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Hypercholesterolemia,+Familial
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C16320565556475
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In
Medicine , is a
Rare Disease characterised by very high
LDL cholesterol and early
Cardiovascular Disease running in families. It is a
Genetic Disorder .
There are two forms:
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 (19p13.1-13.3). It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form.
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 . Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia results from defects in the cell surface receptor that removes LDL particles from plasma.
The excess circulating LDL is taken up by cells all over the body but most notably by
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 body and the ''functionality'' of these receptors. In the hetrozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious forms, the homozygouse form, the "broken" receptor is not expressed at all.
In ''heterozygous'' FH, only one of the two
DNA copies (
Allele s) 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
Statin s (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 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). 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 . As the combination of fibrates and statins is associated with a markedly increased risk of
Myopathy and
Rhabdomyolysis (breakdown of muscle tissue, leading to
Acute Renal Failure ), these patients are monitored closely.
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.
The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr
Joseph L. Goldstein and Dr
Michael S. Brown of Dallas, Texas
{Link without Title} .
- Müller C. ''Xanthoma, hypercholesterolemia, angina pectoris''. Acta Med Scandinav 1938;89:75.
- Brown MS, Goldstein JL. ''A receptor-mediated pathway for cholesterol homeostasis''. Science 1986;232:34-47. PMID 3513311.
- MEDPED (Make Early Diagnosis to Prevent Early Deaths)
- NCBI (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
