1. Dr Catherine Taylor GPST2 Familial Hypercholesterolaemia

2. Why? Curriculum statement 6: Genetics in Primary Care By age 60 if left untreated 50% of men and 30% of women will have had an MI If identified risks can be significantly reduced

3. Pathology and Genetics Caused by a mutation in the pathway that clears LDL – usually the LDL receptor Autosomal dominant so a child has a 50% chance of inheriting the gene from an affected parent In the heterozygous state has a prevalence of 1 in 500 Homozygous state approx 1 in 1 million – symptoms in childhood and early death from CHD

4. Diagnosis Consider a diagnosis of homozygous FHc if LDL >13 (or 11 in individuals under 16 years) If homozgous FHc suspected refer to a specialist centre

5. Diagnosis cont. Consider the diagnosis of heterozygous FHc in adults with a total cholesterol of >7.5mmol/l especially if there is a personal or family history of premature CHD

6. Simon Broome Diagnostic Criteria DEFINITE if: Cholesterol >7.5/LDL >4.9 (6.7/4 in <16) AND either Tendon Xanthomas (in self or 1 st or 2 nd degree relative) OR DNA confirmed mutation

7. POSSIBLE if: Cholesterol >7.5/LDL >4.9 ( >6.7 with LDL 4 if <16) AND EITHER Family Hx of MI (<60 in 1 st degree relative < 50 in 2 nd degree) OR Family Hx of cholesterol > 7.5 in 1 st or 2 nd degree adult relative

8. Referral Refer those with a clinical diagnosis or possible diagnosis to “a specialist centre” Refer to a cardiologist if homozygous FHc is suspected or in anyone who has Sx of IHD or anyone with two or more CV risk factors DO NOT use CHD risk calculators to assess risk – the grossly underestimate in FHc

9. Cascade Testing Detailed family history of at least 3 generations DNA testing – should be offered to everyone with a clinical diagnosis If a mutation is identified genetic testing should be offered to all at risk – DO NOT assess risk using LDL concentration If found not to carry the gene then manage risk as in normal population If has a clinical diagnosis but no mutation identified then use standardised LDL concentrations to diagnose familiy members (Specialist) Consider screening all 1 st and 2 nd degree relatives and 3 rd degree if possible.

10. Management Lifelong treatment with statins first line Other treatments include ezetimibe and bile acid sequestrants Aim to reduce LDL by more than 50% Lifestyle advice Statins not recommended during pregnancy COCP not contraindicated but alternatives should be considered due to slight increased CV risk

11. Evidence BMJ 2008;337:a2423 Immediate vs delayed treatment 2000 pts in Netherlands MI risk reduction of 76% in early treatment group Risk of MI in early treatment group similar to normal population Even though average statin dose lower than currently recommended (mean dose 33mg) mean reduction in LDL around 44%

12. Messages Consider diagnosis when total cholesterol >7.5 Use Simon Broome criteria to make diagnosis Cascade testing required including at risk children Don’t use CV risk calculators Offer specialist referral Early identification and treatment significantly reduces the risk of MI

13. References GP update handbook BMJ 2008:337:a2423 Efficacy of statins in familial hypercholesterolaemia: a long term cohort study NICE guideline on Identification and Management of Familial Hypercholesterolaemia