Printed on: September 9th, 2024

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Familial hypercholesterolaemia

Familial hypercholesterolaemia

• By the age of 60y, 50% of men and 30% of women with familial hypercholesterolaemia will have had an MI (BJGP 2009;59:777).
• Treatment returns cardiovascular risk to near-population risk (BMJ 2008;337:a2423). However, over a third of people with the condition in the UK are under-treated, leaving them at increased risk of CV events (BJGP 2024;e174).

• Worldwide, it affects 1 in 310 people (BMJ 2023;382:e073280). Most familial hypercholesterolaemia genes are inherited in an autosomal dominant pattern. Homozygous states are rare, but need very specialist management: liver transplant may be considered.
• In the UK, the prevalence is about 1 in 608, less than expected, suggesting that familial hypercholesterolaemia is under-recognised in UK primary care (BJGP 2024;e174).

• Reduce LDL by more than 50% from pre-treatment levels.
• Lipids clinic will try to do cascade testing to identify other family members affected.

The NICE FHc guideline (NICE 2008, CG71) was last updated in 2019. The following recommendations caught our eye:

• We should systematically search our records for people at high risk of FHc (cholesterol >7.5 if <30y, >9 if ≥30y).
• The Dutch Lipid Clinic Criteria can be used as an alternative to the Simon Broome Criteria to make a diagnosis of suspected FHc in primary care.

This article was updated in May 2024.

Before we start, just a reminder of who our relatives are:

• First-degree relatives are parents, siblings, children.
• Second-degree relatives are grandparents/grandchildren, aunts/uncles, nieces/nephews, half siblings.

NICE asks us to do two things:

1. Systematically search our records for those who have elevated cholesterols but have not been identified as having familial hypercholesterolemia.
2. Identify new potential cases when filing blood results/talking to patients about their family history.

REMEMBER:

• When measuring LDL, do 2 readings because of biological and analytical variations in levels (NICE gives no indication about the interval needed between readings!).
• If someone has a known mutation, refer regardless of LDL.

The NICE guidance is summarised in this GEMS. Please follow the link for a PDF version of the GEMS for download/printing: Familial hypercholesterolaemia: GEMS

Only 50% of those with xanthelasma (yellowish deposits in the skin around the eyes) have a lipid disorder. The other common causes are type 2 diabetes, hypothyroidism, diet, excess alcohol intake  (J Am Acad Dermatol 1994;30:236, Clin Cosmet Investig Dermatol 2018;11:1).

Clearly, some people who have dyslipidaemia will not meet the criteria for FHc, for example those with hypertriglyceridaemia. Although the NICE guidelines do not offer any advice on the management of these individuals, it would seem sensible to refer them too – they may have another lipid disorder.

Yes!

Obviously, it would be impossible to do an RCT allocating some to statins and others to placebo, but this study was able to look at patients who started treatment immediately compared with those in whom there was a delay in initiating treatment. The study involved over 2000 patients in lipid clinics diagnosed with FHc before 1990 (when simvastatin became available in the Netherlands, where this study took place). Of these, 66% had a mean delay in starting therapy of 4.3y. The two groups were slightly different in other ways – those who received immediate statins were more likely to be older (by 3.5y), have higher LDLs and total cholesterols, and lower HDLs, and be hypertensive. Mean follow-up was 8.5y (BMJ 2008;337:a2423).

• For MIs, risk reduction was 76% in the early treatment group compared with the delayed treatment group (hazard ratio 0.24, CI 0.18–0.3).
• Risk of MI in the early treatment group was similar to that of the normal population.
• Average statin dose was significantly lower than that currently recommended for FHc (mean dose 33mg simvastatin), but the impact was nevertheless impressive. 85% did not have LDLs reduced by 50% from baseline, the current recommendation – although mean reduction of LDL was close at 44%.

• This study confirms that early treatment reduces risk of MI significantly – almost to population risk.
• The editorial encourages us to aim to reduce LDL by 50%, as suggested by NICE.

A 20-year follow-up of 200+ children with familial hypercholesterolaemia and their siblings showed that, with treatment, there was a dramatically lower rate of CV events and deaths compared with their parents at a similar age (NEJM 2019;381:1547).

At age 39y, for those who had been treated since childhood:

• There was a 1% risk of CV events compared with 26% in their parents at the same age.
• CV mortality rates were 0% vs. 7% in their parents.
• This was on a background average fall in LDL of 32%.

Great news and a reminder of why it is so important to cascade test and identify affected families early.

Familial hypercholesterolaemia Consider the diagnosis of FHc in anyone with a total cholesterol of >7.5, and then assess them against the Simon Broome or Dutch Lipid Clinic criteria. Refer if appropriate. Systematically search for any patients meeting the criteria below, and assess them against the Simon Broome/Dutch Lipid Clinic criteria. <30y with a cholesterol >7.5 or ≥30y with a cholesterol >9. Refer anyone with suspected homozygous disease (≥16y with LDL >13 or <16y with LDL >11). Aim for a 50% reduction in LDL on treatment. Cascade testing is required, including testing any children who may be affected. DNA testing should be used when a family mutation is known. Don't use CV risk calculators as they significantly underestimate CV risk. Offer specialist referral to all for management and cascade testing. Remember, early treatment significantly reduces the risk of having an MI.

Run a search to systematically identify any patients <30y with a cholesterol >7.5 or ≥30y with a cholesterol >9, as NICE suggests. These people need assessing against the Simon Broome/Dutch Lipid Clinic criteria. You could also do a broader search looking for anyone with a cholesterol >7.5, and see whether they have had an LDL measurement of >4.9 or any assessment for FHc.