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De Castro-Orós et al

FH was first described by Müller in 1938.2 Initially, the FH defect was long thought to be caused by cholesterol oversynthesis.3 In the middle 1970s, Brown and Goldstein4,5 found that FH defect was due to the absence of a high affinity receptor for uptake of serum low-density lipoprotein (LDL). These investigators characterized the LDL receptor (LDLr) pathway with its implications in other pathways and identifying the genetic defect that caused malfunction of the LDLr.6 Nowadays, FH has become one of the best known genetic diseases.

Although the vast majority of FH cases are caused by mutations in the LDL receptor gene (LDLR) gene, there are other causative genes such as apolipoprotein B (APOB) that codifies for the natural ligand of the LDLr protein7 And a third gene, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been more recently identified as a cause of FH;8,9 however, mutations in this latter gene seems to be rare in the populations studied so far (Table 1).10


FH is one of the most common inherited disorders with frequencies of heterozygotes and homozygotes estimated to be 1:500 and 1:1,000,000, respectively. In certain populations, a small number of mutations predominate due to founder effects and therefore, there is a high heFH frequency in these populations including French Cana- dians,11 Christian Lebanese,12 Druze,13 Finns,14 South

African Afrikaner,15 descent.16

and Ashkenazi Jews of Lithuanian

FH heterozygous patients display a twofold increase in plasma cholesterol (generally above the 95th percentile value

Table 1 Frequency of different types of primary hypercholesterolemia

Monogenic hypercholesterolemia (1:500) Autosomal dominant FH FDB-100 FH type 3 Unknown Autosomal recessive (1:1,000,000) ARH Phytosterolemia Cholesterol 7 α-hydroxylase deficiency Complex hypercholesterolemia (1:50) FCH Polygenic hypercholesterolemia (1:25)



Unknown APOB, APOE, LDLR, unknown

60%–80% 1%–5% 0%–3% 20%–40%

Abbreviations: FH, familial hypercholesterolemia; FDB, familial defective Apo B gene; FCH, familial combined hyperlipidemia; LDLR, low-density lipoprotein receptor; APOE, apolipoprotein e; PCSK9, proprotein convertase subtilisin/kexin type 9; APOE, apolipoprotein B gene; ARH, autosomal recessive hypercholesterolemia.


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for population). In patients with FH, the age–sex standardized mortality ratios are 4–5 times higher than in the general populations.17

Due to the high incidence of premature (,55 years in men and ,65 years in women) cardiovascular disease (CVD) and reduction in the life expectancy in many families with this disease, FH has been considered as a worldwide public health problem.18 Approximately, 85% of males and 50% of females will suffer a coronary event before the age of 65 years if they are not treated.19 It is noteworthy that up to 9% of the total premature CHD in eastern Finland and Germany is associ- ated with FH.20–22

Long-term follow-up studies have shown that the main cause of death in FH patients is CHD.23,24 With adequate long-term pharmacological treatment, many FH patients could achieve substantial reductions in LDLc, and probably increase their life expectancy by 10–30 years.25

Intervention studies in FH

Scientific evidences, coming from large clinical trials, have demonstrated the benefit of LDLc reduction in the prevention of CVD in a broad spectrum of populations, especially in subjects with symptomatic CHD or with absolute high risk.26,27 As mentioned earlier, FH patients should be considered high risk subjects due to the prevalence of CHD, and they should benefit as a group at least as much as other high risk groups.According to the presence of major risk factors and/or clinical or subclinical atherosclerosis, three categories of risk for heFH are suggested (Table 2): (1) low 10-year risk, with no major risk factors; (2) moderate 10-year risk, with one major risk factor; and (3) high 10-year risk: (a) with $2 major risk factors, (b) subclinial atherosclerosis, or (c) clinical CVD.

In the last 15 years, different studies have used well- established surrogates of CVD to study the effects of aggressive LDLc reduction in FH. These studies demonstrate



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Men: $30 yo women: $45 yo or postmenopausal Cigarette smoking: active smokers Family history of premature CHD Male first-degree relative ,55 yo Female first degree ,65 yo very high LDLc: .330 mg/dL (8.5 mmol/L) Diabetes mellitus Lp(a): .60 mg/dL

Table 2 Major CvD risk factors in heterozygous FH

Abbreviations: CHD, coronary heart disease; LDLc, low-density lipoprotein cholesterol; yo, years old.

The Application of Clinical Genetics 2010:3

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