Molecular Biology
and Lysosomal Disease
Diagnosis Laboratory
Center for Research and Diagnosis of Genetic Diseases
Diagnostico: Familial Hypercholesterolemia

Familial Hypercholesterolemia (FH) is an autosomal dominant hereditary disease, a genetic disease of lipoprotein metabolism, mainly due to a defect in the LDLR gene encoding the LDL receptor. The diagnosis is established by clinical and laboratory criteria and should always be a diagnostic hypothesis in patients with low-density lipoprotein cholesterol (LDLc) levels greater than 190 mg/dL; and can be confirmed by genetic tests that determine the mutation. Some diagnostic criteria have been proposed in an attempt to standardize and formalize the diagnosis of FH, such as the Dutch Lipid Clinic Network (Dutch MEDPED). This calculates a patient score based on anamnesis data and physical and laboratory tests such as elevated rates of LDLc; characteristics such as tendinous xanthomas and corneal arch; family history of hypercholesterolemia and/or early coronary artery disease (man < 55 years and woman < 60 years) and identification of genetic mutations. The score determines the probability of an FH diagnosis as possible, probable or definitive FH. The most common mutation related to FH is in the gene encoding the LDL receptor, resulting in LDL receptors with functional reductions in their ability to remove LDLc from the circulation. There are two distinct phenotypes: the homozygous form, where two defective genes are inherited and LDL receptors have no functionality; a rare form,1 in 1 million individuals and in this case are observed LDL levels > 650 mg/dL; and the heterozygous form, where a gene defective to the LDL receptor is inherited from one parent and a normal gene from the other. The absence of a functional gene causes an increase in the plasma level of LDLc; most frequently affects 1 in 500 individuals with LDL levels > 200 mg/dL. The homozygous form tends to present cardiovascular involvement already in childhood. The mutation may also be secondary to defects in the APOB gene encoding apolipoprotein B100, or by functional gain mutations in the pro-protein convertase subutilisin/kexin type 9 (PCSK) gene. -9). In patients with heterozygous FH the LDL particles circulate longer, being more subject to oxidation and chemical transformations that result in high uptake of LDL modified by macrophages, triggering pro-atherogenic mechanisms, causing atherosclerosis, coronary artery disease and arterial disease peripheral. The nutritional therapies, medication, and regular physical exercises help to control LDL levels and to prevent cardiovascular disease. It is recommended to reduce the intake of foods rich in cholesterol and saturated fatty acids. Pharmacological therapy is performed with high-potency statins, such as Atorvastatin (10-80 mg) and Rosuvastatin (10-40mg), in order to obtain a reduction of more than 50% of the baseline level. In patients with intolerant to statin therapy, other hypolipidemic agents, such as ezetimibe, niacin or cholestyramine may be used; and may be also combined with each others in patients who are poorly responding to single statin therapy. Drug therapy should be individually prescribed and maintained in the long term, with regular medical follow-up always evaluating liver (TGO/TGP) and muscular (CPK) enzymes. Lipid profile screening is recommended in all individuals over 10 years of age and in all first degree relatives of individuals diagnosed as having FH. In the presence of risk factors, clinical signs of FH or atherosclerotic disease, the lipid profile should be considered from 02 years old on.

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