Familial hypercholesterolaemia: identification and management

Why this is important

The clinical community recognises that FH is underdiagnosed, with prevalence more likely to be approximately 1 in 250 rather than the widely cited 1 in 500. Searching electronic primary care databases is an effective way of identifying people with FH. One of the ways in which people are identified through electronic primary care database searching is to search using total cholesterol or LDL‑C concentration. Currently, the entire evidence base for identifying cohorts of people with FH through primary care case finding uses a total cholesterol concentration cut-off of 9.3 mmol/l. This is a very high concentration and anecdotal evidence suggests that this identifies older people but may miss younger people with FH. This could lead to missed opportunities to identify and treat people with FH at an earlier age. Research is needed to identify whether using different total cholesterol and LDL‑C concentrations to identify people with FH through primary care database searching affects the diagnostic yield of FH. Additionally, there is a lack of data on the ethnicity, age and triglyceride concentration of people with FH identified through primary care database searching. These should be included as outcomes in future research. [2017]

Why this is important

Although statins are increasing in use, there is still a lack of data on the long-term effects of statins in children. It is particularly important to determine any long-term adverse effects of statin treatment in a population with FH, as people generally take statins for the rest of their lives once treatment starts. [2017]

Why this is important

There have been no published studies to establish target serum LDL‑C concentration in treated children with FH receiving lipid-modifying drug therapy. Treatment is recommended from 10 years onwards; however, this lack of data prevents a recommendation regarding the aim of pharmacological treatment on serum LDL‑C concentrations.

Research (both cross-sectional and longitudinal) should assess the evidence of end-organ involvement (for example, carotid intima medial thickness [IMT]) to determine at which age abnormalities can first be seen in children. The aim would be to identify a threshold effect, with an LDL‑C concentration below which carotid IMT is normal and where thickening is absent, and above which it is abnormal and where thickening is observed. Outcomes should include fasting serum total and LDL‑C concentration, carotid artery IMT, and growth and pubertal development. [2008]

Why this is important

There is limited evidence to inform specific indications for LDL apheresis in people with heterozygous FH. In addition, there is limited published evidence on the cardiovascular outcome of such patients treated with LDL apheresis.

Evidence on the value of investigations (various measures of vascular status, considered to reflect the extent or activity of atherosclerotic vascular disease of the coronary arteries) in predicting outcome from LDL apheresis should ideally be based on evidence from randomised controlled trials with clinical outcomes. It is difficult to identify a suitable alternative treatment because LDL apheresis is generally only considered in people for whom no other treatment is available. One comparator may be novel therapies with antisense oligonucleotides (ApoB).

A national register should be established for all people with FH who are referred for and/or are undergoing LDL apheresis. Data should be collected on the natural history of FH and the temporal relationship of clinical and vascular features in relation to treatments and other parameters. [2008]

Why this is important

There is little information on the outcomes of pregnancy in women with FH. A small number of conflicting studies have suggested a small increase in fetal abnormalities if the mother has taken statins during the first trimester, but there are not sufficient data to provide an accurate estimate of the level of risk. There is also limited information on the risk of pregnancy (including cardiac death) in a woman with FH.

Data on the incidence of cardiac problems in pregnancy and incidence of fetal malformation would inform future recommendations. This could reduce uncertainty for women, and help to identify risks during the pregnancy that could be better managed. The only feasible research method to address these questions is an observational longitudinal study following women with FH and other women (not diagnosed with FH) using statins through their pregnancies using a national register. [2008]

Why this is important

Because of their inherent high risk of developing premature coronary heart disease, a low threshold of suspicion for coronary disease is recommended for people with FH. Routine monitoring to detect sub-clinical atherosclerosis should be non-invasive, sensitive, specific and cost effective. Research to assess the prevalence of both asymptomatic coronary and non-coronary atherosclerosis in people with definite heterozygous FH is required.

As well as exercise, electrocardiogram (ECG) testing followed by stress echocardiography before possible angiography in people with an abnormal exercise test and ankle brachial pressure measures, research should include MRI in addition to other modalities such as carotid IMT and coronary calcification. Outcomes should include changes in exercise ECG or ankle brachial pressure testing, IMT or calcification over time.

Consideration should also be given to the feasibility of conducting a long-term randomised trial to compare the differences in morbidity or mortality attributable to early diagnosis using routine monitoring or symptom-based investigation. [2008]