Atherosclerosis 231 (2013) 223e226

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Invited commentary

Familial hypercholesterolaemia: A pressing issue for European health care Philippa Brice a, Hilary Burton a, Christopher W. Edwards b, Steve E. Humphries c, d, *, Timothy J. Aitman e, ** a

PHG Foundation, 2 Worts Causeway, Cambridge CB1 8RN, UK Imperial College Faculty of Medicine, Division of Medicine, Hammersmith Hospital, London W12 0NN, UK Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK d UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK e Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, W12 0NN, UK b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 September 2013 Accepted 22 September 2013 Available online 2 October 2013

The recent European Atherosclerosis Society (EAS) guidelines for the management of familial hypercholesterolaemia (FH) succinctly reiterate the under-diagnosis and poor management of this common genetic disorder, which is associated with greatly increased mortality from coronary heart disease (CHD), especially in young people. The prevalence of FH is thought to be between 1/500 and 1/200, and thus in Europe 1.8e4.5 million individuals have FH. In most European countries including the UK, fewer than 15% of cases have been identified to date, amounting to over 100,000 undiagnosed cases in the UK alone. There are a number of issues that have impeded the implementation of FH diagnostic and management guidelines in Europe; here, we briefly review the current situation in the UK, and propose ways to start to break down implementation barriers that may be applicable across Europe. Despite guidelines by the UK National Institute of Health and Clinical Excellence (NICE) published in 2008 that recommend genetic testing of index cases and cascade screening of their family members, and the recent NICE Quality Standards for management of FH (QS41), there has been little action towards systematic diagnosis in England despite implementation of systematic screening programmes in Scotland, Wales, Northern Ireland and in other selected countries in Europe. This is surprising because early treatment with statins provides an effective and cheap treatment that reduces mortality to near that found in the normolipidaemic population. With increasing emphasis on preventive medicine and genetic diagnosis across the medical specialties, FH is a clear example of how new genome technologies can - and should - be deployed now for the benefit of patients. Ó 2013 Elsevier Ireland Ltd. All rights reserved.

Keywords: Familial hypercholesterolaemia Low-density lipoprotein cholesterol (LDLcholesterol) Cascade screening Genetic diagnosis DNA testing Policy

The recent EAS guidelines for the management of familial hypercholesterolaemia (FH), have documented the under-diagnosis and poor management of this common genetic disorder [1], which is associated with greatly increased mortality from coronary heart disease (CHD), especially in young people. While the generally accepted estimate for the prevalence of FH is 1/500 members of the general population, a recent study from Denmark suggested a frequency approaching 1/200 [2]. Using these estimates, between 14

* Corresponding author. Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK. Tel.: þ44 0207 679 6962. ** Corresponding author. Tel.: þ44 0208 383 4253. E-mail addresses: [email protected] (P. Brice), hilary.burton@ phgfoundation.org (H. Burton), [email protected] (C.W. Edwards), [email protected] (S.E. Humphries), [email protected] (T.J. Aitman). 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.09.019

and 34 million people are likely to have FH world-wide, including some 1.8e4.5 million individuals in Europe, and at least 120,000 individuals in the UK. The EAS guideline documents the current extent of FH under-diagnosis in Europe, with only Holland and Norway having already identified approaching half of the predicted number of their patients, and most other countries having identified under 10% [1]. FH is characterised by high serum cholesterol levels detectable from birth, caused by genetic defects that prevent the normal clearance of low-density lipoprotein cholesterol (LDL-C), leading to its accumulation in the circulation. This results in the development of accelerated atherosclerosis, as well as the characteristic cholesterol deposits (xanthomas) seen in tendons. The most severe homozygous form of FH is very rare, affecting only one in a million of the general population, and this is usually detected in childhood. It

