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Familial hypercholesterolemia

Familial hypercholesterolemia
Classification & external resources
ICD-10 E78.0
ICD-9 272.0
OMIM 143890
DiseasesDB 4707
MedlinePlus 000392
eMedicine med/1072 
MeSH C16.320.565.556.475

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a rare genetic disorder characterized by very high LDL cholesterol and early cardiovascular disease running in families.


Signs and symptoms


Familial hypercholesterolemia may be either heterozygous (incidence around 1:500) or homozygous (incidence around 1:250,000). Heterozygous FH patients will often exhibit serum cholesterol levels around 400 mg/dl (normal is 200 mg/dl), and make up the majority of patients, as survival for homozygotes is very low, with cholesterol levels often near 1000 mg/dl.

There are four major classes of FH:[1]

  • Class I: LDL receptor (LDL-R) is not synthesized at all
  • Class II: LDL-R is not properly transported from the Endoplasmic Reticulum to the Golgi Apparatus for expression on the cell surface
  • Class III: LDL-R does not properly bind LDL on the cell surface (this may be caused by a defect in either Apolipoprotein B100 (R3500Q) or in LDL-R)
  • Class IV: LDL-R bound to LDL does not properly cluster in Clathrin-coated pits for Receptor-mediated endocytosis


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. FH is caused by defects in LDL-R in most cases, but may also be caused by defects in Apolipoprotein B100 (commonly known as Apoprotein B100 or ApoB100), which is located on chromosome 2 (2p24-p23, 21.08-21.12Mb)[2]


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 normally removes LDL particles from the blood 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 can occur in all people, many FH patients develop accelerated atherosclerosis due to the excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis.[3][4]

The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells 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 (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 alleles 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). Maximum doses are often necessary. Statins work by inhibiting HMG-CoA reductase, stimulating production of LDL receptors in the liver, which will reduce cholesterol levels in the cell. In FH homozygotes, where no functional LDL-R is produced, statins will not be effective. In this scenario, a drug from the fibrate or bile acid sequestrant class can be added, as well as niacin/acipimox to control cholesterol levels. 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

As described above, treatment with statin drugs is dependent on having at least one functional copy of the LDL receptor. In homozygous FH patients, high doses of fibrate or bile acid sequestrant drugs can be used, and high doses of statins may help by inducing high level expression of a partially active 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, for which they won the 1985 Nobel Prize in Medicine.


  1. ^ Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34-47. PMID 3513311.
  2. ^ NIH Entrez Gene: APOB.
  3. ^ Scientific Steering Committee on behalf of the Simon Broome Register Group (Ratcliffe Infirmary, Oxford, England), "Risk of fatal coronary heart disease in familial hypercholesterolaemia", British Medical Journal 303 (1991), pp. 893-896.
  4. ^ E.J.G. Sijbrands, et al., "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study", British Medical Journal 322 (2001), pp. 1019-1023.
  • 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.
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Familial_hypercholesterolemia". A list of authors is available in Wikipedia.
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