Familial hypercholesterolemia
From Wikipedia, the free encyclopedia
| ICD-10 | E78.0 | |
|---|---|---|
| ICD-9 | 272.0 | |
| OMIM | 143890 | |
| DiseasesDB | 4707 | |
| MedlinePlus | 000392 | |
| eMedicine | med/1072 | |
| MeSH | C16.320.565.556.475 | |
In medicine, familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a rare genetic disorder characterised by very high LDL cholesterol and early cardiovascular disease running in families.
Contents |
[edit] Signs and symptoms
- Elevated serum cholesterol, most notably the LDL fraction (VLDL and triglycerides are typically normal)
- on lipoprotein electrophoresis (rarely done), a hyperlipoproteinemia type II pattern is recognised
- Premature cardiovascular disease, such as:
- Angina pectoris, leading to PTCA or 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 tendons due to accumulation of macrophages filled with cholesterol).
- Xanthelasma palpabrum (yellowish patches above the eyelids)
- Arcus senilis corneae, whitish discoloration of the iris
[edit] Types
There are two forms:
- Heterozygous FH (incidence 1:500-1:1,000, dependent on the population)
- Homozygous FH (incidence 1:1,000,000)
[edit] Causes
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.
[edit] Genetics
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.
[edit] Pathophysiology
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.[1][2]
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).
[edit] 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 atherosclerotic disease;
- Tendon xanthomas are found in a patient with high cholesterol.
[edit] Treatment
[edit] 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 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 niacin/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.
[edit] 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 some times 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.
[edit] 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. Goldstein and Dr Michael S. Brown of Dallas, Texas [1].
[edit] References
- ^ 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.
- ^ 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.
[edit] External links
- MEDPED (Make Early Diagnosis to Prevent Early Deaths)
- NCBI (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
