OVERVIEW
Familial hypercholesterolemia (FH) is a rare autosomal dominant metabolic disorder with severe hypercholesterolemia due to mutations in genes critical for the catabolism of low-density lipoprotein cholesterol (LDL-C). The incidence of the disease is about 1/300,000 to 1/160,000, with females being slightly more common than males. Patients are clinically characterized by increased blood LDL cholesterol levels, cholesterol deposition in the skin, eyes and tendons, and a tendency to develop premature atherosclerotic cardiovascular disease.
Etiology
Disease due to pure or heterozygous mutations in genes key to the catabolism of LDL cholesterol. Functional mutations in four genes are known to cause familial hypercholesterolemia, namely, the preprotein convertase Bacillus subtilis protease 9, LDL receptor, LDL receptor articulating protein 1 (LDLRAP1), and apolipoprotein B. Mutations in the LDL receptor gene are the most common.
Symptoms
The most characteristic manifestations are increased serum LDL cholesterol levels, cutaneous xanthomas, corneal arches, and premature coronary artery disease.
1. Hyperlipidemia
Serum cholesterol concentration is usually 6 to 8 times higher than normal (600 mg/dl to 1200 mg/dl) in patients with purest form of the disease.
2.Yellow tumor
Cholesterol is deposited in various tissues of the patient’s body, and those deposited in tendons are called tendon xanthomas, which are more common in the Achilles tendon and extensor tendon of the hand; they are easy to form nodular xanthomas at the elbow and below the knee; and flat xanthomas can be formed at the eyelids. With age, tendon xanthomas are more common.
3. Corneal arch
Cholesterol infiltrates the cornea to form corneal arches, which can appear before the age of 10 years. Corneal arches are also seen in other types of hyperlipidemia.
4. Early onset of atherosclerosis
Symptoms and signs of coronary artery disease usually appear around the age of 10. The descending aorta, abdominal aorta, thoracic aorta and main pulmonary artery are prone to severe atherosclerosis, and yellow tumor plaques may form on the surface of heart valves and endocardium, and the patients often die of cardiovascular diseases before the age of 30.
5. Other
Patients often combine with recurrent polyarthritis and tenosynovitis, mainly involving the ankle, knee, wrist and proximal interphalangeal joints, which cannot be controlled by anti-inflammatory drugs.
Examination
1. Laboratory tests
Serum cholesterol concentration and serum LDL cholesterol level are higher than normal.
2. Imaging examination
(1) Ultrasonography
Aortic root sclerosis can often be detected by echocardiography. The aortic root sclerosis gradually worsens, and aortic valve calcification and/or left coronary artery stenosis may occur at the same time.
(2) Coronary angiography
15% of patients have coronary artery aneurysmal dilatation. Coronary artery aneurysmal dilatation is negatively correlated with plasma LDL cholesterol level, which predisposes to coronary artery aneurysmal disease.
3. Electrocardiography
It may show signs of coronary ischemia, such as ST-segment depression ≥0.1V, or ST-segment level prolongation >0.16 seconds, T-wave flattening or inversion, and prolonged QT interval.
4. Genetic testing
It can find the key pathogenic mutations of genes related to the catabolism and metabolism of LDL cholesterol, and clarify the molecular diagnosis of patients.
Diagnosis
Untreated, serum LDL-C >500mg/dl combined with one of the following conditions is diagnostic:
1. yellow tumors of the skin or tendons before the age of 10 years.
2. elevated serum LDL-C in parents consistent with heterozygous familial hypercholesterolemia.
It is important to note that the disease cannot be excluded in younger children with untreated LDL-C <500 mg/dl.
Differential diagnosis
Pure familial hypercholesterolemia needs to be differentiated from other diseases that cause xanthomas, hypercholesterolemia and early onset coronary artery disease, such as glutathionemia and cerebral tendon xanthomatosis, which can be differentially diagnosed by serum phytosterol profiling and genetic analysis. Other hypercholesterolemia combined with early-onset coronary artery disease can be polygenic, familial complex hyperlipidemia, or secondary to other diseases, which can be diagnosed and differentiated by genetic testing.
Treatment
The main methods include dietary control, drug therapy, lipoprotein plasma removal and surgical treatment, which aim to lower LDL-C levels to reduce the risk of atherosclerotic heart disease.
1. Dietary control
A diet low in saturated fat, cholesterol and cardiovascular benefits is recommended. Growing children should try to eat less than 30% fat per day, and consume more fruits and vegetables to lower blood cholesterol.
2. Medication
When LDL cholesterol in children exceeds 160mg/dl (normal <110mg/dl), careful evaluation of the cardiovascular status is necessary, and medications such as bile acid sequestrants and statins should be prescribed.
3. LDL plasma clearance
LDL plasma removal is an option for pure familial hypercholesterolemia that is refractory to medication and for heterozygous familial hypercholesterolemia with coronary artery disease, intolerance of statins, or ineffective medication.
4.Surgical treatment
(1) Liver transplantation
Transplantation of normal liver tissue is an effective treatment for heterozygous familial hypercholesterolemia.
(2) Other surgeries
Balloon dilatation or coronary artery bypass grafting to treat cardiovascular stenosis to improve the patient’s cardiovascular condition.
Prognosis
The prognosis of familial hypercholesterolemia of the purest form is poor. Dietary and drug therapy should be started as early as possible; otherwise, patients often suffer from atherosclerotic heart disease within 20 years of age and die around 30 years of age.
Prevention
For patients with a clear genetic diagnosis, lipid analysis and genetic analysis should be performed on family members, dietary intervention and genetic counseling should be given to carriers, and prenatal diagnosis should be performed when the mother has another child to facilitate eugenics.