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Familial hypercholesterolaemia: history, diagnosis, screening, management and challenges
  1. Erik Berg Schmidt1,2,
  2. Berit Storgaard Hedegaard2,3,
  3. Kjetil Retterstøl4,5
  1. 1 Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
  2. 2 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
  3. 3 Department of Cardiology, Viborg Regional Hospital, Viborg, Midtjylland, Denmark
  4. 4 Department of Nutrition, Institute of Basic Medical Science, University of Oslo, Oslo, Norway
  5. 5 The Lipid Clinic, Oslo University Hospital, Oslo, Norway
  1. Correspondence to Professor Erik Berg Schmidt, Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; ebs{at}rn.dk

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Learning objectives

  • Acknowledge the history of familial hypercholesterolaemia (FH).

  • Understand the pathophysiology of FH.

  • Acknowledge the importance and significance of FH.

  • Make a diagnosis of FH.

  • Acknowledge the importance of (genetic) screening for FH.

  • Acquire basic knowledge about treatment of FH.

History

Clinical familial hypercholesterolaemia (FH) was systematically described for the first time in 1937. In 17 families and in four generations, xanthomatosis, hypercholesterolaemia and cardiovascular disease (CVD) followed a pattern of an inborn error of metabolism and monogenetic autosomal dominant inheritance.1–3

However, single-patient cases of xanthomatosis and CVD had been reported as early as in 1873 by Fagge, by Lebzen and Knauss in 1889, by Török in 1893 and by Raeder in 1936.4

Genetics

In 1964, the clinical heterozygous and homozygous forms of the disease were described3 and in 1973 Brown and Goldstein showed that FH was caused by defects in the gene coding for the low-density lipoprotein (LDL) receptor (LDLr) resulting in decreased removal of LDL-cholesterol (LDL-C) from the circulation.4 Brown and Goldstein were in 1985 awarded the Nobel Prize for their work. Several genes are known to cause FH, although mutations in the LDLr gene coding for defective LDLr are by far (>90%) the most common. More than 1700 mutations in the LDLr gene have now been described, and of those more than 12005 are believed to be expressed as a severe hypercholesterolaemic phenotype.6 7 Mutation in the apolipoprotein B (apoB) gene may inhibit the receptor-mediated uptake of atherogenic apoB containing particles and thereby cause FH. Gain of function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) cause FH by degrading the LDLr, while LDL adaptor protein 1 (LDLRAP1) may cause FH by inhibiting the LDLr function.8 All, except the recessive LDLRAP1 mutation, cause FH in an autosomal dominant pattern.7 9

In this paper we will focus on heterozygous FH and only briefly mention homozygous FH.

The prevalence of FH

The prevalence of heterozygous FH was for many years estimated to 1 in 500 and the prevalence of homozygous FH to 1 per million.10 Recent data have, however, suggested higher figures, and it is now commonly accepted that the prevalence of heterozygous FH is about 1:25011 and 1 in 160–300 000 in patients with homozygous FH,12 making FH more common than other known genetic diseases.6 To complicate matters, subjects with a pathogenic FH mutation may have LDL-C within the normal reference value. This may in part be explained by other factors affecting plasma LDL-C levels including lifestyle, polygenic hypercholesterolaemia and secondary causes (eg, hypothyroidism) of hypercholesterolaemia. Another aspect of importance for the prevalence is that if in addition to an FH mutation, a markedly elevated LDL-C level of ≥4.9 mmol/L is required, the frequency of FH was 1 in 853, while if using a threshold of ≥3.4 mmol/L in subjects with a mutation, the prevalence would be 1 in 301.13

Clinical findings in FH

LDL-C accumulates in the arteries of subjects with FH leading to atherosclerosis, but cholesterol may also accumulate in tendons as xanthomas, in the cornea (corneal arcus) and around the eye (xanthelasmata) in subjects with FH (figure 1). Xanthomas and a corneal arcus are usually not seen in children with heterozygous FH but are suggestive of homozygous FH.

Figure 1

(A) Corneal arcus in a 45-year-old man, total cholesterol 8 mmol/L. (B) Xanthelasmata in a 25-year-old woman, total cholesterol 10 mmol/L. (C) Tendon xanthomas in a 26-year-old man, total cholesterol 8 mmol/L. (D) Achilles tendon xanthoma in a 26-year-old man, total cholesterol 8 mmol/L.

