I. What is familial hypercholesterolemia?
Lipids in the human body are divided into two main categories. One category is fat, which is the most abundant lipid in the body; the other category is called lipid-like, one of which is called cholesterol. Cholesterol is also divided into HDL cholesterol and low density lipoprotein (LDL) cholesterol. The former has a protective effect on the cardiovascular system and is often referred to as “good cholesterol”; the latter is high and increases the risk of coronary heart disease and is often referred to as “bad cholesterol”. The functions of cholesterol are
1. Forming bile acids.
2. Forming cell membranes.
3. Synthesizing hormones.
Familial Hypercholesterolemia (FH) is an autosomal dominant disorder. Its clinical manifestations include hypercholesterolemia, characteristic yellow tumors, such as tendon yellow tumors and skin yellow tumors; corneal arch; early onset coronary artery disease and positive family history. The clinical manifestations of FH were first described by Norwegian physicians in the late 1930s.
In 1974, foreign researchers discovered LDL receptors on the surface of cell membranes and confirmed that the pathogenesis of FH is caused by mutations in LDL receptor genes on the surface of cell membranes, resulting in defective or abnormal LDL receptor function, abnormal LDL metabolism, increased production and slowed breakdown, resulting in the accumulation of cholesterol and LDL in patients with elevated levels. Increased cholesterol and LDL levels can lead to atherosclerosis, myocardial ischemia, and myocardial remodeling, leading to heart failure, myocardial infarction, or sudden cardiac death.
Depending on the number of LDL receptors in the patient, there are two types of FH: pure and heterozygous. Patients with purely heterozygous FH are symptomatic and extremely rare, with an incidence of one in a million. These patients have almost no normal LDL receptors because they inherit one abnormal LDL receptor gene from each parent, and have high serum total cholesterol levels, usually between 18.1 and 31.1 mmol/L.
Patients with heterozygous FH have milder symptoms and are not uncommon in the population, with an incidence of 1/500. The number of LDL receptors in these patients is only about half of the normal number, so their cholesterol levels are significantly higher than normal, with most patients having cholesterol levels of 6.8 to 15.8 mmol/L. Patients often develop coronary heart disease prematurely, but with milder symptoms.
FH is mainly autosomal dominant, followed by polygenic inheritance. It can be inherited from either parent to both male and female offspring, and at least one parent of a heterozygous child is a patient with the disease, while both parents of a pure heterozygous child must be patients.
II. How to treat familial hypercholesterolemia?
Currently, the treatment strategy for FH is to enhance the control of FH patients at an early stage by improving the diet, changing the lifestyle and medication. This will enable patients to effectively reduce cholesterol and LDL levels, slow down or partially eliminate the development of vascular lesions, reduce the risk of cardiovascular disease, and improve patient prognosis and life treatment. However, pharmacotherapy is mainly effective for heterozygous FH; pharmacotherapy is less effective for pure heterozygous FH.
FH often develops in children and tends to cause a great psychological burden to patients, reflected in the following aspects.
(1) Being labeled with the disease (psychological depression) ;
(2) Insecurity of study, life and work;
(3) Moral censure from immediate family members;
(4) Concerns about future generations. Therefore, it is also important to provide the necessary psychological counseling to FH patients and their family members.
Any pharmacological treatment for FH must be based on improving lifestyle and diet control, including strengthening exercise, maintaining a reasonable body mass index, quitting smoking and limiting alcohol, low-salt and low-fat diet, and reducing the intake of saturated fatty acids and cholesterol. the purpose of FH control diet is to minimize cholesterol and LDL levels and alleviate patients’ symptoms while ensuring the nutrition required for normal human metabolism. The minimum goal of controlled diet is blood cholesterol, LDL levels below the pre-treatment level, and the ideal goal is for patients to have LDL <2.86 mmol/L (110 mg/dl) and cholesterol <4.42 mmol/L (170 mg/dl).
Low cholesterol foods, such as eel, prostitute fish, carp, lean pork, lean beef, lean lamb, duck, etc.; moderate cholesterol foods, such as grass carp, carp, silver carp, eel, river eel, snapper, crab meat, pork chops, chicken, etc.; high cholesterol foods, such as pig kidney, pig liver, pork belly, mussel meat, cavity meat, egg yolk, crab yolk, etc. Patients with hypercholesterolemia should eat as little or as little as possible of high cholesterol foods.
The drug of choice for the treatment of FH is a statin (Statin) lipid-lowering drug. The therapeutic effects of statins on FH include lowering cholesterol and LDL levels, improving vascular endothelial function, and treating vascular inflammation. Statin lipid-lowering drugs have a good safety and tolerability profile, have no significant effect on adolescent growth and development, and can be used for FH treatment in all adolescents aged 8 to 18 years.
However, because cholesterol and LDL are very high in pure and some heterozygous FH patients, the ideal lipid-lowering goal cannot be achieved with any one lipid-lowering drug alone. Other drugs are often used clinically in combination with statins to better control cholesterol and LDL levels. These medications include, among others, the following.
Niacin increases the excretion of cholesterol from the bile and promotes the breakdown of LDL.
Betaine (or phenoxyaromatic acids) inhibit intracellular cholesterol synthesis and enhance LDL receptor activity.
Probucol (also known as probucol), whose mechanism of lipid regulation is still unknown. It is a strong antioxidant that helps to inhibit atherosclerosis and improve the symptoms and prognosis of FH patients.
