Summary
Familial hypercholesterolaemia is an inherited disorder, leading to accumulation of low-density lipoprotein (LDL) particles in plasma and premature cardiovascular disease. Although the phenotype of the rare homozygous form is always severe, the phenotypic expression of the common heterozygous familial hypercholesterolaemia can vary considerably. Beyond the magnitude of the LDL-cholesterol elevation and the type of mutation, additional genetic, metabolic and environmental cardiovascular risk factors lead to the substantial variations in the clinical manifestations and severity of atherosclerotic disease. Heterozygous familial hypercholesterolaemia is often under-diagnosed and under-treated, and there is an unmet need in terms of management of severe heterozygous forms. Homozygous and severe heterozygous familial hypercholesterolaemia should receive more intensive treatment and alternative therapeutic approaches are needed for these high-risk patients. In this article, we review the recommendations for diagnosis and treatment of severe familial hypercholesterolaemia and the agents currently available or under development.
Résumé
L’hypercholestérolémie familiale est une maladie héréditaire qui induit une accumulation de particules LDL dans le plasma et un risque accru de maladies cardiovasculaires précoces. Alors que le phénotype de la rare forme homozygote est toujours sévère, l’expression phénotypique de la forme hétérozygote fréquente peut varier considérablement. En dehors de l’importance de l’élévation du LDL-cholestérol et du type de mutation, de nombreux facteurs de risque cardiovasculaire additionnels génétiques, métaboliques et environnementaux ont un rôle important dans la variabilité des manifestations cliniques et dans la sévérité de la maladie athéromateuse. Les hypercholestérolémies familiales hétérozygotes restent mal diagnostiquées et insuffisamment traitées et il existe un besoin médical non satisfait en termes de prise en charge des formes hétérozygotes sévères. Les hypercholestérolémies familiales homozygotes et hétérozygotes sévères doivent recevoir un traitement plus intensif et de nouvelles alternatives thérapeutiques sont nécessaires pour ces patients à très haut risque. Cet article est une revue des recommandations vis-à-vis du diagnostic et du traitement des hypercholestérolémies familiales sévères, avec présentation des médicaments actuellement disponibles et en développement.
Background
Autosomal dominant familial hypercholesterolaemia (FH) is among the most common inherited disorders . FH is characterized by an elevation of low-density lipoprotein cholesterol (LDL-C) due to reduced uptake of plasma LDL particles by the liver. Affected subjects are at increased risk of all atherosclerotic diseases secondary to lifelong elevations in LDL-C. The pattern of inheritance is autosomal codominant and the main gene involved in FH is the LDL receptor ( LDL-R ) gene. However, mutations leading to FH have been also described in two other genes: apolipoprotein B ( ApoB ) and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ). The vast majority of families show only heterozygous carriage of the causal gene. Homozygotes or compound heterozygotes are rare but are characterized by very high concentrations of LDL-C and severe atherosclerosis during childhood. As a result, all patients with homozygous FH must be classified in the category of severe hypercholesterolaemia.
Although the cause of FH is monogenic, heterozygous FH can have widely different concentrations of LDL-C. Moreover, various additional environmental and metabolic factors are assumed to affect the clinical phenotype of heterozygous FH. Major cardiovascular risk factors in individuals with heterozygous FH have been identified and several categories of risk have been proposed according to the presence of these major risk factors and/or clinical atherosclerosis .
Despite the use of currently available lipid-lowering treatments (LLTs), a high proportion of patients with severe forms of FH, including homozygous FH and severe heterozygous FH, do not reach treatment goals and remain at increased risk of atherosclerotic cardiovascular diseases (CVDs). New therapeutic approaches are crucial for these patients. There is a need to better define the categories of severe FH eligible for these new treatment options.
Diagnosis and cardiovascular risk of FH
FH is caused by mutations mainly in LDL-R gene but also in other genes ( ApoB , PCSK9 , etc.) . Individuals with two mutations (homozygous FH) are easy to diagnose due to the severity of the disease. By comparison, many people with the heterozygous form are undiagnosed or are only diagnosed after their first coronary event.
Homozygous FH
Homozygous FH is a very rare (1 per 1 million people) autosomal dominant disease, usually caused by mutations in the LDL-R gene or other genes, leading to very high plasma concentrations of LDL-C and earlier onset of coronary heart disease (CHD) than in subjects with heterozygous FH. Homozygous FH patients are classified into two major groups based on the amount of LDL-R activity: patients with less than 2% of normal LDL-R activity are classified as receptor-negative and patients with 2 to 25% of normal LDL-R activity as receptor-defective. In practice, children with two heterozygous FH carrier parents have a 25% chance of inheriting both defective genes, leading to homozygous FH with either the same genetic mutation from both parents or two different mutations from each parent (also named compound heterozygous).
