Familial Hypercholesterolemia: It’s Not All Your Fault

Dr. Kang Health Pro
  • In our country we are quick to blame our Western diet and lack of exercise as the main cause of high cholesterol.  I suppose that by doing so, it gives us some hope that we can change our cholesterol levels by sheer will power and thus reduce our risk of heart disease. We have the sense then that high cholesterol is something that we can control and therefore cure. However, we also know that if one of our close family members develops heart disease at an early age, for example <55yrs for men and <65yrs for women, then the risk of our developing heart disease is significantly increase. That's because our genes play a very significant role in determining future risk of high cholesterol and heart disease. In fact, if you look at individuals who develop heart disease at an early age, more than 50% of them have some type of familial or genetic abnormality in cholesterol regulation.

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    Familial hypercholesterolemia is one of the most common inherited disorders that contributes to high cholesterol levels. It is caused by defects in the genes that encode for receptor proteins on LDL particles. These receptor proteins are the apo B and E lipoproteins.  These dysfunctional proteins do not allow LDL to be readily cleared from the circulation which results in high blood levels of LDL.  Furthermore, these abnormal proteins allow LDL to be absorbed more readily by our immune cells which can then contribute to cholesterol build up in the walls of the heart arteries. All of this contributes to the development of atherosclerosis and an increased risk of heart attack.


    Familial hypercholesterolemia is inherited in an autosomal dominant manner.   Our genes are made up of pairs of which the mother and father both contribute one part to the pair.  Autosomal dominant inheritance means that if a child inherits one good gene and one bad gene in the gene pair, then the disease will still be expressed.  Autosomal dominant genetic diseases only need one bad gene to be clinically significant.  Familial hypercholesterolemia is inherited with a gene dosing effect as well. This means that if a child happens to inherit two bad genes (a homozygote) then the disease will be much worse as opposed to if he inherited one good and one bad gene (a heterozygote).  One report showed that if a person is homozygous for familial hypercholesterolemia, his ability to clear LDL from the circulation is reduced by ~50%. If the person is heterozygous, the LDL clearance is reduced by only ~25%. 


    Since LDL levels are increased at an early age, one of the presentations of familial hypercholesterolemia is the development of early atherosclerosis and heart attack.   One early study reported that the risk of developing a coronary event was 24% by the age of 40, 50% by the age of 50, and 85% by the age of 65.  Furthermore, 75% of people will develop xanthomas, depositions of cholesterol in either tendons or skin.  And, if a person is a homozygote for the genetic defect, 50% may even develop narrowing of a heart valve called the aortic valve.  This can then impair blood flow from leaving the heart to the rest of the body.


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    Screening for this disorder is recommended if there is a strong family history of early development of heart disease in first degree relatives (i.e. parents, siblings).  A simple fasting lipid panel can detect abnormal cholesterol levels. Typically, the LDL level is elevated with a relatively normal triglyceride level. High LDL and triglyceride levels may be indicative of another lipid metabolism disorder. The presence of xanthomas is strongly indicative of the genetic disease.  Recently, genetic testing has become commercially available to test for familial hypercholesterolemia.  A product called LIPOchip has been developed to screen for over 200 different variations of this genetic defect and is routinely used in Spain.


    Treatment of familial hypercholesterolemia is similar to the management of non genetic forms of high cholesterol.  A heart healthy diet and regular exercise are recommended.  Aggressive control of other risk factors that contribute to heart disease are implemented.  The use of cholesterol lowering medications such as statins is routinely used to achieve target goals. The main difference is that familial hypercholesterolemia is aggressively treated even at an early age. Homozygotes may be on statin therapy as early as the age of eight depending on their family history and lipid levels. If LDL levels cannot be controlled with multiple medications, then LDL apheresis (removal of LDL directly from the blood stream) may be recommended.


    In summary, not all high cholesterol is from poor diet and lack of exercise.  In fact, a significant determinant of our cholesterol levels is genetic in nature. Familial hypercholesterolemia is a genetic disorder that markedly increases heart disease risk.  Family members of relatives who have developed early heart disease should be screened and, if found to have this genetic defect, aggressively treated.


Published On: January 27, 2009