While xanthelasmata are somewhat unspecific findings, the occurrence of tendon xanthomas is central for a diagnosis of FH by the Simon Broome criteria, and both arcus cornea and xanthomas are findings used in the Dutch Lipid Clinic Network(DLCN) criteria for diagnosis of FH as discussed later.

Xanthomas

FH is the most common dyslipidaemia underlying tuberous and tendon xanthomas. Tuberous xanthomas are nodules frequently located to extensor surfaces of elbows, knees, knuckles and buttocks. Tendon xanthomas are cholesterol deposits formed by collagen and foam cells causing local thickening in fascia, ligaments and tendons, particularly occurring in the Achilles tendons and extensor tendons of the hands that can be detected by physical examination and imaging methods.14 15

In the past, xanthomas were described in 20%–80% of patients with untreated FH increasing with age. However, well-treated patients may never develop xanthomas.

The presence of tendon xanthomas is commonly stated as pathognomonic for FH, but this may not always be the case as tendon xanthomas also may occur in patients with sitosterolaemia and cerebrotendinous xanthomatosis. Tuberous xanthomas can apart from FH also be seen in patients with type III dyslipidaemia (familial dysbetalipoproteinaemia) and sitosterolaemia.

Corneal arcus

Cholesterol deposition in the cornea in the form of a corneal arcus (figure 1) is not uncommon in the elderly (arcus senilis), but this process may be accelerated in subjects with FH, and a corneal arcus in a person before age 45 suggests FH. The deposits tend to start in the cornea at its top or bottom (12 and 6 o’clock) and expand until becoming circular. An arcus cornealis is asymptomatic and does not affect eye function.

Xanthelasmata

Xanthelasmata are yellowish plaques that occur on the eyelid and around the eyes (figure 1). Xanthelasmata occur with a higher frequency in patients with FH, but are not specific for FH and may also appear in subjects with normal cholesterol levels.16 Interestingly, a study from Copenhagen reported that people with xanthelasmata had an increased risk of cardiovascular disease (CVD) regardless of plasma cholesterol and triglyceride concentrations.17

When to suspect and diagnose FH

FH is characterised by high plasma LDL-C and premature CVD in a person or in the close family (box 1).

Box 1

When to suspect familial hypercholesterolaemia (FH)

  • Elevated low-density lipoprotein-cholesterol (LDL-C) (or total cholesterol).

  • History of early cardiovascular disease (CVD).

  • Family history of elevated cholesterol and/or history of early CVD.

Central for the diagnosis of FH is high levels of LDL-C (caveat: this needs not be the case as discussed), a family history of hypercholesterolaemia (including FH) and a family history of premature CVD in particular coronary heart disease (CHD). In addition, objective findings as xanthomas, corneal arcus and/or xanthelasmata may suggest FH. A gene test revealing a pathogenic mutation in the FH gene is the ultimate diagnostic finding. Before gene testing for FH became available and more frequently used, the WHO definition of FH included plasma LDL-C levels >95% by age and sex also implemented in the Make Early Diagnosis to Prevent Early Deaths project for screening, diagnosis and treatment of patients with FH.18 Later, the Simon Broome definition of FH (box 2) was introduced19 and is still widely used. Using Simon Broome criteria, patients with FH can be divided into definite and possible FH (box 2) and in this definition the presence of xanthomas is central which may be problematic, as the evaluation of occurrence of xanthomas may be rather subjective. Furthermore, xanthomas are often not found in younger persons with FH.

Box 2

Simon Broome diagnostic criteria for familial hypercholesterolaemia

Definite familial hypercholesterolaemia

Adult: total cholesterol levels >7.5 mmol/L or low-density lipoprotein-cholesterol (LDL-C) >4.9 mmol/L.

Child <16 years of age: total cholesterol levels >6.7 mmol/L or LDL-C >4.0 mmol/L.

Plus at least one of the two:

  1. Physical finding: tendon xanthomas in patient or in first-degree relative (parent, sibling, child) or in second-degree relative (grandparent, uncle, aunt).

    • OR

  2. DNA-based evidence of an LDL receptor mutation, familial defective apolipoprotein B (apoB)-100, or a proprotein convertase subtilisin/kexin type 9 (PCSK9) mutation.

Possible familial hypercholesterolaemia

Adult: total cholesterol levels >7.5 mmol/L or LDL-C >4.9 mmol/L.

Child <16 years of age: total cholesterol levels >6.7 mmol/L or LDL-C >4.0 mmol/L.

Plus at least one of the two:

  1. Family history of myocardial infarction <60 years of age in first-degree relative or age <50 years of age in second-degree relative.

