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.
