Polygenic hypercholesterolaemia

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, high blood lipids, and hyperlipoproteinemia (elevated levels of lipoproteins in the blood). Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, high blood lipids, and hyperlipoproteinemia (elevated levels of lipoproteins in the blood). Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as type 2 diabetes and an underactive thyroid. Cholesterol is one of three major classes of lipids which all animal cells use to construct their membranes and is thus manufactured by all animal cells. Plant cells do manufacture cholesterol, but in rather small quantities. It is also the precursor of the steroid hormones and bile acids. Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol, are associated with an increased risk of atherosclerosis and coronary heart disease. In contrast, higher levels of HDL cholesterol are protective. Avoiding trans fats and replacing saturated fats in adult diets with polyunsaturated fats are recommended dietary measures to reduce total blood cholesterol and LDL in adults. In people with very high cholesterol (e.g., familial hypercholesterolemia), diet is often not sufficient to achieve the desired lowering of LDL, and lipid-lowering medications are usually required. If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed. About 34 million adults in the United States have high blood cholesterol. Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis (hardening of arteries). Over a period of decades, elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive narrowing of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow. A sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual, blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point tissue ischemia (restriction in blood supply) may manifest as specific symptoms. For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, difficulty speaking, weakness or numbness or tingling, usually on one side of the body. Insufficient blood supply to the heart may cause chest pain, and ischemia of the eye may manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal. Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids), arcus senilis (white or gray discoloration of the peripheral cornea), and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers. Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows. Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include weight, diet, and stress. A number of other conditions can also increase cholesterol levels including diabetes mellitus type 2, obesity, alcohol use, monoclonal gammopathy, dialysis therapy, nephrotic syndrome, hypothyroidism, Cushing’s syndrome and anorexia nervosa. Several medications and classes of medications may interfere with lipid metabolism: thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid, antipsychotics), certain anticonvulsants and medications for HIV as well as interferons. Genetic contributions are usually due to the additive effects of multiple genes ('polygenic'), though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia. In familial hypercholesterolemia, mutations may be present in the APOB gene (autosomal dominant), the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene. Familial hypercholesterolemia affects about one in five hundred people.