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ESSENTIALS OF DIAGNOSIS

  • Elevated serum total cholesterol and LDL cholesterol.

  • Autosomal dominant inheritance.

  • Mutation in LRL, PCSK9, or APOB.

GENERAL CONSIDERATIONS

Familial hypercholesterolemia (FH) is a group of autosomal dominant conditions that result in elevated low-density lipoprotein (LDL) levels in the blood. High LDL predisposes to atherosclerosis, which in turn leads to premature myocardial infarction or stroke. The incidence of these serious complications increases with age and when associated with the other common predispositions to atherosclerosis, such as smoking and hypertension. About 1 in 500 people in the United States have FH; worldwide, the prevalence is about 10 million. Only about 15% percent of people with FH are diagnosed and even fewer are treated effectively.

CLINICAL FINDINGS

A. Symptoms and Signs

Yellow lipid deposits appear on tendons, especially the Achilles (tendon xanthoma).

B. Laboratory Findings

Total serum cholesterol with the LDL component is particularly high. A detailed family history and genetic testing should be obtained when individuals are younger than 40 years with an LDL level greater than 200 mg/mL and for individuals older than 40 years with a level greater than 250 mg/mL.

PREVENTION

In most instances, the elevated LDL is inherited as an autosomal dominant trait. An affected individual in all likelihood inherited FH from one parent, and each of his or her children has a 50/50 chance of inheriting FH. In uncommon cases, both parents have a mutation in the LDL receptor and one-quarter of their children, on average, will inherit two mutant alleles and have homozygous FH, which is a much more serious disease with manifestations in childhood.

Mutations in the following four genes can cause FH: (1) LDLR, which encodes the LDL receptor located on the surface of cells and responsible for moving LDL into the cell for metabolism; the most common mutant gene in FH; (2) APOB, which encodes a component of LDL and mutations inhibit binding to LDL receptor; (3) PCSK9, which encodes a protein that normally reduces production of LDL receptors, so mutations actually protect from hypercholesterolemia; and (4) ARH, which requires mutations in both alleles (autosomal recessive inheritance) to cause FH.

DNA analysis for mutations in all of these genes is readily available.

TREATMENT

Statins, usually at high doses, can reduce LDL levels, occasionally to acceptable levels. If LDL levels remain elevated, other standard medications are required. The earlier in life that treatment is begun, the better the outcome in reducing mortality from atherosclerosis. In homozygous FH, if high-dose statins do not reduce LDL sufficiently, an inhibitor of PCSK9 is a recent option. If all else fails, then plasmaphoresis is needed to reduce LDL.

Another important need in effective management is to screen relatives ...

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