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Familial Hypercholesterolemia Scott Cooper, UW-La Crosse Introduction Familial Hypercholesterolemia (FH) is an autosomal dominant disorder that results in elevated plasma cholesterol levels in affected individuals. This disease has a frequency of 1 in 500 and results in decreased levels or activity of the LDL receptor. This receptor is responsible for binding to apolipoprotein B on low density lipoproteins (LDL) in blood and internalizing these particles. An inability to internalize LDL results in increased cholesterol synthesis by the liver. The combination of decreased clearance of LDL cholesterol and increased cholesterol synthesis forces plasma cholesterol levels to increase to 250-500 mg/dl in heterozygous FH and 600-1000 mg/dl in homozygous FH individuals. Normal plasma cholesterol levels are 150-200 mg/dl. Affected individuals have an increased risk of atherosclerosis and heart disease. Homozygous FH individuals usually die before the age of 10. Table 1. Plasma cholesterol levels in normal and familial hypercholesterolemic individuals. Normal Plasma cholesterol 150-200 mg/dl FH Heterozygote 250-500 mg/dl FH Homozygote 600-1000 mg/dl Table 2. Defects in the LDL receptor. Defect Synthesis Phenotype Most common defect, Receptor not synthesized in the ER Transport Receptor not transported to cell surface, accumulates inside cell LDL Binding Receptor on cell surface, can’t bind to apo B on LDL Internalization Receptor binds to apo B on LDL, can’t internalize LDL Recycling Receptor internalizes LDL, but isn’t recycled to cell surface Figure 1. A schematic diagram of the LDL receptor. Defects in this receptor lead to FH. Figure 2. Example of an atherosclerotic lesion associated with familial hypercholesterolemia. SUMMARY FH is an autosomal dominant disorder which occurs in 1 in 500 individuals. FH is caused by defects in the LDL receptor. Patients with FH over-synthesize cholesterol resulting in markedly elevated plasma cholesterol levels.