Introduction
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 elevated plasma total cholesterol (TC) levels and low-density lipoprotein-cholesterol (LDL-C) levels.
Cause
(1) Causes of the disease
The cause of FH is a natural mutation in the LDL receptor gene. Goldstein and Brown identified different types of genetic mutations, including deletions, insertions, nonsense mutations, and missense mutations. To date, dozens of LDL receptor gene mutations have been identified and can be divided into five major types:
1. Class I mutations are characterized in that the mutant gene does not produce a measurable LDL receptor, and no LDL receptor exists on the cell membrane. It is the most common type of mutation, accounting for more than half of the mutations found. Detection with a polyclonal or monoclonal antibody against the LDL receptor confirmed that the mutant LDL receptor gene produced little or only a very small amount of LDL receptor precursor. Therefore, such a mutant LDL receptor gene is a null allele, also known as a receptor-free synthetic mutation. Named Receptor-O (RO). The molecular basis of class I mutations may include point mutations in the LDL receptor gene, leading to termination of the codon encoding the receptor; promoter mutations block the transcription of mRNA; mutations at the junction of introns and exons cause abnormalities in mRNA splicing and Large fragment gene DNA deletion and the like. Recently, a patient with a receptor-negative type was found to have a 5.0 kb fragment deleted between exon 13 of the LDL receptor gene and the Alu sequence of intron 15 to form exon 13 and Alu recombination.
2. Class II mutations are characterized by the maturation and transport of LDL receptors synthesized by the mutant gene, and the LDL receptors on the cell membrane are significantly reduced. It is also a more common type of mutation. The mutated gene produces an LDL receptor precursor, most of which has a normal molecular weight, hence the name R-120. Analysis found that the processing modification of such receptor precursors is impaired. The molecular basis of this type of mutation is not well understood. It has been experimentally demonstrated that such LDL receptors can be recognized by monoclonal antibodies against the LDL receptor, indicating that there is no change in the structure of such precursors. Scheckman et al. studied a yeast-converting enzyme similar to a class II mutation and found that this defect in the enzyme is mainly caused by a change in the single amino acid in the NH2 terminal hydrophobic signal chain, resulting in the signal chain not being able to leave the enzyme protein. The rate at which the enzyme protein enters the Golgi apparatus is only 2% of normal. The yeast acid phosphatase gene induces a similar mutation in vitro, resulting in the inability of the signal chain to detach from the receptor precursor, causing it to enter the Golgi apparatus for processing modification. Type II mutations mainly affect the 1st and 2nd regions of the LDL receptor, and missense mutations are more common. However, the mechanism by which a single amino acid residue substitution or a small DNA deletion causes the intracellular transport or maturation of the LDL receptor is not fully elucidated.
3. Class III mutations are 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 mutated LDL receptor gene has a substantially normal molecular weight, 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 1 region repeat 2 to 7 or 2 region repeat A. Studies have shown that such mutant LDL receptor precursors can be recognized by monoclonal antibodies against LDL receptors, and the molecular weight is 40kD smaller than that of mature receptors, indicating that the process of receptor precursor modification is normal. However, the receptor binding of this type of mutation to 125I-LDL does not exceed 15% of normal, suggesting that the molecular basis of abnormal binding of mature LDL receptor to 125I-LDL may be the amino acid sequence of the receptor binding domain. It is known that the LDL receptor binding domain has seven repeat sequences, each of which has homology, so that the encoded DNA sequence is easily deleted or the diploid is mismatched, and the structure of the receptor binding domain occurs. Abnormalities lead to a decrease in affinity with LDL.
4. Class IV mutations These mutations are mainly caused by the mature LDL receptors reaching the cell surface and unable to be trapped in the aggregation group. Although the cells can bind to LDL, there is no internal migration, also known as internal migration defect mutation. This type of mutation involves the transmembrane region (region 4) and the C-terminal tail region (region 5) of the LDL receptor. Lehrman et al. showed that a single base mutation in the 17 and 18 exons of the LDL receptor gene can result in an internal migration defect. Recent studies have also found that two class IV mutant FH homozygotes, whose LDL receptor gene is mutated to the intron 15 and the 3' untranslated region of the 18 exon, lacks a DNA sequence of 5.0 kb and 7.8, respectively. Kb, which forms Alu-Alu sequence recombination, and the receptors for cell synthesis lack a transmembrane domain and a cytoplasmic domain. Most of this truncated LDL receptor is secreted into the culture medium, and only a small part of it adheres to the surface of the cell, and it can bind to LDL, but does not move inward.
5.V-type mutations This type of LDL receptor mutation occurs in the epilogous growth factor precursor homology domain, which is characterized by the synthesis of LDL receptor, binding to LDL and subsequent internal shift, but the receptor cannot Recycled onto 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 higher. The LDL receptor gene of 4 FH homozygous patients was found to have a mutation in the middle of the sequence containing the Cys sequence in the second domain of the mutation. The LDL receptor lacks the O-linked sugar chain and crosses. A total of 160 amino acid residues were deleted in the membrane domain and the cytoplasmic domain. This mutated LDL receptor gene is referred to as the "Lebanese allele."
