What Causes Familial Hypercholesterolemia?Familial hypercholesterolemia is a genetic disorder that causes an abnormality in the receptor for LDL cholesterol ("bad" cholesterol). When this receptor malfunctions, LDL cholesterol is not cleared efficiently from the bloodstream. This causes the LDL cholesterol levels in patients with familial hypercholesterolemia to become greatly elevated.
In addition, because the LDL receptors are not functioning normally, scavenger cells in the blood vessel walls take up the excess LDL cholesterol, a process that accelerates atherosclerosis.
The genetic abnormality for familial hypercholesterolemia can be inherited from the father, the mother, or both parents. People who have inherited the abnormality from both parents are said to be homozygous for familial hypercholesterolemia. The homozygous form of familial hypercholesterolemia is a very severe form of the disease. Fortunately it only affects one in 250,000 individuals.
Individuals who inherit the abnormal gene from only one parent are said to be heterozygous for familial hypercholesterolemia. Approximately one in 500 people have heterozygous familial hypercholesterolemia.
More than 1000 different mutations affecting the LDL receptor gene have been identified, and each of them affects the LDL receptor differently. Therefore, the severity of familial hypercholesterolemia can vary greatly among individuals who have this condition.
How Is Familial Hypercholesterolemia Diagnosed?Typically, familial hypercholesterolemia is diagnosed by measuring blood lipid levels, and by the family history.
Blood tests will show high total cholesterol levels and high LDL cholesterol levels. The total cholesterol level with this condition is usually greater than 300 mg/dl in adults, and greater than 250 mg/dl in children. LDL-cholesterol level is usually greater than 200 mg/dl in adults, and greater than 170 mg/dl in children. Triglyceride levels are usually normal.
People with familial hypercholesterolemia almost invariably have relatives who have had either very high cholesterol levels, or early heart disease.
In addition, patients with this condition will often develop fatty deposits beneath the skin. These most commonly occur in the on the elbows, knees, along tendons, and around the cornea of the eyes. These fatty deposits are called xanthomas. Cholesterol deposits on the eyelids, called xanthelasmas, are also common. Whenever a patient has xanthomas or xanthelasmas, familial hypercholesterolemia should immediately come to the doctor's mind.
A presumptive diagnosis of familial hypercholesterolemia can be made if the LDL cholesterol levels are very high, the triglyceride levels are normal, and the family history is compatible. If either xanthomas or xanthelasmas are also present, the diagnosis can be considered fairly definitive. Making an absolutely definitive diagnosis, either with genetic testing or by measuring the function of the LDL receptors, is often useful, especially for purposes of genetic counseling.
What Are The Results Of Familial Hypercholesterolemia?Prior to the era of statins, the incidence of premature coronary artery disease and heart attacks was very high in people with familial hypercholesterolemia. For instance in a large study conducted during the 1970s, relatives of patients with familial hypercholesterolemia had a very high risk of premature heart disease. In this study, 52% of men and 32% of women had heart disease by age 60, compared to the expected risk of 13% and 9%, respectively.
How Is Familial Hypercholesterolemia Treated?The development of the potent, "second-generation" statin drugs has changed the management of familial hypercholesterolemia. Prior to the appearance of these powerful statins, the treatment of this disorder required using multiple drugs, including the less potent "first-generation" statin drugs.
Today, therapy is begun using high doses of a single second generation statin drug - either atorvastatin (Lipitor), rosuvastatin (Crestor), or simvastatin (Zocor). Not only do these drugs produce a large reduction in LDL cholesterol levels, but also studies have shown that their use may produce an actual regression of atherosclerotic plaques. The benefits of adding a second drug to high-dose statin therapy is currently not known.
While the full clinical benefit of high-dose statin therapy in patients with familial hypercholesterolemia has not yet been completely established, experts are confident that their clinical outcomes will be greatly improved.
In patients with the homozygous (severe) form of familial hypercholesterolemia, treatment with high-dose statins in combination with other cholesterol reducing drugs is strongly recommended. Even with this aggressive drug therapy, however, sometimes cholesterol levels remain high in patients with the homozygous form of the disease. In these cases, treatment with apheresis may be required.
The vascular disease caused by familial hypercholesterolemia begins during childhood. For this reason, in families with this disorder children as young as age eight should be screened routinely, and if their cholesterol levels are elevated, therapy with statins should be strongly considered.
While the elevated cholesterol levels greatly increase the risk of heart disease in people with familial hypercholesterolemia, other risk factors remain important. So an important aspect of their treatment is to aggressively control all their other risk factors for heart disease. These risk factors include smoking, obesity, lack of exercise, and blood pressure.
SummaryFamilial hypercholesterolemia is a serious inherited disorder of cholesterol metabolism. People with familial hypercholesterolemia need aggressive treatment to reduce cholesterol levels, and to control other cardiac risk factors, in order to reduce the risk of premature heart disease. In addition, their family members should also be checked for this condition.
Wiegman A, Rodenburg J, de Jongh S, et al. Family history and cardiovascular risk in familial hypercholesterolemia: data in more than 1000 children. Circulation 2003; 107:1473.
Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2006; 114:2710.