Type II or Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevation of plasma LDL cholesterol levels. Mutations at the LDL receptor gene locus on chromosome 19 are

Table 4 Classification of hyperlipidemias according to Fredrickson

Type Plasma cholesterol Plasma Lipoprotein Atherosclerosis Genetic disorder triacylglycerol fraction(s) affected risk

Normal to elevated Very elevated Chylomicrons






Very elevated

Normal or elevated Elevated Normal or elevated Very elevated



VLDL and chylomicrons

No Familial LPL deficiency

Apo C-II deficiency High Familial hypercholesterolemia

Familial combined hyperlipidemia Polygenic hypercholesterolemia High Familial hypercholesterolemia

Familial combined hyperlipidemia High Familial dysbetalipoproteinemia

Moderate Familial hypertriglyceridemia

Familial combined hyperlipidemia Moderate Familial hypertriglyceridemia

responsible for this disorder. Multiple different mutations have been described at this locus resulting in the FH phenotype. In the heterozygous state, subjects develop tendinous xanthomas, corneal arcus, and CHD. Elevations of LDL can result from well-characterized genetic disorders such as FH or familial defective apo B-100.

The ranges of LDL cholesterol levels in plasma of FH subjects are 200-400 mgdl"1 in heterozygotes and above 450mgdl~1 in homozygotes. The frequency of defects at the LDL receptor locus is about 1 in 500 for the heterozygous state and 1 in a million in the homozygous state.

Inhibitors of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A are useful in the treatment of hyperch-olesterolemia. Most pharmacological therapies are ineffective in the homozygous state. FH homozygotes may be treated with LDL apheresis, liver transplantation, and portacaval shunt. More recently, encouraging results have been obtained using ex vivo gene therapy.

The genetic defect(s) associated with a common form of hypercholesterolemia present in most subjects with cholesterol levels between 250 and 300mgdr1 has not been elucidated. This disorder may be due to a combination of minor gene defects (i.e., presence of apo E-4 allele) that in combination with the environment (i.e., diet, lack of exercise) predispose individuals to moderately elevated LDL cholesterol levels. This disorder has been also named polygenic hypercholesterolemia.

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