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Encyclopedia > Familial hypercholesterolemia
Familial hypercholesterolemia
[[Image:|190px|center|]]
ICD-10 E780
ICD-9 272.0
ICD-O:
OMIM 143890
DiseasesDB 4707
MedlinePlus 000392
eMedicine med/1072
MeSH C16.320.565.556.475

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. The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... // E00-E35 - Endocrine diseases (E00-E07) Disorders of thyroid gland (E00) Congenital iodine-deficiency syndrome (E01) Iodine-deficiency-related thyroid disorders and allied conditions (E02) Subclinical iodine-deficiency hypothyroidism (E03) Other hypothyroidism (E030) Congenital hypothyroidism with diffuse goitre (E031) Congenital hypothyroidism without goitre (E032) Hypothyroidism due to medicaments and other... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The International Classification of Diseases for Oncology (ICD-O) is a domain specific extension of the International Statistical Classification of Diseases and Related Health Problems for tumor diseases. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Diseases Database is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... MedlinePlus (medlineplus. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... Medicine is the branch of health science and the sector of public life concerned with maintaining human health or restoring it through the treatment of disease and injury. ... A rare disease has such a low prevalence in a population that a doctor in a busy general practice would not expect to see more than one case a year. ... Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying somewhat in their size and contents, which carry cholesterol in the blood and around the body, for use by various cells. ... Cardiovascular disease refers to the class of diseases that involve the heart and/or blood vessels (arteries and veins). ... A genetic disorder, or genetic disease is a disease caused by abnormal expression of one or more genes in a person causing a clinical phenotype. ...

Contents


Signs and symptoms

Cholesterol chemical structure Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. ... Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying somewhat in their size and contents, which carry cholesterol in the blood and around the body, for use by various cells. ... Very Low Density Lipoprotein (VLDL) is a lipoprotein subclass. ... It has been suggested that Medium Chain Triglycerides be merged into this article or section. ... Electrophoresis is the movement of an electrically charged substance under the influence of an electric field. ... The second type of high blood lipids (cholesterol) in the (dated) Fredrickson classification, which is determided by lipoprotein electrophoresis. ... Cardiovascular disease refers to the class of diseases that involve the heart and/or blood vessels (arteries and veins). ... Angioplasty is the mechanical dilation of an artery that have been obstructed, generally due to atheroma (the lesion of atherosclerosis). ... A coronary artery bypass graft (CABG) or heart bypass is a surgical procedure performed in patients with coronary artery disease (see atherosclerosis) for the relief of angina and possible improved heart muscle function. ... A myocardial infarction occurs when an atherosclerotic plaque slowly builds up in the inner lining of a coronary artery and then suddenly ruptures, totally occluding the artery and preventing blood flow downstream. ... Transient ischemic attacks (TIA) are caused by temporary disturbance of blood supply to a restricted area of brain and cause recurrent and brief (less than 24 hours) neurologic dysfunctions. ... A stroke or cerebrovascular accident (CVA) occurs when the blood supply to a part of the brain is suddenly interrupted by occlusion (an ischemic stroke- approximately 90% of strokes), by hemorrhage (a hemorrhagic stroke - less than 10% of strokes) or other causes. ... A stroke, also known as cerebrovascular accident (CVA), is an acute neurologic injury whereby the blood supply to a part of the brain is interrupted, either by a clot in the artery or if the artery bursts. ... In medicine (vascular surgery), Peripheral artery occlusive disease (PAOD) is a collator for all disease caused by the obstruction of large peripheral arteries, which can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or thrombus formation. ... In medicine, a family history consists of information about disorders that a patients direct blood relatives have suffered from. ... A xanthoma is a deposition of cholesterol-rich material in tendons and other body parts in various disease states: Tendon xanthomas (associated with familial hypercholesterolemia, cerebrotendineous xanthomatosis and phytosterolemia) Palmar xanthomas Eruptive xanthomas See also xanthelasma Categories: Stub | Sign (medicine) ... A tendon (or sinew) is a tough band of fibrous connective tissue that connects muscle to bone. ... A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, makros = long, phagein = eat) are white blood cells, more specifically phagocytes, acting in the nonspecific defense as well as the specific defense system of vertebrate animals. ... Cholesterol chemical structure Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. ... Xanthelasma (or xanthelasma palpabrum) are yellowish collections of cholesterol underneath the skin, usually around the eyes. ... Arcus senilis (or Arcus senilis corneae. ...