    • OR

  2. Family history of elevated total cholesterol >7.5 mmol/L in adult first-degree or second-degree relative or >6.7 mmol/L in child, brother or sister aged <16 years.

Today, the most common way to diagnose FH11 is by DLCN criteria (table 1). DLCN criteria take into consideration family history, personal clinical history, results from physical examination, levels of LDL-C and results from genetic testing. According to scores obtained, patients can be divided into those with definite, probable, possible and unlikely FH (table 1). However, it is well known that LDL-C is influenced by diet which may affect the DLCN score, and diet may therefore change FH scores and the grouping of patients.

Table 1

Dutch Lipid Clinic Network (DLCN) diagnostic criteria for familial hypercholesterolaemia

Importantly, mutations in FH genes may not cause elevated LDL-C. Mutations may be non-pathogenic, and some FH mutations may leave minor residual LDLr function, while in other mutations there is a complete loss of receptor function. In the rare patient with homozygote FH, this is particularly important, since without any LDLr activity at all, treatment may be particularly difficult. This means that patients can have genetically verified FH without clinical FH; clinical FH without a mutation; and the combination of clinical FH and a mutation.

Universal genetic screening may be another way to find subjects with FH, and this is currently undertaken in Slovenia in all children at the age of 5.20 There are pros and cons for universal screening and important ethical aspects involved such as autonomy, confidentiality, privacy and health insurance issues.

Does it matter if the FH diagnosis is made clinically or by genetics?

By tradition, FH is a clinical diagnosis and a clinical diagnosis is rarely as definite and precise as the genetic diagnosis. Mutations are found in 60%–80% of patients with definite or probable FH by clinical criteria.11 However, in a substantial number of patients with clinical FH no known genetic cause can be demonstrated suggesting that polygenic causes, diet, lifestyle or unknown genes are involved.

In a study of 26 025 subjects, those with an LDL-C level ≥4.9 mmol/L were specifically studied including 164 FH mutation carriers. The risk of coronary artery disease (CAD) was 3.7-fold higher in FH mutation carriers compared with those with no detectable FH mutation.13 Despite frequent use of lipid-lowering medications, the HR of the primary endpoint was 1.65 (95% CI 1.17 to 2.33) in mutation-carrying relatives compared with the general population. Also, in 636 patients with severe hypercholesterolaemia the risk of CAD was threefold to fourfold increased in patients with clinical FH or an FH mutation, while the risk was increased more than 11-fold in those with both clinical and mutation-proven FH compared with those without FH.21 These and other data suggest that the prognosis is worse for patients with FH who have a pathogenic mutation.22

An additional very important issue supporting the use of genetic testing is that the finding of a pathogenic mutation makes it much easier to screen and diagnose FH in the rest of the family.

Diseases caused by FH

Myocardial infarction (MI) is the most common manifestation of CVD in FH. However, aortic stenosis is in the lead when it comes to the type of CVD associated with the highest excess risk in FH.23 A priori the risk of ischaemic stroke in patients with FH would be expected to be increased due to accelerated atherosclerosis. However, the risk of stroke in patients with FH is debated with an increased risk reported in clinically diagnosed FH24 25 but not in FH mutation carriers.26 27 These findings warrant further investigations of the role of LDL-C in ischaemic stroke. Finally, patients with FH may also have an increased risk of peripheral artery disease.28 29

What is the risk of untreated FH?

Old data are in many ways useful to answer this question, since before statins became available in the early 1990s, effective treatment of FH was nearly non-existing. Several old studies observed that in patients with MI before the age of 60, about 5% had heterozygous FH.30–32 With the prevalence of 1:500 (or 0.2%) believed at that time, studies therefore reported a 25-fold increased risk. However, given today’s prevalence of about 1:250 (or 0.4%), the excess risk was possibly ‘only’ a 12.5-fold increase of MI.

Other considerations should be accounted for as well. Cholesterol levels have decreased over time in many countries. Thus, in Finland serum cholesterol levels fell 21% in the population of North Karelia between 1972 and 2012.33 Patients with FH probably behaved like the general population, but a 21% reduction of cholesterol levels in patients with FH gives a higher absolute reduction than in non-FH subjects.

The Simon Broome Register Group established a large cohort of patients with FH and in 1991 reported a standardised mortality ratio (SMR) in FH.19 SMR expresses the excess risk associated with FH and an SMR of 3.8 for CHD death was observed in 282 men and 244 women with FH during 1980–1989. The highest SMR for CHD death was observed in the youngest age group (ages 20–39) with a 96-fold increased risk. SMR for all-cause death was 1.8, and again highest at the youngest age with a ninefold increase.

