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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.