Familial hypercholesterolemia

In medicine, familial hypercholesterolemia is a rare diseasecharacterised by very high LDLcholesterol and early cardiovascular diseaserunning in families. It is a genetic disorder.

Signs and symptoms

• Elevated serum cholesterol, most notably the LDLfraction (VLDLand triglyceridesare typically normal)
  • on lipoprotein electrophoresis(rarely done), a hyperlipoproteinemia type IIpattern is recognised
• Premature cardiovascular disease, such as:
  • Angina pectoris, leading to PTCAor CABG
  • Myocardial infarction
  • Transient ischemic attacks(TIA's)
  • Cerebrovascular accidents/Strokes
  • Peripheral artery disease(PAOD)
• A family history of premature atherosclerosis
• Physical signs (not always present):
  • Tendon xanthomas(thickening of tendonsdue to accumulation of macrophagesfilled with cholesterol).
  • Xanthelasma palpabrum(yellowish patches above the eyelids)
  • Arcus seniliscorneae, whitish discoloration of the iris

Types

There are two forms:

• HeterozygousFH (incidence 1:500-1:1,000, dependent on the population)
• HomozygousFH (incidence 1:1,000,000)

Causes

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

Genetics

The LDL-receptor geneis located on the short arm of chromosome19 (19p13.1-13.3). It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form.

Pathophysiology

LDLcholesterol 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 macrophagesand especially the ones in a primary streak(the earliest stage of atherosclerosis). Oxidationof 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 at all.

In heterozygous FH, only one of the two DNAcopies (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).

Diagnosis

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 atheroscleroticdisease;
• Tendon xanthomas are found in a patient with high cholesterol.

Treatment

Heterozygous FH

Heterozygous FH can be treated effectively with statins. These are drugs that inhibit the body's ability to produce cholesterolby 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 fibrateor bile acid sequestrantclass can be added, as well as nicotinic acid/acipimox. As the combination of fibrates and statins is associated with a markedly increased risk of myopathyand rhabdomyolysis(breakdown of muscle tissue, leading to acute renal failure), these patients are monitored closely.

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.

History

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. Goldsteinand Dr Michael S. Brownof Dallas, Texas [1].

References

• Müller C. Xanthoma, hypercholesterolemia, angina pectoris. Acta Med Scandinav 1938;89:75.
• Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science1986;232:34-47. PMID 3513311.

External links

• OMIM143890
• MedlinePlusentry on FH.
• MEDPED(Make Early Diagnosis to Prevent Early Deaths)

This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Familial+hypercholesterolemia Wikipedia article Familial hypercholesterolemia.