Familial hypercholesterolemia

Familial hypercholesterolemia
Other names	Familial hypercholesterolaemia
Xanthelasma palpebrarum, yellowish patches consisting of cholesterol deposits above the eyelids. These are more common in people with FH.
Specialty	Endocrinology

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol (LDL cholesterol), in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly (abnormal trafficking).^{[citation needed]} Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH (such as dietary modification and statin tablets). Nevertheless, treatment (including higher statin doses) is usually effective.

FH is classified as a type 2 familial dyslipidemia.^[1] There are five types of familial dyslipidemia (not including subtypes), and each are classified from both the altered lipid profile and by the genetic abnormality. For example, high LDL (often due to LDL receptor defect) is type 2. Others include defects in chylomicron metabolism, triglyceride metabolism, and metabolism of other cholesterol-containing particles, such as VLDL and IDL.

About 1 in 100 to 200 people have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from circulation, or the APOB gene that encodes apolipoprotein B (ApoB), the part of LDL particles that binds with LDL receptors. Mutations in other genes are rare but important to know, including gain-of-function mutations in the PCSK9 gene coding for the PCSK9 enzyme (which degrades LDL receptors), resulting in less LDL receptors available. PCSK9 mutations cause less than 5% of cases of FH according to most epidemiologic studies.^[2] People who have one abnormal copy (are heterozygous) of the LDLR gene may develop cardiovascular disease prematurely at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:250 people in most countries;^[3] homozygous FH is much rarer, occurring in 1 in 300,000 people.^{[citation needed]}

Heterozygous FH is normally treated with statins, bile acid sequestrants, or other lipid-lowering agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.^[4]