Familial Hypercholesterolaemia<br />Jamie Smith<br />
FH is common <br />~ 110,000 in UK<br />~ 6,000 in Wales<br /><25% diagnosed and treated <br />
Familial Hypercholesterolaemia (FH)<br />Hypercholesterolaemia – Xanthomatosis – Premature CHD<br />
Typical Family Tree<br />Age<br />Cholesterol, mmol/L<br />Age<br />Cholesterol, mmol/L<br />
The Primary Hyperlipidaemias<br />Familial Hypercholesterolaemia (FH) – single gene abnormalities which alter LDL-R functi...
Lipoprotein Structure<br />Surface – amphipathic<br />Free cholesterol<br />Phospholipids<br />Apoproteins – amphipathic h...
Lipoprotein metabolism – endogenous pathway<br />Heart<br />Skeletal muscle<br />Adipose tissue<br />Lactating breast<br /...
Lipoprotein metabolism – endogenous pathway<br />Heart<br />Skeletal muscle<br />Adipose tissue<br />Lactating breast<br /...
The Fate of LDL<br />LDLR<br />
The Fate of LDL<br />LDLR<br />PCSK9 prevents<br />LDLR recycling<br />
FH: LDL-receptor mutations <br />>1000 mutations in LDL-receptor<br />Chromosome 19<br />Heterozygotes 1 in 500<br />Homoz...
Prognosis in heterozygous FH<br />Heiberg & Slack BMJ. 1977;ii:493<br />
Prognosis in heterozygous FH<br />Cumulative risk of fatal and non-fatal CHD<br />50% by age 50yr in men<br />30% by age 6...
Prognosis in HeFH has improved since advent of statins<br />SMR for CHD fell by 37% (RR 3.4 to 2.1, age 20-79) in 1992-200...
Heterozygous FHDiagnosis<br />Simon Broome Register criteria<br />definite FH<br />TC > 7.5 or LDL-C > 4.9 mmol/l<br />(TC...
DOH FH Cascade Testing Audit Project<br />Classification of FH patients according to           Simon Broome Criteria<br />...
National Screening Program Familial<br />Hypercholesterolemia<br />Peter Lansberg<br />StichtingOpsporingFamiliaire Hyperc...
Detection of heterozygous FHCascade screening<br />259 FH probands from Central & South Manchester Lipid Clinics<br />121/...
Gender and age specific LDL-C criteria graphs for cascade testing<br />DOH FH Cascade Testing Audit Project<br />
LDL-C levels in mutation positive (red) and mutation negative (blue) relatives<br />Ages 5-15<br />Ages 45-54<br />Umans-E...
Utility of DNA testing<br />Mutations found in 40-90% of clinical FH depending on degree of clinical suspicion and methods...
Screening for FHConsequences for life insurance<br />Netherlands – programme to detect all (~40,000) patients by 2010 (DNA...
FH in children<br />US guidelines recommend screening children with family history of hyperlipidaemia or premature CVD at ...
Audit of FH diagnosis and management in Torbay 2009<br />Used notes of diagnosed FH patients<br />Filled out ‘questionnair...
Results<br />
Audit standards<br />
How should we implement NICE guidance on FH locally?<br />
Case of SM<br />58 yr old female<br />FH diagnosed in 1980s<br />Cholesterol 16 mmol/L, normal HDL, Trigs<br />No CVD but ...
Re-tried with rosuva 5mg od<br />Chol 9.4		LDL 7.35	HDL 1.4	trig 1.43<br />Family history<br />Mother – raised chol and CH...
Repeat fasting and check TFTs for hypothyroidism <br />Are there any secondary causes of hypercholesterolaemia?<br />(see ...
The Wales FH Cascade Testing Initiative<br />Dr Ian McDowell<br />
Dutch database<br />Dutch national screening programme for FH<br /><ul><li>Over 45,000 family members
18,000 diagnosed with FH.</li></ul>Database: Pass Clinical<br />Wales clinical pilot of database <br />    commenced 2009<...
