Familial Hypercholesterolemia

Front 1

Principles

Back 1

• Autosomal Dominant
• Environmental modifiers
• Founders Effect
• Gene Dosage
• Genetic Modifiers

Front 2

Major Phenotypic Features

Back 2

• Age of Onset

- Heterozygote = early to middle adulthood

- Homozygote = childhood

• Hypercholesterolemia
• Atherosclerosis
• Xanthomas
• Arcus corneae (blue ring around cornea)

Front 3

Disease Etiology and Incidence

Back 3

• Autosomal dominant mutation in LDLR gene
• Prevalence = 1:500 in white populations
• Accounts for <5% of pts w/ hypercholesterolemia

Front 4

Pathogenesis

Back 4

• LDL receptor binds ApoB100 on LDL; ApoE on VLDL, IDL, CM rems, some HDL
• Some mutations are dominant negative
• Higher prevalence in French Canadians, Ashkenazi Jews, Afrikaners
• Decreases hepatic LDL & IDL uptake
• Diet is the major environmental modifier

Front 5

Phenotype and Natural History

Back 5

Heterozygotes

• Hypercholesterolemia is major phenotypic feature and only clinical presentation during first decade of life
• Arcus Corneae & Achilles Xanthomas
• CAD devo depends on age & gender
• Untreated blood cholesterol level = >300mg/dL

Homozygotes

• Xanthomas & Arcus Corneae appear during first decade
• w/o aggressive tx lethal by 30 y/o
• Untreated blood cholesterol level = 600-1000 mg/dL

Front 6

Management

Back 6

• Genetic confirmation difficult and not necessary for tx
• Agressive reduction in LDL levels to reduce CAD risk
• Low fat/high carb diet
• Statins and other drugs
• LDL apheresis (70% reduction in LDL levels)
• Liver transplant (rare)

Front 7

Inheritance Risk

Back 7

• 50% risk of transmission to offspring
• 100% devo of CAD in untreated heterozygotic males
• 75% devo of CAD in untreated heterozygotic females