Recently, Kajinami et al. studied 35 unrelated FH heterozygous receptor genes. Subsequently, the LDL receptor genes of the two family members were analyzed, and the same abnormal LDL receptor gene DNA fragment was found in all patients with FH. Since they all grew up in the Tonami area of Japan, these patients were called "FH-Tonami."
(two) pathogenesis
Defects in LDL receptors can produce a double abnormality in LDL metabolism in vivo, that is, an increase in LDL production and a slowdown in decomposition, the most prominent of which is the decrease in catabolism of LDL from plasma. Intravenous injection of LDL labeled with radionuclide into normal human body, the average catabolic rate of LDL in plasma within 24h was 45%; the same LDL was intravenously injected into heterozygous FH patients, the average catabolic rate of plasma LDL within 24h 28.7%; the average catabolic rate of LDL in homozygous patients was 17.6%. These results support a heterozygous 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 slowing down of LDL catabolism in plasma, there is also excessive production of LDL in the body. When the LDL receptor is normal, part of the IDL can be directly taken up by the liver LDL receptor for catabolism, and the other part of the IDL is converted to LDL. In FH, due to LDL receptor defects, direct catabolism of IDL is blocked, resulting in more IDL conversion to LDL. Therefore, the production of LDL in patients with FH is significantly increased.
symptom
The clinical presentation of FH patients depends on the severity of their LDL receptor deficiency. The plasma cholesterol concentration of a typical heterozygous FH patient is 2 to 3 times higher than that of a normal person, and hypercholesterolemia can be measured in childhood. However, plasma cholesterol levels in some heterozygous FH patients may be normal or only slightly elevated, suggesting that receptor dysfunction due to genetic defects may vary to some extent. It has been reported that the plasma cholesterol concentration of progeny of homozygous FH is basically normal.
Domestic studies have shown that the plasma cholesterol concentration of most diagnosed heterozygous FH patients is only slightly higher than the 95% upper limit of the same sex and normal age group. This indicates that the LDL receptor gene defects in heterozygous FH patients in our population may have different characteristics, or their expression is more affected by environmental factors. The changes of serum apolipoprotein content in 8 patients with homozygous FH and 15 heterozygous FH patients were observed in China. It was found that serum high-density lipoprotein (HDL)-C and apolipoprotein (Apo) AI were significantly decreased in FH patients. The mechanism has yet to be elucidated. They also found that HDL receptor binding ability and cholesterol scavenging ability were significantly increased in skin fibroblasts of patients with homozygous FH, and it is unclear whether this change is associated with decreased levels of HDL-C and Apo AI.
Hypercholesterolemia also causes cholesterol to sink in other tissues. For example, macrophages that devour cholesterol can cause nodular swelling in various parts of the tendon, called tendon yellow tumor, which is more common with Achilles tendon and extensor tendon. Similar cholesterol deposits can also occur in the eyelids, causing flat yellow tumors; corneal cholesterol infiltration causes the corneal arch. However, the latter two are not specific to FH, but can also occur in other types of hyperlipidemia, and occasionally in normal people. Tendon nodules are more common with age, and about 75% of FH patients eventually develop tendin yellow tumors. However, it should also be noted that since all tendon yellow tumors do not occur in all FH patients, no diagnosis of tendon xanthomas can be ruled out.
In male heterozygous FH patients, they can suffer from 30 to 40 years oldCoronary heart disease. Men expect 23% of patients to die of coronary heart disease before the age of 50, and more than 50% of men have obvious coronary heart disease symptoms at age 60. However, women with heterozygous FH are also susceptible to coronary heart disease, but the age of coronary heart disease is about 10 years later than that of male patients.
Homozygous FH patients are caused by an abnormal LDL receptor gene from their parents, and there is no or almost no functional LDL receptor in the patient, resulting in 6-8 times higher plasma cholesterol levels than normal. Often atherosclerosis occurs early, and the clinical signs and symptoms of coronary heart disease occur more than 10 years old. If they are not effectively treated, these patients are difficult to live to 30 years old.
A characteristic manifestation of homozygous FH is that extensive atherosclerosis is prone to occur in the descending aorta. Aortic stenosis can also occur due to infiltration of cholesterol and other lipids into the aortic valve leaflets. Coronary arteries also have typical atheromatous plaques, but luminal stenosis is common in coronary openings. Arteries in other areas can also develop atherosclerosis. For example, carotid atherosclerosis can cause carotid stenosis, and vascular murmurs can be heard in the carotid artery.
The B-mode ultrasound system is most sensitive to the cardiovascular changes in patients with FH. Although there were no clinical manifestations in early patients, no abnormal changes were found in physical examination and electrocardiogram, but aortic root sclerosis was often found in B-mode ultrasound. Along with the onset of angina symptoms and the increase in the duration of hypercholesterolemia (ie, increased age), aortic root sclerosis gradually worsens, and aortic valve calcification and/or left coronary artery stenosis may occur.