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Familial hypercholesterolaemia

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Familial hypercholesterolaemia

  1. 1. Familial Hypercholesterolaemia<br />Jamie Smith<br />
  2. 2. FH is common <br />~ 110,000 in UK<br />~ 6,000 in Wales<br /><25% diagnosed and treated <br />
  3. 3. Familial Hypercholesterolaemia (FH)<br />Hypercholesterolaemia – Xanthomatosis – Premature CHD<br />
  4. 4. Typical Family Tree<br />Age<br />Cholesterol, mmol/L<br />Age<br />Cholesterol, mmol/L<br />
  5. 5. The Primary Hyperlipidaemias<br />Familial Hypercholesterolaemia (FH) – single gene abnormalities which alter LDL-R function (Soutar and Naoumova, Nature Clin Pract Cardiovasc Med 2007;4:214)<br />Autosomal Dominant Hypercholesterolaemia (ADH)<br />LDL-receptor mutations (“Classical FH”)<br />Familial Defective apolipoprotein B (FDB)<br />PCSK9 mutations (FH3)<br />Autosomal Recessive Hypercholesterolaemia (ARH)<br />[Phytosterolaemia (Sitosterolaemia)]<br />Familial Combined Hyperlipidaemia (FCH)<br />Familial Dysbetalipoproteinaemia (type III)<br />Chylomicronaemia<br />
  6. 6. Lipoprotein Structure<br />Surface – amphipathic<br />Free cholesterol<br />Phospholipids<br />Apoproteins – amphipathic helix<br />Core – hydrophobic<br />Neutral lipids<br />-Cholesteryl esters<br />-Triglycerides<br />
  7. 7. Lipoprotein metabolism – endogenous pathway<br />Heart<br />Skeletal muscle<br />Adipose tissue<br />Lactating breast<br />B100<br />TG<br />Chol<br />FA<br />2-MG<br />CII<br />VLDL<br />LPL<br />TG<br />Chol<br />Lp surface<br />FC, PL<br />apoC<br />Remnant<br /> IDL<br />HDL<br />
  8. 8. Lipoprotein metabolism – endogenous pathway<br />Heart<br />Skeletal muscle<br />Adipose tissue<br />Lactating breast<br />B100<br />TG<br />Chol<br />FA<br />2-MG<br />CII<br />VLDL<br />LPL<br />TG<br />Chol<br />Remnant<br /> IDL<br />Hepatic lipase<br />TG<br />Chol<br />LDL<br />Liver<br />Periphery<br />
  9. 9. The Fate of LDL<br />LDLR<br />
  10. 10. The Fate of LDL<br />LDLR<br />PCSK9 prevents<br />LDLR recycling<br />
  11. 11. FH: LDL-receptor mutations <br />>1000 mutations in LDL-receptor<br />Chromosome 19<br />Heterozygotes 1 in 500<br />Homozygotes 1 in a million<br />Founder effects<br />Michael Brown & Joseph Goldstein<br />
  12. 12. Prognosis in heterozygous FH<br />Heiberg & Slack BMJ. 1977;ii:493<br />
  13. 13. Prognosis in heterozygous FH<br />Cumulative risk of fatal and non-fatal CHD<br />50% by age 50yr in men<br />30% by age 60yr in women<br /> (Pre-statin)<br />Slack, Lancet 1969;ii:1380<br />Stone et al. Circulation 1974;49:476<br />See also Marks et al. Atherosclerosis 2003;168:1<br />Austin et al. Am J Epidemiol 2004;160:407-435 (3 papers)<br />
  14. 14.
  15. 15. Prognosis in HeFH has improved since advent of statins<br />SMR for CHD fell by 37% (RR 3.4 to 2.1, age 20-79) in 1992-2006 compared with 1980-1991<br />Excess mortality from CHD mainly in younger patients (<60 yr)<br />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) <br />Neil et al. Eur Heart J 2008;29:2625<br />
  16. 16.