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requires aggressive lipid lowering treatment, usually only being treatable by LDL-apheresis, which has been shown to prevent the onset of CHD that otherwise occurs in the first or second decade of life. [3] The much commoner heterozygous FH is typically asymptomatic, but in the absence of detection and appropriate treatment, CHD develops in 50% of men and 30% of women by the age of 55 [4]. The mutations that cause FH occur in one of three genes, LDLreceptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) [5]. Mutations in any of these genes can partially or wholly block normal uptake of LDL-C and clearance by the liver. A rarer autosomal recessive form of FH is caused by mutations in the LDL-receptor adaptor protein gene LDLRAP1 (also called ARH) [6]. However, the overwhelming majority of cases of FH (>90%) are due to mutations in LDLR. While some of the patients where no mutation can be detected in any of these genes may have a defect in an as yet unidentified ‘FH-gene’, recent evidence shows that the majority of the mutation-negative FH patients have inherited a greater than average number of common lipid-raising variants of small effect [7]. This suggests that a polygenic cause is the most likely explanation for elevated cholesterol in the majority of clinical FH patients in whom monogenic mutations in the known causal genes cannot be found [7]. Effective treatment for FH is available in the form of healthy lifestyle modification including dietary fat restriction, an exercise programme and avoiding smoking, combined with HMG-CoA reductase inhibitors (statins), which lower LDL-C and reduce the risk (or progression) of CHD. Other options include alternative cholesterol-reducing medications, or in extreme cases lipoprotein apheresis, with various potential new therapies in development [8]; some, such as monoclonal antibodies to PCSK9, show promising results in trials [9], with 50e60% additional LDL-C lowering being achievable in patients already being maximally treated with statins. Prior to the introduction of statin therapy, CHD mortality in adult FH patients was almost 100-fold higher for 20e39 year olds and five-fold for 40e59 year olds, although the risk for older FH patients was not markedly different from that of the general population, suggesting a ‘survivor effect’ [10]. Comparison of CHD mortality in FH patient cohorts in the pre- and post-statin eras showed that statin therapy can reduce the risk of CHD in both men and women by around 80%, to almost that of the general population, especially in those who have not yet developed CHD [11]. For children with genetically diagnosed FH, there is evidence that atherosclerosis develops and progresses rapidly from the age of 10 years [12], and current recommendations are that treatment with statins should be considered from this age [13]. The early and definitive identification of FH is therefore crucial for prompt clinical intervention to prevent premature CHD, especially in younger people. There are several clinical diagnostic criteria for FH, with the Dutch Lipid Clinic Score being widely used in Europe [14] while the UK uses the Simon Broome criteria [15]. The sensitivity and specificity of these two methods for identifying carriers of an FH-causing mutation is similar [16]. The “positive” genetic test result of identifying an FH-causing mutation in an individual provides a definitive diagnosis, whereas using cholesterol levels alone results in both false-positive and false-negative results and is therefore unreliable for family cascade testing [17]. However, DNA testing is complicated by the very large number of potentially causative mutations in the LDLR gene; over 1200 have been identified worldwide [5,18]. While FH index cases are usually identified opportunistically because of their very high LDL-C levels (often only after a myocardial infarction), testing their close relatives, who have a 50% chance of also having FH, is an effective way to identify new patients.

