Elevated levels of fasting plasma total cholesterol (>5.2 mmol/L [>200 mg/dL]) in the presence of normal levels of triglycerides are almost always associated with increased concentrations of plasma LDL cholesterol. Elevations of LDL cholesterol can result from single-gene defects, from polygenic disorders, or from the secondary effects of other disease states.
Familial Hypercholesterolemia (Fh) 
FH is a codominant genetic disorder caused by mutations in the gene for the LDL receptor. Plasma LDL levels are elevated at birth and remain so throughout life. In untreated heterozygous adults, total cholesterol levels range from 7.1 to 12.9 mmol/L (275-500 mg/dL). Plasma triglyceride levels are typically normal, and HDL cholesterol levels are normal or reduced. Heterozygotes are prone to accelerated atherosclerosis and premature coronary artery disease (CAD). Tendon xanthomas (most commonly of the Achilles tendons and the extensor tendons of the knuckles), tuberous xanthomas (softer, painless nodules on the ankles and buttocks), and xanthelasmas (deposits on the eyelids) are common. In its homozygous form, FH leads to severe atherosclerosis during childhood.
This autosomal dominant disorder impairs the synthesis and/or function of apo B-100, thereby reducing the affinity for the LDL receptor, slowing LDL catabolism, and causing a phenocopy of FH.
Polygenic Hypercholesterolemia
Most moderate hypercholesterolemia (<9.1 mmol/L [<350 mg/dL]) arises from an interaction of multiple genetic defects and environmental factors such as diet, age, and exercise. Plasma HDL and triglyceride levels are normal, and xanthomas are not present.
| TREATMENT | ||
Isolated HypercholesterolemiaTherapy for all of these disorders includes restriction of dietary cholesterol and HMG-CoA reductase inhibitors (statins). Cholesterol absorption inhibitors and bile acid sequestrants or nicotinic acid may also be required (Table 181-2 Summary of the Major Approved Drugs Used for the Treatment of Dyslipidemia). |