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Familial hypercholesterolemia

In medicine, familial hypercholesterolemia is a rare disease characterised by very high LDL cholesterol and early cardiovascular disease running in families. It is a genetic disorder.


Signs and symptoms


There are two forms:

  • Heterozygous FH (incidence 1:500-1:1,000, dependent on the population)
  • Homozygous FH (incidence 1:1,000,000)


Both forms are caused by the same problem: a mutation in either the LDL receptor or the ApoB protein. There is one known ApoB defect (R3500Q) and a multitude of LDL receptor defects, the frequency of which is different for each population.


The LDL-receptor gene is located on the short arm of chromosome 19 (19p13).


LDL cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the liver. In FH, the half-life of an LDL particle is almost doubled to 4.5 days. This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably HDL.

The excess circulating LDL is taken up by cells all over the body but most notably macrophages and especially the ones in a primary streak (the earliest stage of atherosclerosis). Oxidation of LDL increases its uptake by foam cells.

Although atherosclerosis happens in all people, it is accelerated in FH patients due to the excess LDL. This leads to all the forms of atherosclerotic disease mentioned above.

The degree of atherosclerosis roughly depends of the amount of LDL receptors still produced in the liver and the functionality of these receptors. In some forms of FH the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious forms, however, the "broken" receptor is not expressed al all.

In heterozygous FH, only one of the two DNA copies (alleles) is damaged, and there will be at least 50% of the normal LDL receptor activity (the "healthy" copy and whatever the "broken" copy can still contribute).

In homozygous FH, however, both copies are damaged in some degree, which can lead to extremely high levels of LDL, and to children with extremely premature heart disease. A further complication is the lack of effect of statins (see below).


LDL-receptor gene defects can be identified with genetic testing. Testing is generally undertaken when:

  • A family member has been shown to have a mutation;
  • High cholesterol is found in a young patient with atherosclerotic disease;
  • Tendon xanthomas are found in a patient with high cholesterol.


Heterozygous FH

Heterozygous FH can be treated effectively with statins. These are drugs that inhibit the body's ability to produce cholesterol by blocking the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-reductase). Examples of statins are simvastatin (Zocor), pravastatin, atorvastatin (Lipitor), rosuvastatin (Crestor). Maximum doses are often necessary. Statins work by forcing the liver to produce more LDL receptor to maintain the amount of cholesterol in the cell. This requires at least one functioning copy of the gene (see below).

In case statins are not effective, either a drug from the fibrate or bile acid sequestrant class can be added, as well as nicotinic acid/acipimox .

Homozygous FH

Homozygous FH is a different story. As previously mentioned, the LDL levels are much higher and the most effective treatments (statins) require at least one copy of the functional LDL receptor gene. In this case, high amounts of bile acid sequestrants are often given; occasionally high-dosed statins can help express a dysfunctional (but working) LDL receptor. Other treatments used are LDL apheresis (clearing LDL by blood filtration, similar to dialysis) and - as a last resort - a liver transplant. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.


In the '70's, the cause for FH was described by Dr Joseph L. Brown and Dr Michael S. Goldstein of Dallas, Texas [1].

Sources/further reading

  • OMIM (Online Mendelian Inheritance in Man) entry number #143890
  • MedlinePlus entry on FH.
  • MEDPED (Make Early Diagnosis to Prevent Early Deaths)
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