Familial hypercholesterolaemia (FH) is an inherited condition thought to affect up to 1 in 250 people, and associated with markedly raised serum LDL-cholesterol (LDL-C) levels.¹ The high LDL-C level is present from birth and can lead to early development of atherosclerotic cardiovascular disease. However, as early atherosclerosis doesn’t result in symptoms, FH is often clinically silent until an individual with FH has an acute myocardial infarction or a sudden death. FH patients often present with a myocardial infarction, stroke or sudden death in their 20s, 30s or 40s. At least 50% of men with FH will present with heart disease by the age of 50 and as many as 30% of women will present with heart disease by the age of 60.²

FH is not caused by an unhealthy lifestyle, but is passed from generation to generation through pathogenic variants in the gene sequence of the low-density lipoprotein receptor gene (or less commonly in the sequence of two other genes). As a monogenic disorder, brothers and sisters or children of someone with FH have a 50% chance of having the condition.

While FH patients generally choose healthy life choices, this is insufficient to minimise their risk of cardiovascular disease. As with the population in general, the risk of cardiovascular disease in FH patients is increased significantly by other factors such as high blood pressure, smoking and other unhealthy lifestyle choices. 

Globally, the condition is both underdiagnosed and undertreated, with estimates as low as 5% of those affected being identified.³ Evidence suggests that FH is also significantly underdiagnosed and undertreated in Ireland with little or no data available on its prevalence, diagnosis or management. Some countries, such as the Netherlands, the UK and Northern Ireland have high rates of diagnosis and treatment, principally because they have national programmes of cascade screening supported by the necessary biochemical and genetic testing and developed pathways for clinical management. A strategy that has been effective in a number of jurisdictions is the screening of young children by measuring their cholesterol levels at the time of their vaccination. In Ireland however, there are no formal screening programmes for FH.

In many individuals, the diagnosis of FH is obvious from the personal or family history of CVD, the markedly elevated LDL-C levels and the presence of xanthomata or corneal arcus on examination. However, in many cases the diagnosis of FH is more challenging and relies on a mix of five criteria:

• Family history of premature CVD
• Personal history of premature CVD
• Physical examination for xanthomas and corneal arcus
• Very high LDL-C on repeated measurements
• Causative mutation detected by molecular genetics.

FH likelihood scoring systems

FH likelihood scoring systems have been developed around these criteria – the Simon Broome criteria and the NICE guidelines for diagnostic criteria, for example. Internationally, the most accepted system appears to be the Dutch Lipid Clinic Network Criteria (DLCN),⁴ which classifies patients into ‘possible’, ‘probable’ or ‘definite’ FH (see Table 1). It’s now possible to offer genetic testing to patients to formalise the diagnosis. Such a service has been introduced in the chemical pathology lab at St James’s Hospital by Dr Vivion Crowley.

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Early detection and management of FH and early initiation of lifestyle and pharmacological treatment are imperative to reduce the lifelong burden of CVD. FH is often undertreated, even among those with an established diagnosis. Smoking cessation, diet and other lifestyle interventions are also essential to reducing the risk of CVD in FH patients. However, without the initiation of lipid-lowering therapy from an early age, FH patients will almost certainly be at high risk of CVD throughout their life.

In Ireland, based on the findings of international prevalence studies, it is likely that there are 10-20,000 individuals with FH. A small fraction of these are being actively managed by specialist lipid clinics where they are given a formal diagnosis, genetic counselling and a lifestyle and pharmacological management plan. Many FH patients are being managed in primary care and by other hospital-based outpatient services (eg. endocrinology, cardiology), but in these settings detection and management strategies may not always be optimised.

The use of statins is central to the pharmacological management of FH. However, the addition of other lipid-lowering medications (eg. ezetimibe and PCSK9 inhibitors) is appropriate in more challenging cases. While PCSK9 inhibitors have proven powerful and effective in managing difficult cases worldwide, they have not yet been approved for use in Ireland.

The not-for-profit sector has played an important role in raising awareness of FH. Heart UK – The Cholesterol Charity provides support, information and education on FH for HCPs, patients and families. The charity also works on raising awareness of FH among healthcare professionals (HCPs) and policymakers with the aim of improving services for those impacted by FH. In recent years, Heart UK has been instrumental in creating the European FH Patient Network (FH Europe).

