Familial Hypercholesterolemia (FH) is a genetic disease which results in the reduced clearance of atherogenic LDL-cholesterol (“bad cholesterol”) in the blood, and an increased risk of early heart disease. People with FH have elevated LDL cholesterol levels from birth and children with FH show an increased thickness of their arteries compared to their non-FH siblings by the age of 11, showing the process of atherosclerosis development starts early in life. As a result of their FH, the incidence of fatal or non-fatal myocardial infarction without treatment is about 50% by the age of 50 years in men and about 30% by the age of 60 years in women.
FH in the UK population is believed to be approximately 1 in 250, meaning about 220,000 people in the UK have FH, of whom less than 8% are currently identified.
- The 2019 NHS Long Term Plan has set the ambitious target of finding 25% of the predicted FH patients in England in the next 5 years. For the Pan-London area, this means that of the approximate 8 million people living within the M25 there are likely to be about 30,000 with monogenic FH, and data we have collected suggests that currently only 1500 of these have been identified and are being treated by lipid specialists.
- A typical GP practice with 10,000 patients might have up to 40 patients with FH who have a significantly increased risk of premature heart disease and many of these have not been identified, or if identified are not being offered high intensity statin therapy.
Diagnosis of possible FH
The 2017 NICE FH guideline has recommended case finding in primary care using electronic records as an acceptable and highly cost-effective method for individual practices to identify patients who so far did not have the benefit of treatment. Diagnosis of possible FH is based on the UK Simon Broome FH Register criteria of elevated LDL-cholesterol levels (>4.9mmol/l), and a family history of early coronary heart disease (CHD) and/or elevated cholesterol levels and definite FH in the presence of clinical features such as tendon xanthomas or through a positive genetic test result.
A DNA test is used to provide an unequivocal diagnosis for a patient with a clinical diagnosis of FH. In the last year, NHS England has reconfigured the DNA diagnostic laboratories in the UK, so that now there are 7 Diagnostic Laboratory Hubs where all DNA testing will be carried out . As part of this reorganisation, DNA tests for FH will be included in the “core” tests carried out in all hubs, and the costs for these tests will be covered by NHS. We anticipate that this will be fully operational from April 2020.
FH is usually caused by mutations in the low-density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and one particular mutation in the APOE gene (whose prevalence is currently unknown). In a landmark study  the UCL group showed that in the vast majority of the no-mutation patients the cause of their hypercholesterolemia is “polygenic” and not due to a single unknown gene. While such patients of course need adequate management of their plasma lipid levels, cascade testing in their relatives is clinically of less use than in the monogenic families. As a result of this finding the 2017 updated NICE guidelines for the management of FH are that cascade testing of first-degree relatives should only be performed for those index cases where a mutation can be identified.
Cascade testing for FH
- On average 50% of the first-degree relatives (e.g. son, daughter, sibling etc.) of a patient with FH will have inherited the FH-causing variant of the gene.
- Cascade testing is a cost-effective method of finding additional FH patients, and is fully endorsed by NICE FH guidelines. It involves the identified relative having their DNA tested.
- FH nurses carry out cascade testing in families with an identified mutation, and this has shown enormous benefit to the patients and their relatives. However, they are a limited resource and their efforts should be focussed on those with the monogenic form of the disease, where 50% of their first-degree relatives are “at-risk” of FH.
- Data from the 29 BHF funded nurses have shown there have been more than 20,000 genetic tests, which has resulted in the identification of more than 4150 mutation positive index cases. Cascade testing in the families of these patients has resulted in the testing of more than 10,000 relatives of whom the expected 50% are mutation carriers, making a total of over 9,000 mutation positive FH patients in the UK, representing about 7% of the predicted number. Of these tested relatives, 460 are children and young people under 20 years old.
