Familial hypercholesterolemia

Introduction to familial hypercholesterolemia Familial hypercholesterolemia (FH) is an autosomal dominant hereditary disease. The pathogenesis of this disease is the absence or abnormality of LDL receptors on the surface of the cell membrane, leading to abnormal LDL metabolism in the body, resulting in plasma total cholesterol ( TC) levels and low density lipoprotein-cholesterol (LDL-C) levels are elevated. basic knowledge Proportion of disease: There is a genetic predisposition, family members have this disease, the incidence rate is about 0.5%-0.7% Susceptible people: no specific population Mode of infection: non-infectious Complications: coronary heart disease aneurysm

The cause of familial hypercholesterolemia

(1) Causes of the disease

The cause of FH is the natural mutation of the LDL receptor gene. Goldstein and Brown identify different types of gene mutations, including deletions, insertions, nonsense mutations and missense mutations. So far, dozens of LDL receptor gene mutations have been found. Divided into five major types:

1. Class I mutation

It is characterized by the fact that the mutant gene does not produce a measurable LDL receptor, and there is no LDL receptor on the cell membrane. It is the most common type of mutation, accounting for more than half of the mutations found, and is detected by anti-LDL receptor polyclonal or monoclonal antibody. It is confirmed that the LDL receptor gene of this kind of mutation hardly produces or only produces a very small amount of LDL receptor precursor, so the mutant LDL receptor gene is a null allele, also known as a no-receptor synthetic mutation, and is named as Receptor-O (RO), the molecular basis of class I mutations may include point mutations in the LDL receptor gene, leading to termination before the coding for the receptor; promoter mutations block the transcription of mRNA; introns and exons Mutations at the junction cause abnormal splicing of mRNA and deletion of DNA of large fragments. Recently, a patient with negative receptors was found to have a 5.0 kb fragment between the exon 13 of the LDL receptor gene and the Alu sequence of intron 15. Exon 13 recombines with Alu.

2. Class II mutation

It is characterized by the maturation and transport disorder of LDL receptors synthesized by mutant genes, and the LDL receptors on the cell membrane are significantly reduced, which is also a common type of mutation. The mutant gene can produce LDL receptor precursors, most of which have normal molecular weight. Named R-120, the analysis found that the processing modification of these receptor precursors is disordered. The molecular basis of this type of mutation is not well understood. It has been proved that these LDL receptors can be monoclonal antibodies against LDL receptors. Identification, indicating that there is no change in the structure of these precursors, Scheckman et al. studied a yeast-converting enzyme similar to a class II mutation and found that this defect of the enzyme is mainly caused by a single amino acid in the NH2 terminal hydrophobic signal chain. The change, resulting in the signal chain can not be separated from the enzyme protein, the rate of this enzyme protein into the Golgi apparatus is only 2% of normal, the yeast acid phosphatase gene induces similar mutations in vitro, resulting in the signal chain can not be separated from the receptor precursor In order to make it into the Golgi apparatus processing modification disorder, type II mutation mainly affects the 1st and 2nd regions of the LDL receptor, and the missense mutation is more common, however, from a single amino group Residue substitutions or deletion of subparagraph DNA or cause the transport mechanism of the mature LDL receptor hindered not been fully elucidated in the cell.

3. Class III mutation

It is characterized by the fact that the LDL receptor synthesized by the mutant gene can reach the cell surface, but cannot bind to the ligand. The molecular weight of the mutant LDL receptor gene is basically normal, and it is named R-160b-, and also has R-140b- and -210b-, Type III mutations interfere with normal binding between the receptor and the ligand by involving the L-receptor region 1 repeat 2-7 or 2 region repeat A. Studies have shown that such mutant LDL receptor precursors can be protected by LDL receptors. The recognition of the monoclonal antibody by the body is 40kD smaller than that of the mature receptor, indicating that the process of modification of the receptor precursor is normal. However, the receptor binding of 125I-LDL does not exceed 15% of normal, suggesting that the mature LDL is affected. The molecular basis for the binding of 125I-LDL to the abnormality may be the amino acid sequence of the receptor binding domain. It is known that the LDL receptor binding domain has seven repeats, each of which has homology, and thus the encoded DNA sequence. It is easy to delete or form a mismatch in the diploid, and the structure of the receptor binding domain is abnormal, resulting in a decrease in affinity with LDL.

