ISSN ONLINE: 2558-815X
ISSN PRINT: 1584-9244
ISSN-L: 1584-9244

Familial hypercholesterolemia – a secret enemy discovered late


Familial hypercholesterolemia (FH) is one of the most common hereditary diseases, with an estimated 20 million cases globally(1,2). Notwithstanding the elevated susceptibility to cardiovascular complications, this condition continues to be inadequately diagnosed1. The heterozygous form is expected to have a global prevalence of around 1 case per 200-250 individuals, while the homozygous form is estimated to have a global prevalence of 1 case per 100,000-160,000 individuals(2).
FH can be caused by the pathogenic dysfunction of any protein implicated in low-density lipoprotein (LDL) catabolism3. This condition is characterized by autosomal dominant transmission and occurs when mutations are detected in the LDL-R genes (in 80-85% of cases), apoB100 (in 2-10% of cases), PCSK (in around 2% of cases), or LDL receptor adapter protein 1 (LDLRAP1 – in less than 1% of cases)(2,3). Additionally, although their frequency is considerably lower, a sequence of additional mutations in the genes APOE, ABCG5, ABCG8, lysosomal acid lipase (LIPA), or signal transducing adapter family member 1 (STAP1) can result in FH3. Until now, over 3000 LDLR variants have been documented, with this particular gene being a pivotal component in the pathogenesis of FH3. Deregulation of the synthesis of the receptor for low-density lipoprotein (LDL-R) or anomalies in the binding of LDL to this receptor, which is responsible for removing LDL from the plasma circulation, are related to mutations in the LDL-R genes(4,5). The final result is an increase in serum LDL-cholesterol (LDL-C) concentrations, phagocytosis by macrophages transforming into foam cells, and the formation of atherosclerotic lesions(4,5). Additionally, APOB gene mutations are linked to an inadequate affinity between LDL and its particular receptor(3). However, it was shown that the serum levels of LDL-C were lower in these instances compared to patients with mutations in the LDL-R genes(3). PCSK9 mutations can be broadly classified into two categories: gain-of-function variants and loss-of-function variants3. Both of them are related to lower LDL-R expression and higher serum LDL-C levels(3).
The screening for hypercholesterolemia is recommended by the Canadian Cardiovascular Society for males aged 40 years and above, and for women aged 50 years and above or after menopause6. In the case of individuals with a family history of premature atherosclerotic cardiovascular disease, or FH, in a first-degree relative, it is recommended to evaluate the serum cholesterol level at the age of 11 years or even 12 months(6). Once the diagnosis of FH has been confirmed, it is imperative to assess all individuals in the family, to prevent any possible adverse effects(2). This statement is supported by research indicating that around half of a patient’s first-degree relatives will have FH-specific mutations(2).
The Dutch Lipid Clinic’s diagnostic criteria for FH are the most widely used in clinical practice(2). The variables assessed are serum lipids, the familial history of ischemic heart disease (such as premature death caused by myocardial infarction), the patient’s previous occurrence of early coronary disease, the identification of certain indicators during the objective examination (such as arcus cornealis and tendon xanthoma), and a lipidogram(2). It is recommended that patients whose serum total cholesterol exceeds 7.5 mmol/L or LDL-C exceeds 5.5 mmol/L be referred to a specialist for a comprehensive evaluation and genetic testing(2).
To summarize, FH is a hereditary disorder linked to an elevated susceptibility to cardiovascular events during early stages of life. It is critical to establish the diagnosis as soon as possible, to effectively implement suitable therapeutic measures. Enhancing the quality of life and prolonging life expectancy are the overarching objectives. Additionally, after the diagnosis of FH has been confirmed, it is critical to assess the total cholesterol and LDL-C levels in the serum of every member of the patient’s family. The management of FH is complex and includes dietary interventions, as well as prolonged hypolipidemic pharmacological therapies.

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Camelia C. DIACONU


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Diaconu CC. Familial hypercholesterolemia – a secret enemy discovered late. Arch Balk Med Union. 2024;59(1):5-7.