Familial Hypercholesterolemia
المؤلف:
Marcello Ciaccio
المصدر:
Clinical and Laboratory Medicine Textbook 2021
الجزء والصفحة:
p153
2025-06-09
605
Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease due to mutations in genes encoding for key proteins of the LDL metabolism, leading to an increase in circulating LDL cholesterol. Mutations in R-LDL gene, with loss of function; the APOB gene, with alterations in the binding domain of ApoB with R-LDL; and the PCSK9 gene, with a gain of function. Mutations in the R-LDL gene are the most frequent. To date, more than 1000 mutations in the R-LDL gene associated with different functional alterations of the receptor have been described: from a lack of synthesis to a lack of transport to the cell surface, failure to internalize the receptor-LDL complex, or failure to recycle the receptor after internalization.
FH can occur in heterozygous (HeFH) or homozygous (HoFH) forms. HeFH has a relatively high frequency in the population, with an incidence of 1/250 individuals worldwide, and is characterized by an increase in LDL cholesterol of about 2–3 times. From a clinical point of view, subjects who present the heterozygous form, often, before developing an acute event, such as acute myocardial infarction or stroke, do not show any discomfort objectable by the physician. Usually, the finding occurs incidentally during routine blood laboratory tests. Early diagnosis and adequate treatment allow for maintaining a cardiovascular risk similar to that observed in the general population.
HoFH is a rarer and more severe condition characterized by increased LDL cholesterol of about 6–8 times.
From a clinical point of view, subjects with the homozygous form develop cardiovascular events very early (18–20 years).
Both forms (both homozygous and heterozygous) are characterized by the presence of xanthelasmas, skin, and ten don xanthomas due to the accumulation of cholesterol in tis sue macrophages that infiltrate the skin and tendons. Homozygous individuals may present with xanthomas before 10 years of age, whereas in heterozygotes, the incidence of xanthomas increases with each decade. In some cases, especially in women, inflammation of the Achilles tendon is recurrent.
There is also a form of familial autosomal dominant hypercholesterolemia due to mutation in the LDLRAP1 gene, which encodes for the R-LDL adaptor protein 1, which has a fundamental role in the correct functioning of the LDL receptor. It is a very rare and severe familial dyslipidemia.
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