4 th or 5 th 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 8.1 FH DIAGNOSIS IN FAMILY Y 4.1 7y 5.4 5y 4.4 Chol/TG mmol/l Does Dad have FH? Can we find the genetic cause? Can we use this information to see if either son has FH? MI age 35yrs Make a detailed family tree

10 1 3 2 4 7.7/3.5 72y 7.8/1.9 68y 6.7/2.5 8.1/1.7 CONFIRMING FH DIAGNOSIS IN FAMILY Y Confirm FH, Encourage maintenance of good diet etc Reassure 5 8.7/1.6 4.1 7y 5.4 5y 4.5 9y 5.7 6y 5.64.4 Chol/TG mmol/l Is this true FH ? or is it something else “Familial Combined” MI 59 FH Carriers ? Using DNA assay None carry mutation * ** Used DNA techniques to Screen LDLR gene. DNA change Pro664Leu * Carrier LDLR mutation Average for Children ~4.9. FH > 6.7

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

12 DNA improves Cost effectiveness of CT A Mutation identifies best families for cascade testing - Humphries et al 2006 Mutation +ve probands 50% relatives will be FH Mutation -ve families only 25-30% have high cholesterol, Efficiency of CT based on assumption that 50% of 1 st degree relatives will be FH Allows unambiguous diagnosis in relatives and for further cascading 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 Those with a detected mutation have higher rate of CHD – Humphries et al 2006

13 The Overlap Problem FH 4.44 + 1.43mmol/l 2.2mmol/l 4.6mmol/l 3.2mmol/l False +ve = 8% False –ve = 15% Collaboration with John Kastelein et al Amsterdam Data on 2469 non-carriers and 825 carriers of family mutation. Analyse by age DNA test avoids false –ve diagnosis Gets worse with age! Data from Starr et al 2008

14 DNA testing for identification of relatives 2.2 mMol/l 4.6 mMol/l As mean LDL-C rises with age in non-FH, overlap increases. DNA testing gives an unambiguous result 5-15 years45-54 years False +ve = 8%, False –ve = 15% False +ve = 16%, False –ve = 46% 3.1 mMol/l 4.6 mMol/l SB 4.2mmol/l Starr et al Clin Chem Lab Med 2008

15 LDL-C Diagnostic Tables for 1º relatives Age  Key Likely FH Uncertain Unlikely FH SB LDL-Cut-offs too high for Relatives Appropriate specificity and sensitivity for 1/500 In 1 0 relatives probability = ½ NICE recommends to use diagnostic chart from Starr et al 2008 Considerable “grey aea” – have to retest and follow up Cascade Method uses Trained and supported “Genetic Nurses”

16 Method used for Cascading 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. Need GPs to identify and refer suspect FH and to support CT in relatives. 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. Fact File Hadfield et al Ann Clin Chem 2008

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

18 DH-Cascade based on LDL-C cut-offs 545 index cases  591 relatives tested  211 “FH” 1.1 / proband 35.7% DH-Cascade based on DNA diagnosis 100 index cases  296 relatives tested  166 Mut+ve 2.9 / proband * 56.1% * * p < 0.001 vs LDL-C arm Improved detection rate in DNA cascade Supports acceptance and utility of DNA based-cascade testing. Hadfield et al Ann Clin Chem 2009, Taylor et al Clin Genet in press

19 NICE Health Economics Modeling of CT 1LDL-Cholesterol only 2DNA only (only CT from mutation +ve probands) 3DNA where mutation plus LDL-C in DFH 4DNA where mutation plus LDL-C in DFH + PFH Compared CT by Cost/QALY £1184 £1463 £1456 £1376 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 ! Nehero, Thorogood, Neil, Humphries in prep

20 Audit of FH management in UK On-going through Royal College of Physicians Funding now identified for 2009-2010 national roll out Humphries, Young, Potter et al 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

21 What do we need for an integrated effective FH Management Programme ?  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 Agreed and stable funding streams from commissioners Programme must be a UK-wide Network X X X

22 FH Research - the Time Line Madonna Lisa Maria di Gherardini Born Florence 1479 Died 1526 age 37 years Xanthoma? 1503 - 24 years Xanthelasma? Dequker et al 2004, Medical Archaelogy IMAJ Challenge for next 10 years is to find the 100,000 FH patients in UK

23 Computer and IT needs Key Requirements are: Why a National Register? Hadfield et al DH report 2007 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

24 Why is a National Register Needed ? Efficiency of any CT requires ability to contact distant relatives. Hadfield et al 2008 Examined in DH FH project On ave 34% 1 0 rels lived outside catchment area Highest % in London and SE Lowest contact success DNA testing by postal mouthwash sample

25 Proposed by Wald et al BMJ 2007 What about Screening children? Currently only CT from known adult index cases is tried and tested and demonstrated to be acceptable and cost effective 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

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