Online-only article: Familial hypercholesterolaemia - diagnosis and management

Dr Anthony Wierzbicki, consultant chemical pathologist at St Thomas' Hospital, London, discusses the identification and treatment of familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disease of lipid metabolism.1,2   It has a UK prevalence of 1 in 500.

Dysfunction of clearance of LDL-cholesterol leads to increased plasma LDL-cholesterol and to increased rates of atherosclerosis, affecting the coronary circulation in particular. As a result, cholesterol deposition occurs in the tissues, with extensor tendons being a prime site. The prevalence of tendon xanthomata is related to the extent and degree of exposure to hypercholesterolaemia. These are pathognomonic. Other signs of lipid deposition, such as juvenile arcus, are not specific for FH.

In untreated FH, the rate of CHD is increased 2-200 fold with the greatest relative risk increase being seen in younger patients (aged < 50 years).2 Some 70% of men and 50% of women with FH will have a CHD event before age 65.

FH is caused by mutations in the genes controlling LDL-receptor function, with 95% being due to a wide variety of mutations in the LDL-receptor, 2% due to mutations in apolipoprotein B-100 (its ligand on LDL particles) and 2% being due to mutations in a protein that controls the LDLR - preprotein convertase subtilisin kexin-9 (PCSK-9). The phenotypes of all these conditions are generally similar, with a slightly better prognosis and milder phenotype being seen with apolipoprotein B3500 mutations.

Mutation identification rates in clinically suspicious cases are as high as 70% in children where lipid levels between FH and polygenic disease are clearly differentiated, to 50% in adults with tendon xanthomata and 25% in patients without obvious clinical signs.3

Patients with FH are identified by the use of clinical criteria such as those established by the Simon Broome group: total cholesterol > 7.5mmol/l or LDL-cholesterol > 4.8mmol/l, presence of tendon xanthomata and/or a family history of CHD in first-degree relatives prior to age 60 or age 50 in second-degree relatives.2

Use of cholesterol levels alone does not sufficiently discriminate FH cases from polygenic controls, and 15% of cases overlap. Different lipid cut-offs are used to establish the diagnosis in family members when FH has been confirmed in an index case by DNA mutation detection or by clinical criteria.3

In the UK, about 15% of patients with FH have been identified.4

The autosomal dominant inheritance makes it easier to identify subsequent cases by family tracing and testing, an approach named cascade testing.4,5

Initial index cases have been identified by lipid clinics or can be identified in primary care databases by the combined use of lipid and personal or family histories of early-onset CHD.6

As many patients have elevated cholesterol and a family history of early onset CHD and tendon xanthomata are comparatively rare, increasing use is being made of other stratification techniques e.g. carotid intima media thickness (cIMT), given the relationship of this surrogate marker of atherosclerosis with lifetime cholesterol exposure.7

Given the lifetime exposure to high LDL-cholesterol, patients with FH need to be investigated with the high clinical suspicion of having significant cardiac disease, especially if they have additional CHD risk factors.8

There are no endpoint trials of the efficacy of lipid lowering in FH because of ethical concerns. All the evidence for its treatment is based on surrogate markers such as cIMT or coronary mean lumen diameter allied to data on the efficacy of drugs on lowering LDL-cholesterol in FH. The results of the Atorvastatin Simvastatin Atherosclerosis Prevention Study (ASAP) showed that a 50% LDL-cholesterol reduction with 80mg atorvastatin stopped progression of cIMT while 40mg simvastatin producing a 42% reduction did not.9

A subsequent study using a similar protocol but with treatment-experienced patients showed that addition of ezetimibe to 80mg simvastatin, producing 56% (compared with 42%) reduction in LDL-cholesterol, did not show any additional benefit. The overall rate of progression in both groups was minimal.10

Ezetimibe is still recommended for use in FH as it reduces LDL-cholesterol by an additional 23%, and is safe and well tolerated. However, in the recent Simvastatin and Ezetimibe and Aortic Stenosis (SEAS) study, the combination of ezetimibe and simvastatin reduced the secondary endpoint of cardiovascular events by a smaller amount than expected.11

There is limited evidence for the alternatives as, although colestyramine in combination with niacin and statins did reduce MLD progression in the Familial Atherosclerosis Treatment Study, this was a post-hoc open-label analysis. Tolerability limits the use of both bile acid sequestrants and niacin, although colesevelam and laropiprant have a better side-effect profile than older agents. There are some data for the lipid effects of fibrates in monotherapy and combination with statins in FH. It is likely that the injected antisense oligonucleotide to apolipoprotein B will be licensed soon and will form an additional option for the treatment of homozygous FH.12

A 50% reduction in LDL-cholesterol from baseline levels is an  accepted  target for successful treatment in FH and audits suggest it can be achieved in 50% of patients.2

In FH cholesterol levels are raised from childhood, so it is sometimes necessary to consider early drug treatment, especially if the family history shows a pattern of very early aggressive disease (CHD at <40 years).13

A number of drugs are licensed for use in childhood and most management is performed in specialist paediatric or family clinics using lower dosage statins, ezetimibe and fibrates.

Statins are potentially teratogenic, so young women with FH are advised to use adequate contraception. Previously, because lipid levels were generally poorly controlled in FH, it was advised that progestagen-only oral contraception was recommended but with modern treatments there is no such limitation. Women should be advised to discontinue lipid-lowering therapies during planned periods of conception, pregnancy and breastfeeding.

Homozygous FH
While most cases of FH are heterozygous a few cases of homozygous FH do exist.14

This has a prevalence of 1 in 1,000,000 and is distinguished by far higher LDL-cholesterol (>12mmol/l), more aggressive disease and often florid clinical signs. Homozygous FH needs to be managed in specialist units, as many patients show a poor response to statin therapy because of lack of functioning LDL-receptors.

It may be necessary in severe cases for the patient to undergo physical removal of LDL-cholesterol by apheresis or plasmapheresis on a regular basis to prevent progression of disease.2

In some cases LDL-receptor function is restored by liver transplantation.

As FH is common, identifiable and treatable it meets the international criteria for screening and indeed cascade screening has been shown to be cost-effective in all health systems. National screening programmes exist in Holland, are starting in Spain and Norway and have been piloted in the UK. The NICE guidelines on FH recommend that a programme of systematic case identification and treatment of FH  is set up in the UK.2


Statement of interests
Dr Wierzbicki has served on the NICE technology appraisal for ezetimibe and was guideline development group member for the familial hypercholesterolaemia guideline.

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2. National Institute of Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia . London: National Institute of Health and Clinical Excellence; 2008.

3. Starr BJ, Hadfield G, Hutten BA, et al. Development of sensitive and specific age- and gender specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing. Clin Chem Lab Med 2008; 46(6): 791-803.

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9. Smilde TJ, van WS, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357(9256): 577-81.

10. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358(14): 1431-43.

11. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359(13): 1343-56.

12. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375(9719): 998-1006.

13. Wierzbicki AS, Viljoen A. Hyperlipidaemia in paediatric patients: the role of lipid-lowering therapy in clinical practice. Drug Saf 2010; 33(2): 115-25.

14. Marais AD, Firth JC, Blom DJ. Homozygous familial hypercholesterolemia and its management. Semin Vasc Med 2004; 4(1): 43-50.

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