Familial hypercholesterolemia is an autosomal dominant disorder. It affects the gene that encodes a certain LDL cell surface receptor. This receptor is responsible for the hepatic uptake of LDL cholesterol. The milder, heterozygous form of the disease is more common, affecting approximately 1 in 500 persons. Homozygous familial hypercholesterolemia occurs at a rate of less than 1 in 1,000,000.
The heterozygous form is characterized by marked (2-3x normal) elevations of LDL cholesterol and premature atherosclerosis that typically manifests itself in the fourth decade of life. Clinical clues to the presence of this disorder include a strong family history of early atherosclerotic cardiovascular disease, a family history of familial hypercholesterolemia, and physical evidence of lipid deposition, including tendon xanthomata, xanthelasma, and corneal arcus. The more severe homozygous phenotype is characterized by similar findings, but at an even earlier age. Patients may experience their first clinical events during the first or second decade of life. Aortic stenosis is also a characteristic abnormality that may be clinically apparent and hemodynamically significant before the age of 20.
Treatment of familial hyperlipidemia should include aggressive attempts to lower cholesterol, including strict dietary modifications, escalating doses of potent lipid-lowering medications, LDL apheresis, and consideration of liver transplantation. Genetic counseling is also a critical component of management of these patients and their families.