Later, after statins became available, a study attempting to study all deceased patients with FH in Norway during 1989–2010, more than 90% had established CVD at the time of death (mean 60 years). In 5518 FH mutation carriers the highest excess risk of CVD death was observed at the youngest age (20–39 years) during 1992–2013. For CVD deaths occurring out of hospital, SMR was as high as 12.4 for those aged 20–39 years.34 In 5538 patients in the same registry, the mean age at first hospitalisation for CHD was 45.1 years with no sex differences.35

A cohort study36 of FH mutation carriers without prior CHD (n=2.795) during 2001–2009 reported that standardised incidence ratios (SIR) for a first time event were highest in the young (25–39 years) and higher in women (17.3) than in men (11.1). The SIRs decreased with age and reached 3 at ages 70–79 years. This corresponds well with observations from Simon Broome Register Group with no excess coronary SMR37 in patients above 60 years and the highest SMR in patients 20–39 years of age.38 In this cohort, CHD mortality remained elevated in patients with treated FH up to 2016.39 This demonstrates excess risk also in a time when statins were widely used.

Accumulated LDL-C load (cholesterol load year)

The importance of the concept of ‘accumulated cholesterol load’ based on plasma cholesterol levels in mmol/L multiplied by the number of years (outlined in figure 2) is being increasingly acknowledged11 and was first used to assess risk in patients with homozygous FH.40 In FH mutation carriers, the artery wall has been exposed to high LDL-C and accelerated atherosclerosis from birth. In patients with FH and plasma LDL-C of 5.0 mmol/L the hypothetical threshold value is reached at 40 years of age compatible with what was observed with first time admissions for CHD at 45 years in Norwegian FH mutation carriers.35 For the person with LDL-C of 2.5 mmol/L, this threshold will not be reached until the age of 80 years (figure 2).

Figure 2

The concept of accumulated low-density lipoprotein (LDL)-cholesterol years.

The number of years with high LDL-C also indicates that it may be important to start treatment of FH early, and an age of 8–10 years is now recommended.7 It also helps us understand the background for the very low treatment targets for LDL-C (1.8, 1.4 or even 1.0 mmol/L) recently advised in high-risk patients.11

FH affects the whole family

FH runs through families. Patients with FH have a 50% risk of passing the gene defect to their children. It is therefore important that the whole family is examined for FH which initially includes first-degree relatives (parents, siblings and children) and depending on results from other family members.

Families with FH can often report that their parents or grandparents were affected by CVD early in life. This may leave concern among the subjects affected by FH, and parents with FH may feel guilt by passing on a gene defect to their children. These findings and concerns about reaching treatment targets need to be addressed in the management of patients with FH,41–43 and FH should be considered a family disease.

Also, associations and foundations of patients with FH available in some countries are important and can support families with FH.

Treatment

There have been no long-term large randomised clinical trials investigating the effect of lipid-lowering treatment on hard clinical endpoints in patients with FH, and for ethical reasons there will never be. However, data not least from registries44 have indicated that statin treatment reduces CVD as it does in the general population. Also, Simon Broome Register Group compared CHD mortality in the period before and after statins became available.38 A cohort of 605 men and 580 women aged 20–79 years with clinical FH was followed prospectively from 1980 to 1995 and a decline in excess risk of CHD mortality was observed after statins became available, from eightfold before statins to 3.7-fold after statins were introduced.

Treatment of patients with FH is dynamic. Recent guidelines (2019) from European Atherosclerosis Society/European Society of Cardiology11 recommend the goals for plasma LDL-C shown in Box 3.

Box 3

Plasma low-density lipoprotein-cholesterol (LDL-C) goals for patients with familial hypercholesterolaemia (FH)

  • LDL-C <3.5 mmol/L in children.

  • LDL-C <1.8 mmol/L and a reduction in plasma LDL-C of >50% in subjects without other major risk factors (high risk).

  • LDL <1.4 mmol/L and a reduction in plasma LDL-C >50% in subjects with one or more major cardiovascular disease (CVD) risk factors and/or existing CVD (very high risk).

Diet

Diet is an important part of the treatment of FH. Importantly its effect cannot be judged solely from its effect on plasma LDL-C levels and other lipids and lipoproteins as diet might beneficially affect vascular risk by other mechanisms, perhaps best shown for a Mediterranean type of diet. A low saturated fat/low-cholesterol diet may lower cholesterol and the use of oat fibre and plant sterols/stanols may also be beneficial. Healthy diets for the general population benefit those with FH as well, and therefore those affected by FH and the whole family should eat healthy, again emphasising that FH is a family disorder.