4. Class IV mutation

Such mutations are mainly caused by the mature LDL receptors reaching the cell surface and unable to be trapped and integrated into the cell. Although the cells can bind to LDL, but there is no internal migration, also known as internal migration-deficient mutation, which involves the cross of LDL receptors. In the membrane region (region 4) and the C-terminal tail region (region 5), Lehrman et al. showed that a single base mutation in the 17,18 exon of the LDL receptor gene can cause an inward-shift defect, and recent studies have also found that Two class IV mutant FH homozygotes, whose LDL receptor gene was mutated to the deletion of 5.0 kb and 7.8 kb, respectively, between the intron 15 and the exon 18 of the 3' untranslated region, forming Alu-Alu Sequence recombination, the receptors for cell synthesis lack the transmembrane domain and the cytoplasmic domain. Most of this truncated LDL receptor is secreted into the culture medium, and only a small part adheres to the non-resolved surface of the cell surface, although it can bind LDL. , but no internal shift occurs.

5.V mutation

This type of LDL receptor mutation occurs in the epilogous growth factor precursor homologue, which is characterized by the synthesis of LDL receptors, binding to LDL and subsequent internal shifting, but the receptor cannot be recycled to the cell membrane. After the defective LDL receptor binds to LDL and enters the cell, both of them cannot be separated and are simultaneously degraded in the lysosome.

In addition, Lehrman reported that the incidence of FH in Lebanon is high. The LDL receptor gene study of four FH homozygous patients found that the gene mutation occurred in the middle of the coding mutation in the second domain containing the Cys sequence and the mutation was terminated. Results LDL receptor lacks O-linked sugar chain, transmembrane domain and cytoplasmic domain, and a total of 160 amino acid residues are deleted. This mutant LDL receptor gene is called "Lebanese allele".

Recently, Kajinami et al studied 35 unrelated FH heterozygous receptor genes, and then analyzed the LDL receptor genes of these two family members. It was found that all patients with FH showed the same abnormal LDL receptor gene DNA fragments due to their Both are grown in the Tonami area of Japan, and these patients are called "FH-Tonami."

(two) pathogenesis

Defects in LDL receptors can cause double abnormalities in LDL metabolism in vivo, that is, LDL production increases and decomposition slows down. The most prominent abnormality is that LDL is degraded from plasma catabolism, and intravenous injection of LDL labeled with radionuclide into normal In the human body, the average catabolic rate of LDL in plasma within 24 hours was 45%; the same LDL was intravenously injected into heterozygous FH patients, the average catabolic rate of plasma LDL within 24 hours was 28.7%; and the average catabolic rate of LDL in homozygous patients At 17.6%, these results support the homozygous FH to homozygous FH, and as LDL receptor activity decreases in vivo, LDL clearance from plasma is also reduced.

In patients with FH, in addition to the slowdown of LDL catabolism in plasma, LDL is produced excessively in the body. When the LDL receptor is normal, some IDL can be directly taken up by the liver LDL receptor for catabolism, and the other part of IDL is transformed. For LDL, in FH, due to LDL receptor defects, the direct catabolism of IDL is blocked, resulting in more IDL conversion to LDL, so the production of LDL in FH patients is significantly increased.

Familial hypercholesterolemia prevention

1. At present, there is no good preventive measure for this disease. It is necessary to strengthen the prevention and treatment personnel's understanding of the disease and understand the harm and serious consequences of the disease.

2. Patients with this disease should take the initiative to receive low-fat and low-carbohydrate diet treatment, and timely use appropriate lipid-lowering drugs to adhere to treatment.

3. Patients should regularly check their blood lipids to maintain normal levels.

4. Actively prevent complications.

Familial hypercholesterolemia complications Complications coronary heart disease aneurysms

The proportion of patients with coronary heart disease is significantly increased in this disease, early onset, severe degree, poor prognosis; in addition, aortic ( descending aorta, carotid artery, etc.) extensive atherosclerosis; coronary aneurysm-like expansion.

