Dr Kate Shipman Consultant Chemical Pathologist University Hospitals Sussex - PowerPoint Presentation

1. Dr Kate ShipmanConsultant Chemical Pathologist University Hospitals SussexFamilial Hypercholesterolaemia

2. 2Learning ObjectivesUse a screening tool to identify possible cases of familial hypercholesterolaemia.Counsel a patient in regards to a referral for genetic testing.Perform a focussed annual review on known people with FH as per locally commissioned service.

3. NHS Long Term Plan (2021)CVD cause of 25% of deaths in UK and inequitable (poorer outcomes in deprived areas)Focus on: ABC – AF, Blood Pressure, CholesterolIdentify 25% of familial hypercholesterolaemia cases (currently 7%) within 5 yearsAim is to prevent 150,000 heart attacks, strokes and dementia cases over 10 years3

4. 4Introduction to Familial HypercholesterolaemiaAffects 1 in 250 people 20% of whom are childrenAutosomal dominant inheritance (five different genes)Mutations prevent LDL particle uptake which leads to uninhibited intracellular cholesterol synthesis and high circulating cholesterol concentration

5. Low LDL-C Levels are Physiologically Normal30 (0.8 mmol/L) at birthFigure 1: Yi et al. Scientific Reports. 2009;9:1596; Hochholzer et al. Ther Adv Cardiovasc Dis 2010;4(3):185191.

6. Presentation Title6LDL is associated with increased CVD risk

7. European Heart Journal 2015 36;2425-37LDL ‘burden’Star B et al Clin Chem and Lab Medicine 2008 48(6):791-803EventsEvents avoided*MI141Stroke262Heart Failure142Revascularisation34Unstable Angina41CV Death101*per 1000 optimally treated vs no treatmentHeart UK Saving Lives Saving Families

8. Star B et al Clin Chem and Lab Medicine 2008 48(6):791-803Detecting FHThe wide variety of mutations and phenotypic variability have made it difficult to establish definite diagnostic criteria.Multiple sets of clinical criteria: Simon Broome criteriaDutch Lipid Clinic criteria Modified WelshAmerican criteria

9. HomozygoteLDL-C11 mmol/L13 mmol/LPremature atheroscl. CVD

10. And: Dutch Lipid Network Criteria for Heterozygous FH in adults ... PointCriteria1DNA mutation2Tendon xanthomas in patient or 1st/2nd-degree relative3Family history MI <50 in 2nd-degree or <60 in 1st-degree relative4Family history of cholesterol >7.5 in 1st/2nd-degree relative5Cholesterol >7.5 (adult) or >6.7 (age <16 years)6LDL-C >4.9 (adult) or >4.0 (age <16 years)Definite(5 or 6) + 1Probable(5 or 6) + 2Possible(5 or 6) + (3 or 4)Also: Modified Simon Broome Criteria

11. CriteriaPointsGroup 1: Family Hx1st degree relative with CHD <55 men (<60 women) or11st degree relative with LDL-C >95th centile by age, gender for country11st degree relative with tendon xanthomata and/or corneal arcus or2Children <18 with LDL-C >95th centile by age, gender for country2Group 2: Personal clinical historyCHD <55 men (<60 women)2Cerebrovascular or peripheral vascular disease <55 men (<60 women)1Group 3: Physical examinationTendon xanthomata6Corneal arcus in subject <454Group 4: LDL-c level (mmol/L) >8.58 6.5-8.45 5.0-6.43 4.0-4.91Group 5: Genetic testingCausative mutation (LDLR, ApoB, PCSK9)8Scoring: Definite: >8, Probable: 6-8, Possible: 3-5, Unlikely: 0-2

12. Scoring Criteria for index cases with possible Familial Hypercholesterolaemia (Modified Welsh)PointsFamily HistoryFirst degree relative (FDR) known with CHD <60yrsFDR known with LDL-C > 5mmol/lFDR with tendon xanthomata and/or arcus (< 45yrs)FDR (<18yrs) with LDL-C > 3.5mmol/l1122PhysicalExaminationTendon xanthomataCorneal arcus (< 45yrs)64LipidLoweringTreatmentIs patient on lipid lowering treatment? YES / NOIf NO, go to Untreated LDL- Cholesterol ConcentrationsIf YES, find untreated or estimate using Correction FactorsUntreated or corrected LDL- C (mmol/l)LDL-C > 8.5 LDL-C 6.5 – 8.4 LDL-C 5.0 – 6.4 LDL-C 4.0 – 4.9 8531Fasting Triglycerides(mmol/l)Tg 2.5 – 3.5Tg 3.5 – 5Tg > 5minus 2minus 3minus 4>8 usually eligible for genotyping , 6-8 eligible if funding available, 5 or less usually not unless exceptional circumstances

13. 13K. Haralambos et al. Atherosclerosis 240 (2015) 190e196

14. Genetics>2000 mutations described in:LDLR, APOB, PCSK9, APOEMost people with no mutation have ‘polygenic’ hypercholesteterolaemia so no cascade screening (and importance to validate the existing register)NHS England and NHS Improvement London » Familial Hypercholesterolemia (FH)VUS rarely found, but can be investigated if so14

15. Cascade ScreeningServices not commisioned however:Lipid clinic will attempt as much as possibleFH nurse being provided to cover all of London/KSSRoyal Brompton direct access serviceRelative led screening (Heart UK ‘Find a lipid clinic’)All relatives <10 years old with one parent (<5 years old if both, or already showing signs)15