Treatment for FH patients
All FH patients require statin lowering therapy, which results in a highly significant reduction in CHD rates and improved life expectancy for FH patients. Analysis of the Simon Broome FH register follow up data has shown that in FH patients identified and treated with statins before they develop heart disease (primary prevention) there was no excess mortality compared to the general population. For FH patients with evidence of heart disease before starting a statin (e.g. having had a heart attack already), the death rate is still elevated compared to the general population. According to NICE guidance a proportion of FH patients (probably ~15-20%) are likely to qualify for the latest lipid lowering agents, known as PCSK9 inhibitors.
As well as statin therapy, all identified FH patients are helped to make changes in lifestyle including dietary intervention, and smoking cessation. Interestingly, treated FH patients had a lower death rate from cancer, mainly due to the lower than average rate of smoking in identified patients and so lower risk of, particularly, lung cancer .This supports the public health importance of strategies to identify FH patients and offer them appropriate lifestyle and lipid-lowering therapies before CHD has developed.
Lipid Clinics in London
FH Children’s Register
In 2008 the NICE guideline CG71 was published documenting the care pathway and management of adults and children with FH. One of the strong recommendations was that all children with FH should be identified before the age of 10, in order that lifestyle, and where necessary statin treatment, should be initiated to reduce their subsequent risk. These children will be primarily found through ‘cascade testing’ by tracing the relatives of the 15,000 or so known index cases with FH currently being treated in lipid clinics throughout the UK. In 2010 the National Audit of FH management estimated that less than 400 children with FH had been identified, but over the next few years, in part driven by the funding from the BHF of FH Nurses, we anticipate that a large number of children with FH will be identified.
While it is clear that statin treatment in adults has a good safety record, there are no long term studies of safety in children, with the longest studies usually not extending past two years, and simply following up lipid levels, growth rates, progression through puberty, and capturing information on any major side effects. An electronic register of these children has been created so that their management can be audited, and will provide valuable data and questions about the safety and efficacy of long-term statin treatment.
The unique aspect of the registry is that on an annual basis the registering clinician is prompted to update information from the latest outpatient visit with additional information collected about lipid profile, height and weight, progression through puberty, treatment, side effects and information about development of symptoms or measurement of carotid IMT. The data shows that FH children on statin treatment report no clinically relevant side effects and are growing at the same rate as untreated FH children . Interestingly, the children with FH have a significantly lower prevalence of obesity than that reported in the general UK population, demonstrating the benefit of adopting a healthy diet and lifestyle.
We are currently undertaking a piece of work to map the paediatric services available in the London area, and to see how well they align with recent UK consensus guidelines on the management of children with FH .
- Talmud PJ, ShahS, Whittall R, Futema M, Howard P, Cooper JA, Harrison SC, Li K, Drenos F, Karpe F, Neil HA, Descamps OS, Langenberg C, Lench N, Kivimaki M, Whittaker J, Hingorani AD, Kumari M, Humphries SE. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. 2013 Apr 13;381(9874):1293-301. doi: 10.1016/S0140-6736(12)62127-8.
- Neil, A., Cooper, J., Betteridge, J., Capps, N., McDowell, I., Durrington, P., Seed, M. and Humphries, S. (2018). Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. [online] Available at: https://doi.org/10.1093/eurheartj/ehn422 [Accessed 28 Jan. 2020].
- Humphries, S., Cooper, J., Dale, P. and Ramaswami, U. (2017). The UK Paediatric Familial Hypercholesterolaemia Register: Statin-related safety and 1-year growth data. J Clin Lipidol. 2018 Jan – Feb;12(1):25-32. doi: 10.1016/j.jacl.2017.11.005.
- Ramaswami, U., Humphries, S., Priestley-Barnham, L., Green, P., Wald, D., Capps, N., Anderson, M., Dale, P. and Morris, A. (2019). Current management of children and young people with heterozygous familial hypercholesterolaemia – HEART UK statement of care. Atherosclerosis. 2019 Nov;290:1-8. doi: 10.1016/j.atherosclerosis.2019.09.005.