Types

There are two forms:

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

Heterozygote cells are diploid or polyploid and have different alleles at a locus (position) on homologous chromosomes. ... Homozygote cells are diploid or polyploid and have the same alleles at a locus (position) on homologous chromosomes. ...

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. Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying somewhat in their size and contents, which carry cholesterol in the blood and around the body, for use by various cells. ... This page may meet Wikipedias criteria for speedy deletion. ...


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. This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... Figure 1: Chromosome. ...


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 removes LDL particles from plasma. Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying in their size and contents, which carry cholesterol in the blood and around the body, for use by cells. ... The liver is one of the largest internal organs of the human body. ... High density lipoproteins (HDL) form a class of lipoproteins, varying somewhat in their size (8-11 nm in diameter) and contents, that carry cholesterol from the bodys tissues to the liver. ...


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. Macrophages (Greek: big eaters) are cells found in tissues that are responsible for phagocytosis of pathogens, dead cells and cellular debris. ... The most fundamental reactions in chemistry are the redox processes. ...


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 (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). The general structure of a section of DNA Deoxyribonucleic acid (DNA) is a nucleic acid —usually in the form of a double helix— that contains the genetic instructions specifying the biological development of all cellular forms of life, and most viruses. ... An allele is any one of a number of viable DNA codings of the same gene (sometimes the term refers to a non-gene sequence) occupying a given locus (position) on a chromosome. ...


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). Lovastatin, the first statin to be marketed The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceuticals to lower cholesterol levels in people at risk for cardiovascular disease because of hypercholesterolemia. ...


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.

Atherosclerosis is a disease affecting the arterial blood vessel. ...

Treatment

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). Lovastatin, the first statin to be marketed The statins form a class of hypolipidemic agents. ... Cholesterol chemical structure Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. ... HMG-CoA reductase HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) is the first enzyme (EC 1. ...


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. In pharmacology, the fibrates are a class of amphipathic carboxylic acids. ... In pharmacology, bile acid sequestrants a group of medication used for binding bile in the gastrointestinal tract. ... Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitamin whose derivatives such as NADH play essential roles in energy metabolism in the living cell. ... In medicine, a myopathy is a neuromuscular disease in which the muscle fibers dysfunction for any one of many reasons, resulting in muscular weakness. ... Rhabdomyolysis is the breakdown of skeletal muscle due to injury, either mechanical, physical or chemical. ...


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 medicine, LDL apheresis is a form of apheresis, resembling dialysis, to eliminate the cholesterol-containing particle low-density lipoprotein (LDL) from the bloodstream. ... In medicine, dialysis is a type of renal replacement therapy which is used to provide an artificial replacement for lost kidney function in renal failure. ...


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]. Joseph L. Goldstein (b. ... Dr. Michael S. Brown (b. ...


References

  • 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.

Science is the journal of the American Association for the Advancement of Science (AAAS). ...

External links

  • MEDPED (Make Early Diagnosis to Prevent Early Deaths)

  Results from FactBites:
 
eMedicine - Hypercholesterolemia, Familial : Article by Elena Citkowitz (7148 words)
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc).
Their family history should be positive for severe hypercholesterolemia and premature CAD in both parental family lines.
The NCEP recommendations for the dietary management of hypercholesterolemia are not highly restrictive, but a more stringent regimen may have a greater impact on lipid levels (see Table 2).
Discovery Health :: Diseases & Conditions :: familial hypercholesterolemia (362 words)
Familial hypercholesterolemia is an inherited disease that causes high cholesterol levels.
A person with familial hypercholesterolemia inherits an abnormal gene for the docking site from one or both parents.
Genetic counseling may be useful to couples with a family history of the disease.
  More results at FactBites »

 
 

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