16. ManagementLDL target is <50% = easily possible, not what is preferableUse secondary prevention target if applicableLDL reduction may be less that expected All treated by 10 years old (note not whilst trying to get/are pregnant or breast feeding)CVD annual reviewNote baseline LDL will increase overtime so targets become more difficult to meet16

17. SSX-LCS016 Familial HypercholesterolaemiaNHS Long Term Plan prompting systematic case findingIn the anticipation we succeed in identifying our FH population we need a robust plan to then provide long term excellent careLipid clinic is lacking in resource to expand greatly, FH long term care mostly very straight forward Therefore provides information on case finding and then subsequently management17

18. SSX-LCS016; FH Case IdentifcationFirstly validate existing ‘FH’ diagnoses. All should be confirmed genetically unless there are no relatives who would benefit.Excluding those already diagnosed, assessed, or having declined assessment for FH,Younger than 30y with a recorded: TC >7.5 mmol/l; non-HDL >6.0 mmol/l; LDL >4.9 mmol/l30y or older with a recorded:TC >9.0 mmol/l; non-HDL >7.5 mmol/l18‘Low hanging fruit’ i.e. the most obvious first for screening. Avoid wasted appts

19. SSX-LCS016; FH Case IdentifcationLipids measured twice at least, and secondary causes excluded:uncontrolled diabetes mellitusobesityexcess alcohol consumptionuntreated hypothyroidismthiazide diureticsciclosporin19Then use Simon Broome or DLCNcriteria

20. Whilst awaiting clinicIf you have measured lipids twice and you think this is FH then no barrier to stop you from starting treatmentPrimary prevention, document target (LDL <50%)Atorva 20mg, then dose increase and add ezetimibe 10 mg until at targetConsider injectables and bempedoic acid as per lipid modification pathways – note some thresholds lower if ‘FH’20

21. Values only if LDL-C is persistently >value.1 High risk CVD is a history of: ACS (MI or unstable angina needing hospitalisation); coronary or other arterial revascularisation procedures; chronic heart disease; ischaemic stroke; peripheral arterial disease.2 Very high risk CVD is defined as recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed.PCSK9 InhibitorsAlirocumab or EvolucumabWithout CVDWith CVDHigh risk of CVD1Very high risk CVD2Primary non-FH or mixed dyslipidaemiaNot recommended>4.0 mmol/l>3.5 mmol/lPrimary heterozygous-FH>5.0 mmol/l>3.5 mmol/l

22. lipid-management-pathway-03092020.pdf (england.nhs.uk)Lipid Update22NHS Accelerated Access Collaborative » Summary of national guidance for lipid management (england.nhs.uk)

23. SSX-LCS016; Annual ReviewLast part of LCSWith validated register, offer structured annual review (>16 yo and not under specialist review)1) Symptoms of CVD2) Baseline ECG3) Enquire re progress of cascade screen (particularly children) – prompt pt/refer if they are ‘your’ patients23

24. SSX-LCS016; Annual Review4) Lifestyle review: smoking, alcohol, exercise etc… (note diet will not significantly change cholesterol – FH is genetic NOT dietary)5) check LDL is at target (target should be clear at entry on register)6) Medication review, concordance etc.7) Contraception/pregnancy issues if relevant (see advice in guidance but effectively stop statin prior to pregnancy and refer to obstetricians)8) addresss concerns and refer to lipid specialist according to guidance… 24

25. SSX-LCS016; Reasons to be seen in secondary careLDL is above target and eligible for drug escalation e.g. PCSK9iComplex counselling requirements such that patient wishes to discuss with clinic (note Heart UK also have helpline e.g. if question is about diet, insurance etc)Significant new comorbidity complicating managementNote new onset diabetes or alcohol etc are better referred to diabetes/alcohol servicesNote low threshold for considering atherosclerotic complication despite young ages e.g. a 23 yo with chest pain could be suffering ACS, SOB after delivery may not just be post-partum anaemia(Obstetric review if pregnant, Paediatrics for children, Cardio if chest pain , Lipid clinic otherwise)25

26. Where else to go to for help?Heart UK: CPD, courses, conferences, patient resources, helpline, dietary and lifestyle informationBritish heart foundation: information, more slanted towards ACS/heart failure but still a lot of excellent resources FH Europe: the european patient network – for relatives not in the UK (note various other global charities etc)26

27. 27Questions

28. Statins safe in childrenEuropean Heart Journal 2015 36;2425-37

29. 29TestResultTotal Cholesterol (mmol/l)8.2Triglyceride (mmol/l)1.3HDL (mmol/l)1.1LDL (mmol/l)6.5Family history: <60 yo in 1st degree relatives, <50 yo in 2nd degree; Atherosclerotic CVD; not severe Type 1 DM etc… Sudden death = red flagDifficult – poor knowledge/never knew, non-paternity etc.35 year old man, family history of premature CVD

30. 30TestResultTotal Cholesterol (mmol/l)8.2Triglyceride (mmol/l)1.3HDL (mmol/l)1.1LDL (mmol/l)6.5[Rule out hypothyroidism and nephrotic syndrome (post menopausal FH, polygenic)]Familial hypercholesterolaemia35 year old man, family history of premature CVD