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Inherited Cholesterol Disorders

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Updated January 16, 2013

Written or reviewed by a board-certified physician. See About.com's Medical Review Board.

Elevated levels of LDL cholesterol are strongly associated with cardiovascular disease. Unfortunately, the majority of people living in Western cultures sooner or later develop higher-than-optimal cholesterol levels. And in most cases, these elevated levels are caused by a combination of lifestyle choices and genetic predisposition.

Our cholesterol metabolism is modulated by numerous genes in very complex ways, and countless variations in these genes have created countless variations in how people handle cholesterol. Some people will have high cholesterol levels no matter how pristine their habits; others will have low cholesterol levels no matter how much they abuse themselves. Most people will find themselves somewhere in the middle of this broad range, but the fact is that our genes play at least some role in determining all of our cholesterol levels.

It's fortunate (though perhaps annoying) that for many of us, any genes we may have that are trying to push our cholesterol levels upward can be overcome by making wise food choices and getting enough exercise. And if we cannot maintain adequate cholesterol levels with lifestyle choices (and if our cardiovascular risk is judged to be significantly elevated), adding a statin drug usually does the trick. But in some people, the genetic propensity toward high cholesterol levels cannot be overcome even with rigorous lifestyle management, and even drug therapy to lower cholesterol can be very challenging. As a result, their risk of developing cardiovascular disease at a young age can be very high. While several specific genetic cholesterol disorders have been identified, three in particular are reasonably common: familial hypercholesterolemia, familial combined hyperlipidemia, and polygenic hypercholesterolemia.

All three of these inherited cholesterol disorders tend to run in families, and all three are characterized not only by high cholesterol levels, but also by a high risk of premature cardiovascular disease — often at a rather young age. Indeed, the risk can be so high that family members of anyone who has been diagnosed with any of these conditions ought to have their blood lipids measured, and treatment should be started as soon as possible if they, too, have very high cholesterol levels.

Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is the best known of the inherited cholesterol disorders. It is characterized by very high cholesterol levels with normal triglyceride levels, and by fatty deposits beneath the skin. These deposits, called xanthomas, are most often seen over the knees and elbows, over tendons, and around the cornea of the eyes. Cholesterol deposits, called xanthelasmas, can also occur on the the eyelids. There are several genetic variants of FH, and the severity of this condition — and consequently, the risk of cardiac disease — can vary from modestly elevated to severe. It is important to make the diagnosis of FH as early as possible, and to take aggressive measures to lower cholesterol levels.

Familial Combined Hyperlipidemia

Familial combined hyperlipidemia (FCH) is probably the most common of the serious inherited cholesterol disorders, affecting 1 or 2 people out of 100. In contrast to FH, FCH causes elevations in both cholesterol levels and triglyceride levels. (Some affected individuals have one or the other; others have both.) FCH is a genetically complex disorder with many variants, and therefore the severity of the condition varies quite a bit from person to person. The degree of cardiovascular risk borne by these individuals, however, is mostly dependent on their LDL cholesterol levels rather than their triglyceride levels.

It appears that lifestyle choices in people with FCH have a lot more to do with determining their risk of premature cardiovascular disease than in FH. That is, in FCH, the "environment" (the Western lifestyle in particular) seems to play a relatively large role in worsening outcomes. But even in people who have exemplary lifestyles, FCH produces a substantial elevation in cardiovascular risk.

Patients with FCH usually require aggressive treatment with statin drugs, and if triglyceride levels are elevated, with a fibrate or nicotinic acid as well.

Polygenic Hypercholesterolemia

Polygenic hypercholesterolemia (PH) is less common than either FH or FCH. People with PH have high LDL cholesterol levels, and a high risk of early cardiovascular disease. As in FH, the triglyceride levels are usually normal. In fact, the main distinguishing feature between PH and FH is that in PH, no xanthomas or xanthelasmas are seen.

Treatment virtually always begins with a statin. Bile acid sequestrants or nicotinic acid may be needed as well if cholesterol levels remain elevated despite treatment with a statin drug.

Summary

While genes play an important role in determining cholesterol levels and cardiovascular risk in everyone, there are a few specific inherited cholesterol disorders that are important to recognize, and they are important for at least two reasons. First, without aggressive therapy, premature cardiovascular disease is very likely in people with these conditions. Second, because they are familial disorders, family members of patients who have these conditions are also at risk.

This means that if any of your close family members have any of these conditions, or if a family member should develop coronary artery disease at an early age (before age 55 in men, and before age 65 in women), you and the rest of your family should have your blood lipids tested. The earlier any of these inherited cholesterol disorders is recognized and therapy is begun, the more effective treatment can be in lowering your cardiac risk.

Sources:

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.

National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143.

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