Homozygous FH is characterized by extremely high concentrations of total cholesterol (usually in the range 6.0–10.0 g/L) and LDL-C. In a large homozygous FH cohort, the mean LDL-C concentration for untreated subjects was 6.15 g/L . High-density lipoprotein cholesterol (HDL-C) concentrations are often decreased and triglyceride (TG) concentrations are usually normal .
In childhood, patients with homozygous FH develop multiple types of xanthomas, including tendinous and tuberous xanthomas, xanthelasmas and particularly cutaneous planar xanthomas, being considered as pathognomonic of the disease . Accelerated atherosclerosis appears in childhood and develops initially in the aortic root, causing valvular and supravalvular aortic stenosis, then extension into the coronary ostia. Untreated patients with homozygous FH who are receptor-negative rarely survive beyond the second decade; receptor-defective patients have a slightly better prognosis but, with few exceptions, develop clinically significant atherosclerotic vascular disease by the age of 30 years (and often sooner) .
Heterozygous FH
The prevalence of heterozygous FH is 1 in 300–500 in Western populations, making heterozygous FH one of the most common inherited disorders. Known causes of heterozygous FH include mutations in three major genes: the LDL-R , ApoB and PCSK9 genes . However, heterozygous FH is most commonly attributable to mutations in the LDL-R gene. In a recent French cohort, the respective contributions of each known gene were 73.9% for LDL-R , 6.6% for ApoB and only 0.7% for PCSK9 . No mutation was found in 19% of the probands, underscoring the existence of mutations located in still unknown genes.
The clinical criteria used to identify patients with heterozygous FH include high plasma concentrations of total cholesterol and LDL-C, the presence of tendon xanthomas in the patient or first-degree relative, a family history of hypercholesterolaemia (especially in children) and a personal or family history of premature CHD . Usually, heterozygous FH patients have LDL-C concentrations ranging from 1.9 to 4.0 g/L. However, the range of total cholesterol and LDL-C concentrations in heterozygous FH overlaps with concentrations observed in polygenic hypercholesterolaemia. Moreover, heterozygous FH patients can have LDL-C concentrations less than 1.90 g/L. Thus, additional criteria are needed to confirm the diagnosis of FH. TGs are usually in the normal range but some patients with FH have elevated TG concentrations explained either by environmental factors or by interactions with other genes. Plasma concentrations of lipoprotein(a) (Lp[a]) are also often elevated in FH patients. Tendon xanthomas are essentially pathognomonic of FH. However, tendon xanthomas are rare until the fourth decade of life. Additional sites of cholesterol deposits are the cornea (cornea arcus) and the eyelids (xanthelasmas) but these sites are not specific for heterozygous FH.
In practice, clinical diagnosis can still be difficult due to the variability of clinical expression, even among individuals who share the same genetic defect. By consequence, several sets of criteria have been developed for diagnosing FH. Among the best validated criteria, the Simon Broome Register criteria ( Table 1 ) and the Dutch Lipid Clinic Network criteria ( Table 2 ) for FH are the most widely used. Using these scores, a clinical diagnosis of FH can be made on the basis of clinical characteristics and laboratory findings. When the diagnosis is uncertain (possible or probable), the detection of a mutation in the causal gene provides the only unequivocal diagnosis. Diagnosis of heterozygous FH using DNA-based mutation screening methods should be proposed to decrease the rate of under-diagnosis. The NICE guidelines state that all patients with a clinical diagnosis of FH should be offered a DNA diagnostic test and referral for family cascade testing in order to identify relatives affected . Indeed, the most effective strategy for diagnosing patients with FH is to screen close relatives of patients already diagnosed with FH . Cascade screening involves testing lipid concentrations in all first-degree relatives of diagnosed FH patients. In families where the mutation has been identified, genetic testing should also be included in cascade screening.