Familial hypercholesterolemia symptoms common symptoms nodular atherosclerotic vascular murmur calcified angina

According to the number of I-DL receptors, there are two types: homozygous familial hypercholesterolemia and heterozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia is extremely rare clinically, with a rate of only a million. Due to the lack of LDL receptors, these patients have high serum total cholesterol levels shortly after birth, generally between 18.1 and 31.1 mmol/L. Skin yellow tumors and myoma yellow tumors can occur in many parts of the body as they age. Most patients have severe and extensive atherosclerosis before the age of 40. Coronary, carotid, iliac, femoral, etc. are affected, and even die at 3 years of age.

Heterozygous familial hypercholesterolemia is not uncommon in clinical practice. The number of LDL receptors in these patients is only half of the normal number, so the serum total cholesterol level is significantly higher than that of normal people. The serum total cholesterol level of most patients can reach 9.1 to 12.9 mmol/L, accompanied by cutaneous yellow tumor. And the occurrence of myoma of the myocardium. Patients often have premature coronary heart disease. Male patients usually have coronary heart disease symptoms between the ages of 40 and 50, while female patients are about 10 years later than men.

Familial hypercholesterolemia check

1. Plasma cholesterol concentration increased more than 9.1mmol / L (350mg / dl), generally not associated with hypertriglyceridemia; but about 10% of FH patients also have hypertriglyceridemia.

2. Blood LDL-C is continuously increased.

3. LDL receptor function determination

The method of cell culture is used to determine the function of LDL receptor, which is helpful for the diagnosis of FH. The earliest reported method is to culture 125 Iodine (125I) together with fibroblasts of patients, and then carry out 125I combined with 125I internal migration. 125I degradation assay, and compared with normal human fibroblast control, FL can be diagnosed if the LDL receptor activity is below 25% of normal.

4. B-type ultrasound system: the most sensitive to cardiovascular changes in patients with FH examination and follow-up. B-mode ultrasonography can often find aortic root sclerosis, aortic root sclerosis gradually worsens, and aortic valve calcification and/or aortic The left coronary artery is stenotic.

5. Coronary angiography: 15% of them had coronary aneurysm-like dilatation (referring to the limitation or diffuse dilatation of the coronary artery, which was 1.5 to 2 times larger than the adjacent normal coronary artery), while the age- and sex-matched controls Only 2.5% of the patients (non-FH patients with coronary heart disease) had coronary aneurysm-like dilation, and at the same time, coronary aneurysm-like dilatation was found to be negatively correlated with plasma HDL-C levels. Therefore, FH patients were considered to be prone to coronary aneurysm-like disease.

Diagnosis and diagnosis of familial hypercholesterolemia

Diagnostic criteria

1. Diagnosis basis of simple familial hypercholesterolemia

(1) The concentration of plasma cholesterol exceeds 9.1 mmol/L (350 mg/dl), and there is almost no difficulty in diagnosing FH.

(2) Plasma LDL is continuously increased and can be detected after birth.

(3) If the following other performances are combined, the diagnosis of FH is more supported:

1 The patient himself or his first-degree relatives have a tendon xanthomas.

2 Patients with first-degree relatives have hypercholesterolemia.

3 Patients with family members were found to have hypercholesterolemia in childhood.

2. Heterozygous familial hypercholesterolemia

The plasma cholesterol concentration is 6.5 to 9.1 mmol/L (250 to 350 mg/dl), and if one of the other characteristics is also present, the diagnosis of FH can be made.

Based on the patient's family history, age at which it was detected, and plasma cholesterol levels, the diagnostic criteria for FH were presented (Table 1) with specificity and sensitivity of 98% and 87%, respectively.

Differential diagnosis

What needs to be distinguished from FH is multi-gene hypercholesterolemia. In general, the typical multi-gene hypercholesterolemia patients have only mildly elevated plasma cholesterol levels, which are not manifested in childhood, and are not accompanied by tendon yellow. Tumors do not show dominant inheritance in first-degree relatives. However, a positive family history of early-onset coronary heart disease does not help in the identification of both, because both FH and polygenic hypercholesterolemia can have early-onset crowns. A positive family history of heart disease, about 10% of patients with FH also have hypertriglyceridemia, which is difficult to distinguish from familial mixed hyperlipidemia, unless the patient has other clinical features.

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