In Ireland, Croí, the West of Ireland Cardiac and Stroke Foundation, is the only organisation with membership of FH Europe. Croí and its affiliate, the National Institute for Prevention and Cardiovascular Health (NIPC) have begun to engage on some of the FH challenges facing Ireland.

Strategic policy framework

In 2017, Croí and the NIPC contributed to an FH strategic policy framework report, commissioned by Amgen, to understand the barriers to establishing and implementing a standardised best practice approach to FH diagnosis and treatment in Ireland.⁵ This report put a spotlight on many issues and challenges that need to be addressed to ensure that people living with FH in Ireland are identified and optimally treated. Included in these issues and challenges are:

• Low awareness of the condition among the general public and relevant stakeholders. This lack of awareness extends from patients themselves, through primary and secondary clinical care settings, to politicians and policymakers
• Low prioritisation of preventive screening in both primary and secondary care. It appears that identification of FH in Ireland is largely opportunistic, often only identified after surviving an acute presentation. UK research suggests that about a third of people with FH don’t survive their first heart attack. Preventive screening therefore would not only potentially prevent a cardiovascular event but prevent unnecessary damage to the heart and cardiovascular system
• Low and disparate access and availability of patient services. In the UK, everyone between the ages of 40 and 75 can avail of free lipid-testing every five years. In Ireland, by contrast, the majority of residents must pay for GP visits and specialist care appointments. Furthermore, there are only a limited number of dedicated lipid clinics in secondary care capable of diagnosing and treating FH. In fact, there is low awareness among GPs of both the referral pathway and of where to refer the patient for further testing and treatment. Another barrier exists with regard to genetic testing, which is currently only available in one Dublin hospital with a very limited capacity. Other hospitals are sending samples to the UK, which is not always possible due to budgetary constraints
• No national screening programme or database for the purpose of cascade screening of family members when someone has been diagnosed with FH. Ireland joins Romania and Bulgaria at the bottom of the EU table for the lack of an aligned national strategy for FH screening, with the resulting absence of cascade screening, and the absence of national registers for either children or adults. International evidence confirms that cascade screening is the most cost-effective means of identifying previously undiagnosed FH patients.

Last year, Croí and the NIPC collaborated with Dr Damian Griffin, consultant chemical pathologist, who runs a lipid clinic in Galway University Hospital, and four primary care practices in Galway, to conduct a therapeutic review of hypercholesterolaemia. The aims were to ascertain the prevalence of marked hypercholesterolaemia in the Galway area and to gain insights into how these patients are investigated. Based on the information available it was possible to draw conclusions as to the likelihood that these patients had FH. The management of these patients was also reviewed.

Lipid profiles on patients attending the four practices over a 15-year period were reviewed. Patients with marked hypercholesterolaemia, defined as having a total cholesterol ≥ 8mmol/L (in line with ECS guidelines), were selected. Medical records of the highlighted patients were then interrogated to ascertain whether or not these patients were likely to have FH based on the DLCNC scoring system. 

While 137 patients were found with markedly elevated cholesterol levels, it was only possible to conclude that seven patients had definite FH. It was felt that in many other cases, there was a strong probability that the patients could have FH, but variances across practices in documenting criteria associated with FH meant it was not possible to reach firm conclusions in most cases. The GPs who participated in this study were provided with a more extensive list of patients who possibly had FH, but where further investigation was required before this could be confirmed.

This project highlighted some of the difficulties that need to be addressed in estimating the prevalence of FH in Ireland but did also provide a good insight that will inform future research endeavours. An integrated approach at every level of the healthcare system is required. 

Research, awareness and education

There are plenty of international best practice guidelines that could be adopted to vastly improve the CV health of those living with FH in Ireland. The NIPC is committed to supporting the research agenda in this arena and Croí is committed to mobilising the patient voice for awareness, education and advocacy. As part of this commitment, NIPC has recently appointed Prof Bill McEvoy as its medical and research director. He has taken up a post as professor of preventive cardiology at NUI Galway and consultant cardiologist at Galway University Hospital, having returned from working in the US. 

Prior to returning to Ireland, he was a faculty member in the Johns Hopkins Ciccarone Center for the prevention of cardiovascular disease and was active in the advanced lipid clinic at the hospital. He has a track record of successful research in hyperlipidaemia and is widely published in this area, including a review on the treatment of hyperlipidaemia, due to be published this year in the New England Journal of Medicine. He plans on using his expertise to advance our understanding of FH in Ireland and to improve the treatment of Irish patients.