Recently, 197 patients with heterozygous FH have undergone coronary angiography and found that 15% of them have coronary aneurysm-like dilatation (referring to the limitation or diffuse dilatation of the coronary artery, which exceeds the diameter of the adjacent normal coronary artery by 1.5 to 2). B), and at the same time found that coronary aneurysm-like dilatation was negatively correlated with plasma HDL-C levels, and therefore FH patients were considered to be prone to coronary aneurysm-like disease.
The risk of atherosclerosis in patients with FH is clearly related to the extent and timing of elevated plasma cholesterol levels. Someone studied 17 patients with homozygous FH, multiplying the plasma cholesterol concentration by the time (year) after the patient diagnosed FH, that is, calculating the risk factor of the patient's atherosclerosis (plasma cholesterol·year), which can be more Accurately predict the severity of atherosclerosis in patients.
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 plasma cholesterol concentration is 6.5 ~ 9.1mmol / L (250 ~ 350mg / dl), if one of the other characteristics mentioned above, the diagnosis of FH can be made.
Based on the patient's family history, age at the time of detection, and plasma cholesterol levels, the diagnostic criteria for FH were presented (Table 1) with specificity and sensitivity of 98% and 87%, respectively.
diagnosis
What needs to be distinguished from FH is polygenic hypercholesterolemia. In general, typical multi-gene hypercholesterolemia patients have only mildly elevated plasma cholesterol levels, which are not manifested in childhood, are not associated with tendon xanthomas, and do not show dominant inheritance in first-degree relatives. . However, a positive family history of early-onset coronary heart disease does not contribute to the identification of both, as both FH and polygenic hypercholesterolemia have a positive family history of early-onset coronary heart disease. About 10% of patients with FH also have hypertriglyceridemia. For this part of the patient, it is difficult to distinguish from familial mixed hyperlipidemia unless the patient has other clinical features as described above.
complication
The proportion of patients with coronary heart disease is significantly increased, the incidence is early, the degree is heavy, the prognosis is poor; in addition, there are extensive atherosclerosis of the aorta ( descending aorta, carotid artery, etc.; coronary aneurysm-like expansion.
treatment
(a) treatment
1. Dietary therapy is an important method for FH patients. Studies have shown that patients with FH respond more to dietary therapy than those with normal plasma cholesterol levels and mildly elevated plasma cholesterol levels. Animal experiments have confirmed that cholesterol and fatty acids in food can down-regulate the activity of LDL receptors on the liver cell membrane, so the intake of these two dietary components should be restricted for patients with FH.
2. The lipid-lowering drug β-hydroxy β-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor is the drug of choice for the treatment of patients with FH. When combined with other lipid-lowering drugs such as bile acid sequestrants, 70 can be used. LDL-C levels in % of heterozygous FH patients fell to normal. The response of FH patients to lipid-lowering drugs depends on the type of individual LDL receptor mutations and the extent of their remaining LDL receptor activity. Other factors also affected the efficacy of HMG-CoA reductase inhibitors in the treatment of FH patients, with the most prominent factor being 40.7% in the Apo E3 genotype and 46.5% in the Apo E2 genotype.
Based on the current mechanism of action of HMG-CoA reductase to inhibit cholesterol lowering, such drugs are generally considered to have no therapeutic effect on patients with homozygous FH. However, it has recently been reported that Simvastain can reduce cholesterol levels by 30% in FH patients without LDL receptor functional activity, suggesting that simvastatin may have other cholesterol-lowering mechanisms.
3. Plasma LDL separation is an effective method for the treatment of FH. It has been reported that some patients have been treated for this treatment for up to 16 years. Although these patients have plasma cholesterol levels higher than 25.0 mmol/L during childhood, there is still no clinical manifestation of coronary heart disease after 30 years.
4. Chinese medicine reported in China that the application of Zhihe Jiangzhi tablets (composed of Chinese medicine Jingjing, lotus leaf, Chuanxiong, pepper) to treat the clinical effect of 5 cases of homozygous FH, after 15 months of treatment, plasma cholesterol level from 19.22mmol / L (742 mg/dl) was reduced to 14.81 mmol/L (572 mg/dl) with no significant side effects.
(two) prognosis
Male heterozygous FH patients can have coronary heart disease between the ages of 30 and 40. Men expect 23% of patients to die of coronary heart disease before the age of 50, and more than 50% of men have obvious coronary heart disease symptoms at age 60. However, women with heterozygous FH are also susceptible to coronary heart disease, but the age of coronary heart disease is about 10 years later than that of male patients.
Homozygous FH patients are caused by an abnormal LDL receptor gene from their parents, and there is no or almost no functional LDL receptor in the patient, resulting in 6-8 times higher plasma cholesterol levels than normal. Often atherosclerosis occurs early, and the clinical signs and symptoms of coronary heart disease occur more than 10 years old. If they are not effectively treated, these patients are difficult to live to 30 years old.
prevention
1. At present, there is no good preventive method 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 diets. 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.
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