This document discusses Familial Hypercholesterolaemia (FH), a common genetic condition characterized by abnormally high cholesterol levels. It notes that FH affects approximately 110,000 people in the UK, but less than 25% are currently diagnosed and treated. The document then provides details on the causes and inheritance of FH, clinical diagnosis criteria, prognosis if left untreated, and strategies for screening and managing FH patients and their families.

1. Familial Hypercholesterolaemia Jamie Smith

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

3. Familial Hypercholesterolaemia (FH) Hypercholesterolaemia – Xanthomatosis – Premature CHD

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

5. 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

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

7. 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

8. 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

9. The Fate of LDL LDLR

10. The Fate of LDL LDLR PCSK9 prevents LDLR recycling

11. 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

12. Prognosis in heterozygous FH Heiberg & Slack BMJ. 1977;ii:493

13. 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)

15. 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

17. 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.

18. DOH FH Cascade Testing Audit Project Classification of FH patients according to Simon Broome Criteria July 2007

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

20. 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

23. Gender and age specific LDL-C criteria graphs for cascade testing DOH FH Cascade Testing Audit Project

24. 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

25. 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

26. 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

27. 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

28. 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

30. Results

34. Audit standards

35. How should we implement NICE guidance on FH locally?

36. 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

37. 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)

40. 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 +

41. The Wales FH Cascade Testing Initiative Dr Ian McDowell

43. 18,000 diagnosed with FH.Database: Pass Clinical Wales clinical pilot of database commenced 2009

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

46. Family registration

47. Family Tracing

48. 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

49. 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)