In the Netherlands, systematic screening and family cascade testing was established in 1994, leading to detection of more than 33,000 Dutch FH cases since that time [19]. In the UK, cascade screening initiatives have been established in Scotland, Wales and Northern Ireland but, despite the 2008 National Institute of Health and Clinical Excellence guidance recommending genetic testing of index cases and family members [15], there is no systematic programme in England and FH therefore remains a compelling public health issue. A recent UK audit by the Royal College of Physicians indicated that 85% of the estimated 120,000 or more affected individuals in the UK remain undiagnosed, leaving more than 100,000 individuals at high risk of early death [20], including some 75,000 in England. Health economic studies argue strongly in favour of systematic screening for FH. Analysis of the clinical and cost-effectiveness of different approaches to such cascade screening showed that using diagnostic DNA testing for the relatives of patients with identified mutations combined with diagnostic cholesterol testing for relatives of those patients in whom mutations were not identified, was the most cost-effective method, with an incremental costeffectiveness ratio (ICER) of £2700 per Quality-Adjusted Life Year (QALY) [21]. This compares very favourably with the typical NHS benchmark for cost-efficacy of £20e30,000/QALY. Later analysis confirmed that comprehensive genetic testing to diagnose FH in a patient was more cost effective than cholesterol measurement, and supported the previous recommendation for cascade screening using diagnostic DNA testing (targeted sequencing) for the relatives of patients with identified mutations [22]. Recently, economic modelling has estimated that treatment of every 1000 FH patients (between the ages of 30 and 85 years) with high intensity lipidlowering statin therapy would lead to 101 fewer cardiovascular deaths when compared with no treatment. Overall, the UK could save almost £380 million from CHD events avoided if all relatives of index cases were identified and treated optimally over a 55 year period, equating to savings of £6.9 m per year [23]. We believe that in the UK there have been three major impediments to introduction of cascade screening for FH, and that these are also important in European countries. Firstly, FH is not considered a rare disease (the usual definition of rare disease is less frequent than 1 in 2000, whereas FH has an estimated prevalence of 1 in 500), and thus the funding for FH screening cannot come from this source. The second issue is that paradoxically FH is seen as too common to be affordable, with the cost of comprehensive genetic testing being around £400e£800 per index case, although much less for testing relatives for an identified family mutation. However, the introduction of next-generation sequencing technologies and use of simultaneous targeted sequencing of all three FH-causing genes will reduce the cost of testing an index case by as much as four-fold [24,25], paving the way for effective testing at lower costs than has previously been possible. Including known ‘polygenic’ variants in such a test would add negligibly to the cost and would allow a distinction between those with a likely polygenic aetiology and those with an unidentified monogenic cause [5]. While all individuals with elevated LDL-C will require statin treatment, whether due to a monogenic or a polygenic aetiology, to focus scarce resources on cascade testing in the 40% of clinical FH patients with a monogenic cause (where cascade testing has demonstrated clinical utility [26]) will also lead to greater cost efficiency. Besides offering improved diagnosis, advanced sequencing approaches may even facilitate improved management by incorporating pharmacogenetic markers that can predict risk of statinassociated toxicity [25]. Despite the major longer-term cost savings that an FH cascade screening programme would generate, we believe that the third major impediment to its introduction is a bias in health care

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commissioning towards funding more high-tech drugs and interventions and less on preventative programmes. Updated models for commissioning genetic testing and screening programmes are needed, but the new investment in genome sequencing [27] and the new NHS commissioning and public health structures in place since April 2013 in the UK represent an opportunity for delivering systematic genetic screening for FH, which we argue can be a quick win for reducing cardiovascular death and disability in young people in England. Given the political will, the barriers to realising the potential of FH cascade screening to improve health and prevent disease in England in a cost-effective manner are by no means insurmountable. Similar considerations undoubtedly apply to other European countries where genetic testing and family cascade screening have yet to be implemented. In the current climate where investment in genome sequencing in the UK has opened new opportunities for translating genomic advances into clinical benefit for patients, genetic diagnosis of FH could be a key exemplar of ‘low hanging fruit’ to demonstrate the clinical impact of genomic technology. The capacity to prevent a major economic, health and social burden from premature cardiovascular disease and deaths due to FH is already here. Improved identification of cases of FH has recently been identified as Action Point 5 in the new UK Department of Health cardiovascular outcomes strategy [28], and a newly issued set of NICE Quality Standards underline the existing guidance for the diagnosis, cascade screening and management of FH in England [29]. These Standards cover eight key issues in the care pathway for FH, calling for specialist assessment and care for all those diagnosed (including children), and for their relatives to be offered diagnostic DNA testing via a national cascade screening process (Table 1). The quality standard for FH specifies that services should be commissioned from and coordinated across all relevant agencies encompassing the whole FH care pathway. NICE states that ‘A personcentred, integrated approach to providing services is fundamental to delivering high-quality care to people with FH’. We believe that the adoption of this integrated approach is key to the development of effective care for patients with FH and their families, and will be of further value if governments in other European countries can also be persuaded to adopt a similar strategy. We also believe that the genetic testing services in England and across Europe are well positioned to seize this opportunity and demonstrate how new genome sequencing technology can be used to save lives without Table 1 2013 NICE quality standards for FH. Standard 1 Standard 2 Standard 3 Standard 4 Standard 5

