Familial hypercholesterolemia (FH) is a hereditary pathology characterized by a marked increase in the amount of low–density lipoproteins (LDL) in the bloodstream and a high risk of early development of coronary heart disease. In most cases, it is asymptomatic. Sometimes there is chest pain, blisters on the hands, knees and around the eyes, tendon and subcutaneous deposits of cholesterol. The main diagnostic methods are the collection of a hereditary history, a blood test for total cholesterol and LDL. For treatment, a hypolipidemic diet, regular physical activity, drug correction with lipid-lowering drugs, apheresis of atherogenic lipoproteins are used.
E78.0 Pure hypercholesterolemia
Synonyms of familial hypercholesterolemia are primary, hereditary hypercholesterolemia. It is not an independent disease, but a condition of predisposition to cardiovascular diseases – vascular atherosclerosis, coronary heart disease, acute myocardial infarction. Data on the prevalence of GHS have a wide range, since in many cases the pathology remains undiagnosed. The frequency of the heterozygous form, in which a patient has one defective gene from a pair, is 1 case per 108-300 people. The homozygous form, characterized by the presence of two mutational genes in the allele, is more severe and occurs much less frequently – in 1 person out of 1 million. Among all variants of hypercholesterolemia, familial HHS accounts for 10% of cases.
FH is a hereditary autosomal dominant pathology that is caused by mutation of genes responsible for LDL metabolism and the activity of their receptors. In the presence of one defective gene in a pair, heterozygous hypercholesterolemia occurs – a mild to moderate violation of lipid metabolism. In rare cases, patients have two paired altered genes (from the mother and from the father), homozygous hypercholesterolemia develops – a severe disorder of lipid metabolism with a malignant course. The cause of familial hypercholesterolemia is a mutation in one of the following genes:
- 1LDLR. The gene sets the functionality of the LDL receptor, located mainly on the surface of liver cells. When mutated, its activity decreases, the process of binding and removing circulating lipoproteins from the bloodstream is disrupted. More than 1600 types of LDLR gene mutations have been identified. Their share in the total number of FH is 85-90%.
- 2APOB. A gene defect leads to a change in the structure of apolipoprotein B100, which is part of LDL, ensuring their binding to the receptor. Mutational changes in APOB are present in 5-10% of patients with hereditary hypercholesterolemia. They provoke a less pronounced increase in LDL than LDLR mutations.
- 3PCSK9. This gene encodes the enzyme proprotein convertase of subtilisin-kexin type 9, which enhances the destruction of LDL receptors. Mutations in the PCSK9 gene increase the activity of the enzyme, as a result of which the number of receptors decreases. Pathology of this type occurs in 5% of cases of CFS.
Familial hypercholesterolemia is based on a genetically determined increase in LDL levels. Most often it is caused by a decrease in the activity of a specific receptor responsible for the excretion of lipoproteins. LDL is the most atherogenic particles. Atherosclerotic plaques are formed when they accumulate in the subendothelial space. The higher the level of low-density lipoproteins in the blood, the more intense the process.
LDL is the worst excreted in people with homozygous primary hypercholesterolemia: both paired genes have a mutation, the functionality of the receptor is reduced by more than 50%, the concentration of LDL is high, it is difficult to correct with medication and diet. Atherosclerosis and its complications develop in childhood and adolescence. With heterozygous hypercholesterolemia, only one gene is defective, half or more of the receptors remain functional, the amount of LDL increases, but does not manifest clinically for a long time. Often, atherosclerosis, coronary heart disease or myocardial infarction becomes the first sign of CFS.
FH develops from birth, but often has no pronounced clinical signs. The diagnosis is made late with the manifestation of cardiovascular diseases, such as coronary heart disease, heart muscle infarction, atherosclerosis. Symptoms of hypercholesterolemia are observed in less than half of patients. About a third of patients develop tendon xanthomas – seals of a fat-like substance (cholesterol), palpable above the tendons. Nodules are particularly easy to identify on the brushes. Cholesterol is deposited under the skin of the eyelids, near the eyes in the form of xanthelasm – yellowish or flat nodules that do not have a specific color.
