Genetic Issues in Hypercholesterolemia
by Beth A. Pletcher, MD, November 1999

Familial hypercholesterolemia (FH) or hyperlipoproteinemia type IIA affects 1 in 500 individuals and accounts for a great deal of cardiac morbidity and mortality each year in the US. It is an autosomal dominant condition and approximately 5% of people with myocardial infarction under 60 years of age are affected. Laboratory findings generally include: cholesterol values between 300 and 600 mg/dl and LDL values greater than 200 mg/dl. Affected individuals may exhibit fatty deposits along extensor tendons (such as the Achilles tendon), in the periorbital regions or in the periphery of the corneas. Once diagnosed in one person, it also identifies many more at-risk individuals since first degree relatives would be at 50% risk themselves of having the condition. However, it is important to note that many individuals with similar cholesterol and LDL profiles do not have the familial form of the disease, but rather hypercholesterolemia of unknown origin.

The genetic defect in familial hypercholesterolemia results in decrease in or poor function of LDL receptors on the cell surface. The rare individual with a homozygous LDL receptor defect (with cholesterol levels between 600 and 1200 mg/dl and coronary artery disease in the teens and twenties) have complete failure of LDL binding and, therefore, LDL cannot be brought into cells. This failure of LDL internalization results in excessive cellular production of hydroxy-beta-methylglutaryl-CoA reductase (HMG-CoA reductase) which is a key rate-limiting enzyme in cholesterol biosynthesis. Elucidation of this genetic defect has lead to improved treatment for patients with this condition.

Unlike many genetic conditions for which there is no treatment currently available, identification of children and adults with this condition permits early intervention and measures to prevent or minimize premature coronary artery disease. Medical intervention for patients with this condition would include prescribing lovastatin which is an HMG-CoA reductase inhibitor as well as a bile acid sequestering medication, on top of routine dietary and exercise recommendations. Unfortunately, for those rare individuals with a homozygous LDL receptor defect, medications alone are not effective and some patients have benefitted from liver or liver and heart transplantation.

There are a number of other genetic abnormalities of cholesterol and lipid metabolism that have been characterized over the past decade. Familial combined hyperlipidemia is probably the most common disorder of lipid metabolism and may be seen in as many as 1% of the population. Unlike FH, it is only rarely detected in childhood and may not be diagnosed on lipid profile until well into adulthood. In the children with abnormal lipid profiles and this condition, one generally would find hypertriglyceridemia initially. Affected individuals are usually identified because of elevations in VLDL and LDL and certainly face increased risks for developing atherosclerosis. Hyperlipoproteinemia type III is associated with not only an elevation in plasma cholesterol, but also hypertriglyceridemia. This variant of FH is associated with defects in the apolipoprotein E gene with homozygosity for some very common alleles resulting in gross hyperlipidemia. Familial hypercholesterolemia type B is associated with a defect in LDL binding secondary to mutations in the apolipoprotein B gene. Patients with this form of FH tend to have lower total cholesterol and LDL levels as well as lower rates of coronary artery disease compared to the type IIA group. Hyperlipoproteinemia type I is a rare recessive condition associated with mutations in the apolipoprotein C-II gene, laboratory evidence of significant hyperchylomironemia and hypertryglyceridemia and clinical features of recurrent pancreatitis and xanthomas. Familial hypertryglyceridemia and hyperlipoproteinemia type IV have similar laboratory profiles and clinical features. Both appear to be transmitted as autosomal dominant traits and in both conditions, cholesterol levels are normal, but plasma triglycerides are persistently elevated. Premature atherosclerosis, xanthomas and cardiovascular disease are seen in adulthood. Since the precise genetic defects for these conditions have not been fully elucidated, there is a good chance that these disorders represents a number of genetic variations with significant heterogeneity.