Standard 6 Standard 7

Standard 8

Adults with a baseline total cholesterol above 7.5 mmol/l are assessed for a clinical diagnosis of FH. People with a clinical diagnosis of FH are referred for specialist assessment. People with a clinical diagnosis of familial hypercholesterolaemia (FH) are offered DNA testing as part of a specialist assessment. Children at risk of FH are offered diagnostic tests by the age of 10 years. Relatives of people with a confirmed diagnosis of monogenic FH are offered testing through a nationwide, systematic cascade process. Adults with FH receive lipid-modifying drug treatment to reduce LDL-C concentration by more than 50% from baseline Children with FH are assessed for lipid-modifying drug treatment by a specialist with expertise in FH in a child-focused setting by the age of 10 years. People with FH are offered a structured review at least annually.

NICE quality standards describe high-priority areas for quality improvement in a defined care or service area. Each standard consists of a prioritised set of specific, concise and measurable statements based on expert opinion. They draw on existing guidance (NICE CG71 published in 2008), which provides an underpinning, comprehensive set of recommendations, and are designed to support the measurement of improvement.

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excessive expenditure, and to save many millions of pounds of expenditure for the health services, by reducing the burden of young, undiagnosed FH patients needing treatment for premature myocardial infarction. Conflicts of interest The authors declare that we have no financial conflicts of interest. SEH is the Medical Director and minority shareholder of the UCL start-up CHD risk genetic testing company Storegene, and has received honoraria for speaking at educational meetings with a pharmaceutical sponsor, but has donated all of these to various medical charities. SEH confirms that Storegene does not have at this time a product of the gene panel score for hyperlipidaemia, nor does it have any plans to develop such a panel. TJA has submitted a patent application for a genetic test on a microfluidics and next generation sequencing platform for mutation detection in genes that underlie monogenic and polygenic hypercholesterolaemia and statin toxicity. TJA confirms that he has no present financial interest in, nor have there been any financial transactions for developing this patent. TJA further declares that he is a co-investigator of a clinical trial to evaluate safety, tolerability and efficacy of an Amgen pharmaceutical product in subjects with heterozygous familial hypercholesterolaemia. TJA has received no financial recompense or other payments for participation in this trial. CWE is Chairman of the British Heart Foundation Council and TJA is a Trustee of the PHG Foundation, but all authors are expressing their personal views in this Viewpoint and not those of the PHG Foundation, their host institutions or funding agencies. Acknowledgements SEH is supported by the British Heart Foundation (PG08/008). TJA is supported by the MRC Clinical Sciences Centre and the Imperial College BHF Centre of Research Excellence. PB and HB are employed by the PHG Foundation, an independent non-profit organisation. References [1] Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus Statement of the European Atherosclerosis Society. Eur Heart J August 2013;15. http://dx.doi.org/10.1093/eurheartj/eht273 [Epub ahead of print]. [2] Benn M, Watts GF, Tybjaerg-Hansen A, et al. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab 2012;97:3956e64. [3] Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 2012;223:262e8. [4] Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet 1969;2:1380e2. [5] Futema M, Plagnol V, Whittall RA, et al. Use of targeted exome sequencing as a diagnostic tool for familial hypercholesterolaemia. J Med Genet 2012;49(10): 644e9. [6] Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4(4):214e25. [7] Talmud PJ, Shah S, Whittall R, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 2013;381(9874):1293e301. [8] Goldberg AC. Novel therapies and new targets of treatment for familial hypercholesterolemia. J Clin Lipidol 2010;4(5):350e6. [9] Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterollowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation 2012;126(20):2408e17. [10] Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial

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Familial hypercholesterolaemia: a pressing issue for European health care.

The recent European Atherosclerosis Society (EAS) guidelines for the management of familial hypercholesterolaemia (FH) succinctly reiterate the under-...
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