Treatment of other risk factors than LDL-C

Having high levels of LDL-C makes it even more important that other modifiable risk factors for CVD are optimised and treated, such as hypertension, tobacco smoking, obesity and sedentary behaviour. Furthermore, high plasma lipoprotein(a) is a risk factor—perhaps in particular in patients with FH—and recent guidelines suggest that lipoprotein(a) should be measured in these patients.

Pharmaceutical treatment

Medications are necessary for control of LDL-C levels in the vast majority of patients. First line of treatment consists of statins, usually high-intensity statins (atorvastatin or rosuvastatin) in the maximally tolerated dose. This will on average half the levels of LDL-C in patients with heterozygous FH. This will, however, commonly not lead to LDL-C levels at target goals and very often statins need to be combined with ezetimibe, which will further reduce LDL-C by 15%–20%. If LDL-C levels are still not satisfactory some might try to add an anion inhibitor before PCSK9 inhibitors are considered. PCSK9 inhibitors reduce LDL-C by approximately 60% and are given as injections typically every second week. This treatment on top of statins has shown beneficial effect on CVD in two major endpoint trials.45 46 While short-term effects and safety look promising, really long-term data are still not available. A main limitation is their very high price, and in most countries their use is therefore regulated by health authorities. However, without the use of PCSK9 inhibitors it may be difficult for many patients with FH to reach the recommended goals, not least those who are statin intolerant. Very few patients in the European Union (EU) are treated with LDL apheresis, but this is an option in selected patients. New drugs are used to a limited extent mainly in patients with homozygote FH (lomitapide and mipomersen), and other compounds are under investigation.47

Challenges in the finding and treatment of FH

Unfortunately, most patients with FH are unaware of their FH, since high cholesterol levels are asymptomatic. Recently, it was thus estimated that 90% of the FH population remains undiagnosed,48 meaning that approximately 1.9 million EU citizens may have undiagnosed FH given a prevalence of 1:250.

Awareness of the significance of cholesterol and FH for CVD needs to be improved. Another obstacle may be that genetic testing often is regarded as expensive. Prices for testing persons without known family mutation vary considerably and are between €300 and €1000 within the Scandinavian countries, but a reduced price may be expected in the future. It should be emphasised that the test is done only once during a lifetime, and that the price is much cheaper when testing family members for known mutations. Systematic investigation of patients with FH and their families using genetic testing (cascade screening) would be a major step forward in the recognition of FH. Furthermore, patients with genetically proven FH seem to have a worse prognosis than those clinically diagnosed as mentioned previously and should therefore perhaps be treated more aggressively.

Another major problem is undertreatment. Thus, in a Danish general population no more than 48% of subjects with clinical FH used cholesterol-lowering medication despite the fact that 33% of them had CHD.49 In patients with FH who did not use statins, the adjusted OR for CHD was 13.2 compared with non-FH subjects. Furthermore, patients with FH on statins also had a disappointingly high odds risk ratio of 10.3 for CHD compared with non-FH subjects.50 51 Also the cost of new drugs (eg, PCSK9 inhibitors) is very high for society and may limit their use. In this context the cost of premature morbidity and increased early mortality from CVD must be taken into consideration and health economic studies of patients with FH, their treatment and prognosis should be encouraged.

FH needs to be prioritised by health authorities and knowledge about FH needs to be further disseminated to the public and promoted by international networks like the Familial Hypercholesterolaemia Studies Collaboration.52

Key messages

  • Familial hypercholesterolaemia (FH) is common and occurs in approximately 1:250.

  • FH is underdiagnosed with only approximately 10% of those affected diagnosed.

  • FH is undertreated with a high proportion not reaching guideline targets and many start treatment too late in life.

  • Genetic testing should be used more often in diagnosing FH.

  • Family screening, including genetic testing, is of utmost importance for diagnosing more persons with FH.

  • Diagnostic testing and screening for FH need to be better organised.

  • Knowledge about FH needs to be better disseminated among and between the public, general practitioners, lipid clinics, health authorities and health organisations.

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View Abstract

Footnotes

  • Contributors Design of paper, first draft, final draft (shared by all coauthors).

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

  • Data availability statement There are no data in this work

  • Author note References which include a * are considered to be key references

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