| A definite diagnosis of FH requires | ||
| Cholesterol concentrations as defined in this table and tendon xanthomas in the patient or in a first- or second-degree relative | ||
| OR | ||
| DNA-based evidence of an LDL-R mutation, an ApoB mutation or a PCSK9 mutation | ||
| A possible diagnosis of FH requires cholesterol concentrations as defined in this table and at least one of the following | ||
| Family history of myocardial infarction before age 50 years in a second-degree relative or before age 60 years in a first-degree relative | ||
| OR | ||
| Family history of raised cholesterol > 2.9 g/L (7.5 mmol/L) in an adult first- or second-degree relative or > 2.6 g/L (6.7 mmol/L) in children aged < 16 years | ||
| Cholesterol concentrations to be used as diagnostic criteria for the index individual | ||
| Total cholesterol | LDL-C | |
| Child/young person | > 2.60 g/L | > 1.55 g/L |
| (> 6.7 mmol/L) | (> 4.0 mmol/L) | |
| Adult | > 2.90 g/L | > 1.90 g/L |
| (> 7.5 mmol/L) | (> 4.9 mmol/L) | |
| Characteristics | Number | ||
|---|---|---|---|
| Family history | |||
| First-degree relative known to have premature a CVD | 1 | ||
| First-degree relative known to have LDL-C > 95th percentile | |||
| OR | |||
| First-degree relative with tendon xanthoma or arcus cornealis | 2 | ||
| Children aged < 18 years with LDL-C > 95th percentile | |||
| Clinical history | |||
| Patient has premature a CAD | 2 | ||
| Patient has premature a cerebral or peripheral vascular disease | 1 | ||
| Physical examination | |||
| Tendon xanthomas | 6 | ||
| Arcus cornealis below age 45 years | 4 | ||
| Laboratory analysis | |||
| LDL-C | > 3.30 g/L | > 8.5 mmol/L | 8 |
| LDL-C | 2.50–3.29 g/L | 6.5–8.4 mmol/L | 5 |
| LDL-C | 1.90–2.49 g/L | 5.0–6.4 mmol/L | 3 |
| LDL-C | 1.55–1.89 g/L | 4.0–4.9 mmol/L | 1 |
| DNA analysis | |||
| Functional mutation gene present | 8 | ||
| Diagnosis of FH | |||
| Certain when | > 8 points | ||
| Probable when | 6–7 points | ||
| Possible when | 3–5 points | ||
Untreated patients with FH are at very high risk of premature CHD and death. Before statin treatment, around 50% of men experienced cardiovascular disease by the age of 50 years and around 30% of women by the age of 60 years . However, among people with FH, the phenotypic expression in terms of onset and severity of atherosclerotic disease varies considerably. The type of genetic mutation, as well as other genetic factors, may contribute to this variability . However, the risk differs even among individuals who share the same defect and LDL-C concentrations are a more important risk factor than the type of LDL-R mutation . Additional atherogenic risk factors play a crucial role in the clinical expression of FH . Risk factors for cardiovascular disease are similar in individuals with or without FH. However, in the setting of high cholesterol concentrations, the effect of each risk factor is amplified .
In summary, the clinical prognosis of heterozygous FH is related not only to the magnitude of the LDL-C elevation and to the longer duration of high LDL-C exposure but also to the presence of other genetic or environmental cardiovascular risk factors. Individuals with FH who are at highest risk, especially those with the more severe forms of FH, must be identified and should receive more intensive treatment.
Identification of severe FH
An important step in improving the management of patients with severe FH is better definition of this patient subpopulation that needs specific therapeutic options. Indeed, despite the use of currently available LLTs, a significant proportion of patients with severe forms of FH, including homozygous FH and severe heterozygous FH, do not reach treatment goals and therefore remain at elevated risk for atherosclerotic CVD.
Until now, no clear definition of severe heterozygous FH has been proposed . Recommendations from the National Lipid Association (NLA) Expert Panel on FH have defined characteristics of FH patients at the highest cardiovascular risk : established CHD or other atherosclerotic CVD, or the presence of additional major risk factors, including diabetes, smoking and family history of very premature CVD ( Table 3 ), places patients with heterozygous FH in the very-high-risk category .
| Homozygous FH patients |
| Heterozygous FH patients with any of these very-high-risk characteristics |
| Established CHD or other CVD |
| Smoker |
| Diabetes mellitus |
| Family history of very-premature-onset CHD |
| First- or second-degree male relative with onset before age 45 years |
| First- or second-degree female relative with onset before age 55 years |
| Two or more cardiovascular risk factors among this list: |
| Increasing age (men > 30 years; women > 40 years) |
| LDL-C > 2.50 g/L |
| Male sex |
| Family history of premature-onset CHD |
| First-degree male relative with onset before age 55 years |
| First-degree female relative with onset before age 65 years |
| Metabolic syndrome |
| HDL-C < 0.40 g/L |
| Hypertension (BP > 140/90 mmHg or drug treatment) |
| Lp(a) ≥ 0.50 g/L |
| Tendon xanthoma |
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