Ezetimibe is a new lipid-regulating drug that potently inhibits cholesterol absorption in the small intestine and reduces cholesterol synthesis in the liver. Ezetimibe does not affect the absorption of other nutrients, does not increase the secretion of bile acids, and has few gastrointestinal adverse effects. The combination of ezetimibe and statin has been shown to reduce LDL by an additional 21% in pure FH, and this combination is the most potent combination of drugs available to reduce LDL levels.
For heterozygous FH, LD-C levels can be reduced by drugs that stimulate the expression of LDL receptors. However, for patients with pure heterozygous FH and severe heterozygous FH, it is difficult to achieve the therapeutic goal with drug therapy alone. For patients who do not respond well to drug therapy, LDL purification therapy can be used. This treatment method uses immunosorbent or heparin precipitation to remove cholesterol and LDL from the blood, and a single treatment can reduce LDL by 65% to 70%, effectively delaying the formation and development of atherosclerosis. Patients have been reported to have received such treatment for more than 10 years, and these patients had plasma cholesterol levels as high as 25 mmol/L (985 mg/dl) during childhood, but still had no manifestations of coronary heart disease after 30 years.
FH is an inherited disease, and therefore gene therapy should be the most direct and effective treatment. In recent years, with the completion of molecular cloning, the Human Genome Project and the development of gene transfer technology, gene therapy for hereditary diseases has made great progress and is expected to fundamentally solve the genetic defects of patients. However, in general, it still takes a long time for gene therapy to be applied to clinical practice.
III. Case presentation
Zeng, a 17-year-old female, was admitted to the hospital with a yellow tumor of the skin found for more than 10 years and chest pain after activity for 1 year. The patient had a yellow scattered mass of variable size and unknown number on her buttocks without obvious cause 10 years ago and was not taken seriously. The lump developed progressively from the hip to both elbow joints, interphalangeal joints, knee joints, and ankle joints without any pressure pain, redness, swelling, rupture, or pus flow. The patient developed chest pain after severe activity with no obvious cause 1 year ago, and the activity was reduced compared with normal people, without syncope, palpitations and other discomfort, which resolved on its own after 5 to 6 minutes of rest, and was not taken seriously.
On January 18, 2007, the patient underwent a physical examination at a major hospital and was found to have a blood cholesterol of 19.1 mmol/L and LDL of 15.56 mmol/L. He was diagnosed with “familial hypercholesterolemia” and was treated with atorvastatin 20 mg/d and other medications, with regular hospital follow-ups. She is now taking proscar 0.5 twice daily and ezetimibe 10 mg/d. She was admitted to the hospital for further treatment.
The patient’s mother had a cholesterol of 7.99 mmol/L (2007.2.6). Her father’s cholesterol was 8.60 mmol/L. One of her two younger brothers had a cholesterol of 3.9 mmol/L. The other brother died suddenly in December 2006 (age 14) while ice skating, after having been examined at a local hospital for cholesterol of 20.1 mmol/L in October 2005 due to a yellow tumor found nearly 10 years earlier. The autopsy proved that the cause of death was acute myocardial infarction. The rest of the family members were physically keyed, with no history of specific infectious or genetic diseases.
Positive signs: the patient had scattered distribution of yellow masses on the surface of the skin, the size of a soybean, medium quality, no pressure pain, no bleeding point and rash, and the rest of the examination was normal. Patient’s blood lipid examination (2007.6.30): cholesterol 13.49mmol/L, LDL 10.85mmol/L, TG 1.06mmol/L, HDL-C 0.59mmol/L
Admission diagnosis: 1. familial hypercholesterolemia; 2. cause of chest pain: coronary artery disease?
Treatment plan: 1, low-fat diet, increased exercise, weight control.
2. Combined lipid-lowering therapy: Combined use of various lipid-regulating drugs: atorvastatin 20mg once daily; ezetimibe 10mg. once daily; probucol 0.5 twice daily; regular review of blood lipids, liver function and creatine kinase.
3. Other treatment: Aspirin 0.1, once daily. Add β-blocker.
IV. Case review
This patient meets the typical diagnosis of FH with.
(1) Typical clinical presentation: hypercholesterolemia, characteristic yellow tumor, early onset coronary artery disease;
(2) Positive family history;
(3) Lipid profile with elevated LDL and cholesterol.
The main risk in this group of patients is atherosclerosis-related diseases such as coronary artery disease, which can lead to death from acute myocardial infarction or sudden cardiac death at a young age. The main focus of treatment is to lower cholesterol and LDL, and to emphasize early detection and treatment. This patient was found to have a yellow tumor 10 years ago, but because he did not pay attention to it, the early diagnosis and treatment were delayed and coronary heart disease occurred.
In the absence of contraindications, statins are recommended as the first choice of lipid-lowering agents for the treatment of FH. The drug mainly lowers LDL and is effective in lowering cholesterol. From the available studies and dosing experience, it is important to start statins at sufficient doses to lower LDL and cholesterol to target values in the treatment of FH. In adult patients without risk factors for coronary heart disease, it is recommended that LDL and cholesterol be controlled at appropriate levels, i.e., LDL ≤ 3.4 mmol/L (130 mg/dL) and cholesterol ≤ 5.2 mmol/L (200 mg/dL).
Once a patient has developed a critical condition such as coronary artery disease or coronary heart disease, intensive lipid-lowering therapy is required to control LDL below 2.6 mmol/L (100 mg/dL).