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Familial Hypercholesterolemia


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NORD is very grateful to Elena Citkowitz, MD, PhD, Director, Cholesterol Management Center, Hospital of St. Raphael, New Haven, CT, and Associate Clinical Professor of Medicine, Yale University School of Medicine, for assistance in the preparation of this report.

Synonyms of Familial Hypercholesterolemia

  • autosomal dominant hypercholesterolemia

Disorder Subdivisions

  • familial ligand-defective apolipoprotein B
  • heterozygous familial hypercholesterolemia
  • homozygous familial hypercholesterolemia
  • LDL receptor disorder
  • PCSK9

General Discussion

Familial hypercholesterolemia (FH) is characterized by very high levels of total and low-density lipoprotein (LDL) cholesterol, often called the "bad" cholesterol. The levels of another blood lipid, triglycerides, are usually normal and the levels of high-density lipoprotein (HDL) cholesterol (the "good" cholesterol) are typically low or normal. The condition greatly increases the risk of atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions. Untreated men with FH often develop symptoms of coronary heart disease (CHD) in their early forties and women, in their early fifties. If one or more other major risk factors for CHD are present, especially cigarette smoking and diabetes mellitus, the risk of developing symptomatic CHD is greatly increased. Women without other major risk factors for CHD may survive to old age without developing symptomatic disease. The current National Cholesterol Education Program Adult Treatment Panel III defines major CHD risk factors as cigarette smoking, high blood pressure, age (men 45 or older; women 55 or older), family history of premature CHD in parents or siblings (men before age 55; women before age 65) and HDL cholesterol below 40 mg/dL. Patients with diabetes are currently considered to have a risk for a heart attack (fatal or nonfatal) as great as those who have already had a heart attack.

In 1973, Joseph Goldstein and Michael Brown identified and characterized a cell membrane protein they called the LDL receptor and the mutations in the gene that interfered with its function. A normally functioning receptor lowers the blood levels of LDL cholesterol by taking up the particles (lipoproteins) that carry the bad cholesterol. A mutation in one of the genes caused a decrease either in the number or function of the receptors, resulting in the extreme LDL cholesterol elevations of FH. Goldstein and Brown became the first investigators to identify a mutation that caused a metabolic disorder when only a single abnormal gene was present. In 1985 they won the Nobel Prize in Medicine for this work. Since that time, other genes have been identified that cause severe hypercholesterolemia.

Almost all genes have two copies, one inherited from each parent's chromosome. A dominant mutation is expressed if only one copy is present. A recessive mutation must be present in both chromosomes. FH patients who carry a single mutation have heterozygous FH and those with a mutation on both chromosomes have homozygous FH.

Organizations related to Familial Hypercholesterolemia

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