The pathognomonic sign of FH is the lipoid arch of the cornea. It is an accumulation of cholesterol along the edge of the cornea, which are detected during an ophthalmological examination and look like a white or gray-white rim. In some cases, patients note pain and discomfort in the chest area, watery rashes on the skin of the hands, elbows and knees. At the stage of development of atherosclerosis, mosaic symptoms of internal organ damage are revealed.
In the absence of treatment, homozygous primary hypercholesterolemia contributes to the development of atherosclerosis up to the age of 20, the life expectancy of patients does not exceed 30 years. Untreated patients with a heterozygous form of pathology have a high risk of developing coronary heart disease, by the age of 60, the diagnosis is confirmed in 85.5% of men and 53% of women. The average life expectancy for men is 53 years, for women – 62 years. Coronary heart disease causes the death of half of men with hereditary heterozygous hypercholesterolemia. About 20% of cases of myocardial infarction before the age of 45 are associated with the presence of CFS.
The examination of patients is carried out by a therapist, a cardiologist, a geneticist. An important stage of diagnosis is the collection of personal and family history. The age of the patient and the time of onset of symptoms are taken into account, because early onset is characteristic of hereditary pathology. In favor of the diagnosis of familial hypercholesterolemia, the presence of two or more close relatives (especially children) with elevated blood cholesterol, xanthomas and/or corneal lipoid arches is considered. The main task of differential diagnosis is the exclusion of secondary hypercholesterolemia. Examination of patients is carried out by the following methods:
- Physical examination. With careful palpation of the tendons of the feet, shins and hands, xanthomas are detected. The presence of a complete or partial lipoid arch is determined on the cornea, in persons younger than 45-48 years, it indicates CGHS. The absence of xanthomas, xanthelasm and corneal arch does not exclude the presence of hypercholesterolemia.
- Lipidogram. A comprehensive laboratory study of the lipid profile is the most informative diagnostic method. The indicator of total cholesterol in heterozygous pathology is 7.5-14 mmol /l, in homozygous – 14-26 mmol / l. The LDL level increases accordingly to 3.3-4.9 mmol/l and to 4.15-6.5 mmol/l.
- Genetic screening. Identification of mutations and their nature is necessary if it is impossible to confirm the diagnosis by other means, as well as to draw up an optimal treatment plan. 80% of patients have defects in LDLR, APOB or PCSK9 genes. In the remaining 20%, genetic changes are not diagnosed even with the developed symptoms of CFS.
Therapy includes a set of measures aimed at reducing the amount of LDL. Tactics are determined by the form of hypercholesterolemia, the magnitude of the deviation of the lipidogram from the norm, the severity of symptoms and the age of the patient. A significant part of medical procedures is carried out on an outpatient basis with regular monitoring of effectiveness by the attending physician. Patients are assigned:
- Drug therapy. Drugs that lower the level of lipids in blood plasma are used. The most appropriate combination of statins, fibrates, bile acid sequestrants and cholesterol absorption inhibitors in the intestine.
- Lifestyle correction. All risk factors of hyperlipidemia are excluded: complete cessation of smoking, blood pressure control, normalization of body weight, regular physical activity is required. Diet therapy is based on limiting the amount of saturated fats and trans fats. The daily intake of cholesterol with food is no more than 200 mg.
- LDL apheresis. With homozygous type of hypercholesterolemia, drug treatment is often not effective enough. Procedures for removing lipoproteins from the blood are carried out. Apheresis can also be indicated in patients with coronary heart disease and atherosclerosis with heterozygous CGHS, especially if taking medications does not give the expected positive effect.
- Stimulation of LDL receptors. Recently, pathogenetic therapy of CFS has been introduced into medical practice. A drug is used that stimulates an increase in the number of LDL receptors in liver cells. As a result, the capture and excretion of lipoproteins from the body increases.
Prognosis and prevention
A favorable course of familial hypercholesterolemia is most likely with a heterozygous type, early initiation of treatment and periodic monitoring of cholesterol levels throughout life. Due to the hereditary nature of the pathology, it is impossible to prevent its development. Preventive measures are aimed at early diagnosis of hypercholesterolemia, which reduces the likelihood of atherosclerosis, coronary heart disease, heart muscle infarction. To do this, a cascade screening is carried out – a study of the level of blood lipids in all the patient’s closest relatives.