  17. 17. Heterozygous FHDiagnosis<br />Simon Broome Register criteria<br />definite FH<br />TC > 7.5 or LDL-C > 4.9 mmol/l<br />(TC > 6.7 or LDL-C > 4.0 for children < 16 yr)<br />plus Tendon xanthomata in 1st or 2nd degree relative<br />or LDL-receptor or apoB-100 mutation<br /> possible FH<br />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<br />Simon Broome Register Group. BMJ 1991;303:893-6.<br />Simon Broome Register Group. Atherosclerosis 1999;142:105-12.<br />
  18. 18. DOH FH Cascade Testing Audit Project<br />Classification of FH patients according to Simon Broome Criteria<br />July 2007<br />
  19. 19. National Screening Program Familial<br />Hypercholesterolemia<br />Peter Lansberg<br />StichtingOpsporingFamiliaire Hypercholesterolemie (StOEH)<br />
  20. 20. Detection of heterozygous FHCascade screening<br />259 FH probands from Central & South Manchester Lipid Clinics<br />121/200 first degree relatives had FH<br />Need to screen 60,000 individuals to find same number with non-selective screening<br />Cascade screening reviewed<br />Hadfield and Humphries, Curr Opin Lipidol 2005;16:428<br />Bhatnagar et al.<br />BMJ 2000;321:1497<br />
  21. 21.
  22. 22.
  23. 23. Gender and age specific LDL-C criteria graphs for cascade testing<br />DOH FH Cascade Testing Audit Project<br />
  24. 24. LDL-C levels in mutation positive (red) and mutation negative (blue) relatives<br />Ages 5-15<br />Ages 45-54<br />Umans-Eckenhausen et al. 2001. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357:165-168<br />
  25. 25. Utility of DNA testing<br />Mutations found in 40-90% of clinical FH depending on degree of clinical suspicion and methods used<br />Facilitates diagnosis in children especially<br />DNA testing gives unequivocal diagnosis<br />~25% of individuals in families may be misclassified on cholesterol testing alone<br />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<br />Cost<br />£400 for entire gene screen<br />£60 for 20 commonest mutations<br />£60 to test relative in family with known mutation<br />Gail Norbury (norbug@gosh.nhs.uk)<br />Humphries et al. Curr Opin Lipidol 2008;19:362<br />
  26. 26. Screening for FHConsequences for life insurance<br />Netherlands – programme to detect all (~40,000) patients by 2010 (DNA testing)<br />FH regarded as serious but treatable<br />Insurers can use clinical information to calculate mortality ratings<br />Risk should be assessed on phenotype and not on presence or nature of mutation<br />Accepted at normal rates if LDL-C <4 and no other CVD risk factors<br />Homsma et al. Eur J Hum Genet 2008;16:14<br />
  27. 27. FH in children<br />US guidelines recommend screening children with family history of hyperlipidaemia or premature CVD at 2-10 yr<br />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)<br />Statins safe and effective over 6 weeks to 2 years (meta-analyses of atorva, lova, prava and simva trials)<br />Limited data suggest improvement in IMT and endothelial function<br />Treating children and adolescents at highest risk (male, family history of event in 3rd or 4th decade) probably justifiable. Statins may be teratogenic<br />Arambepola Atherosclerosis 2007;195:339<br />Avis et al. ATVB 2007;27:1803<br />Daniels et al. Pediatrics 2008;122:198<br />
  28. 28. Audit of FH diagnosis and management in Torbay 2009<br />Used notes of diagnosed FH patients<br />Filled out ‘questionnaires’ on various aspects of management of the condition<br />Collated results in a database and analysed the data<br />Set audit standards according to what results should be reached using NICE guidelines on FH<br />Patient demographics:<br />Total of 24 patients<br />10 females, 14 males<br />Age range: 14 to 70<br />Average age: 47<br />
  29. 29.
  30. 30. Results<br />
  31. 31.
  32. 32.
  33. 33.
  34. 34. Audit standards<br />
  35. 35. How should we implement NICE guidance on FH locally?<br />
  36. 36. Case of SM<br />58 yr old female<br />FH diagnosed in 1980s<br />Cholesterol 16 mmol/L, normal HDL, Trigs<br />No CVD but hypertension (BP 170/90) and obesity (BMI 35)<br />Ongoing problems with suspected tendonitis associated with xanthomas<br />Problems tolerating lipid-lowering meds<br />Cholestyramine – GI problems<br />Statins<br />Nicotinic acid<br />ezetimibe<br />
  37. 37. Re-tried with rosuva 5mg od<br />Chol 9.4 LDL 7.35 HDL 1.4 trig 1.43<br />Family history<br />Mother – raised chol and CHD in 60s with CABG<br />Died aged 89 of stroke<br />2 brothers with possible FH – neither has CHD<br />3 children – 33 yr old daughter with chol 6.8, 31yr and 24yr old sons – chol unknown (although tested in childhood)<br />
  38. 38.
  39. 39.
  40. 40. Repeat fasting and check TFTs for hypothyroidism <br />Are there any secondary causes of hypercholesterolaemia?<br />(see table)<br />YES<br />NO<br />Manage secondary causes and reassess<br />Repeat fasting LDL-C is > 4.9 mmol/l?<br />YES<br />NO<br />Is there a personal or family history of premature CHD*or<br />tendon xanthoma<br />Manage CVD risk as per guidelines for primary and secondary prevention and type 2 diabetes<br />*Premature CHD:<br /><60 years in 1st degree relative and <50 years in 2nd degree relative <br />NO<br />YES<br />REFER TO LIPID CLINIC<br />Total cholesterol > 7.5 mmol/l and/or LDL–C (fasting) > 4.9 mmol/l<br />Some causes of secondary hypercholesterolaemia:<br />Cause Cholesterol <br />hypothyroid ++ <br />CKD + <br />Nephrotic synd ++ <br />Hepatic cholestasis ++/+++ <br />Pregnancy +/- <br />Anorexia + <br />Long term steroids + <br /> antipsychotics +/+++ <br />Ciclosporin + <br />
  41. 41. The Wales FH Cascade Testing Initiative<br />Dr Ian McDowell<br />
  42. 42. Dutch database<br />Dutch national screening programme for FH<br /><ul><li>Over 45,000 family members
  43. 43. 18,000 diagnosed with FH.</li></ul>Database: Pass Clinical<br />Wales clinical pilot of database <br /> commenced 2009<br />
  44. 44. Key Features<br />Pedigree drawing function<br />Workflow management<br />Templates and archiving<br />Multisite working<br />Audit and research<br />
  45. 45. ???FH<br />Family Cascade Programme <br /><ul><li>Full Pedigree
  46. 46. Family registration
  47. 47. Family Tracing
  48. 48. Test 1st degree relatives </li></ul>??FH<br />Hospital<br />(eg Cardiology)<br />General <br />Practice<br />Lipid Clinic<br />Cascade from<br />relatives<br />Clinical and lipid assessment Provisional diagnosis of FH using SB criteria<br />Genotype positive<br />FH <br />FH X<br />Document family history<br />FH diagnosed<br />Referred to lipid clinic<br />FH excluded<br />in relative<br />Consultation to advise on FH treatment options<br />Genotyping<br />Treat hyperlipidaemia<br />Discharged from cascade programme: <br />Continuing care<br />Primary care (most)<br />Continuing care<br />Secondary care(some)<br />Continuing care<br />Paediatrics (some)<br />Patient Pathway with Cascade Testing<br />
  49. 49. Welsh Assembly Government<br />Cardiff and Vale NHS Trust<br />Cardiac Networks for Wales<br />Clinical Director<br />All Wales Genetic Service<br />FH professional steering group<br />Senior Nurse manager<br />AWGS Lead genetic counsellor<br />FH Project Manager<br />Data base & project administrator<br />FH genetic counsellor<br />(S)<br />FH genetic counsellor<br />(N)<br />FH nurse<br />(M&SW)<br />FH nurse<br />(SE)<br />FH nurse<br />(N)<br />

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