From Wikipedia, the free encyclopedia - View original article
|Classification and external resources|
|Classification and external resources|
In medicine, amyloidosis is a non-specific term that refers to a number of different diseases collectively called amyloidoses. Amyloids are proteins whose secondary structure changes, causing the proteins to fold in a characteristic form, the beta-pleated sheet. When the normally soluble proteins fold to become amyloids, they become insoluble and deposit in organs or tissues, disrupting normal function. Different types of amyloidoses have different signs and symptoms depending on where and in which organs the amyloid proteins aggregate. Amyloidoses can be inherited or acquired.
Historical classification systems were based on clinical factors. Until the early 1970s, the idea of a single amyloid substance predominated. Various descriptive classification systems were proposed based on the organ distribution of amyloid deposits and clinical findings. Most classification systems included primary (i.e., idiopathic) amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis (i.e., secondary to chronic inflammatory conditions). Some classification systems included myeloma-associated, familial, and localized amyloidosis.
The modern era of amyloidosis classification began in the late 1960s with the development of methods to make amyloid fibrils soluble. These methods permitted scientists to study the chemical properties of amyloids. Descriptive terms such as primary amyloidosis, secondary amyloidosis, and others (e.g., senile amyloidosis), which are not based on etiology, provide little useful information and are no longer recommended.
The modern classification of amyloid disease tends to use an abbreviation of the protein that makes the majority of deposits, prefixed with the letter A. For example, amyloidosis caused by transthyretin is termed "ATTR". Deposition patterns vary between patients but are almost always composed of just one amyloidogenic protein. Deposition can be systemic (affecting many different organ systems) or organ-specific. Many amyloidoses are inherited, due to mutations in the precursor protein.
Other forms are due to different diseases causing overabundant or abnormal protein production - such as with overproduction of immunoglobulin light chains (termed AL amyloidosis), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloidosis).
The names of amyloids usually start with the letter "A". Here is a brief description of the more common types of amyloid:
|AL||amyloid light chain||AL amyloidosis / multiple myeloma. Contains immunoglobulin light-chains (λ,κ) derived from plasma cells.||254500|
|AA||SAA||Serum amyloid A protein (SAA) is an acute-phase reactant that is deposited in the tissues in AA amyloidosis.|
|Aβ||β amyloid/APP||Found in Alzheimer disease brain lesions.||605714|
|ATTR||transthyretin||A mutant form of a normal serum protein that is deposited in the genetically determined familial amyloid polyneuropathies. TTR is also deposited in the heart in senile systemic amyloidosis. Also found in Leptomeningeal amyloidosis.||105210|
|Aβ2M||β2 microglobulin||Not to be confused with Aβ, β2m is a normal serum protein, part of major histocompatibility complex (MHC) Class 1 molecules. Haemodialysis-associated amyloidosis|
|AIAPP||amylin||Found in the pancreas of patients with type 2 diabetes.|
|APrP||prion protein||In prion diseases, misfolded prion proteins deposit in tissues and resemble amyloid proteins. Some examples are Creutzfeldt–Jakob disease (humans), BSE or "mad cow disease" (cattle), and scrapie (sheep and goats). A recently described familial prion disease presents with peripheral amyloidosis causing autonomic neuropathy and diarrhea.||123400|
|AGel||GSN||Finnish type amyloidosis||105120|
|ACys||CST3||Cerebral amyloid angiopathy, Icelandic-type||105150|
|AApoA1||APOA1||Familial visceral amyloidosis||105200|
|AFib||FGA||Familial visceral amyloidosis||105200|
|ALys||LYZ||Familial visceral amyloidosis||105200|
|?||OSMR||Primary cutaneous amyloidosis||105250|
|ITM2B||Cerebral amyloid angiopathy, British-type|
|AKer||keratoepithelin||Familial corneal amyloidosis|
|AANF||atrial natriuretic factor||Senile amyloid of atria of heart|
|ACal||calcitonin||Medullary carcinoma of the thyroid|
An older clinical method of classification refers to amyloidoses as systemic or localised
Another classification is primary or secondary.
Additionally, based on the tissues in which it is deposited, it is divided into mesenchymal(organs derived from mesoderm) or parenchymal(organs derived from ectoderm or endoderm).
Native cells have two different ways of making different proteins. Some proteins cells make in one piece; others, cells make only protein fragments, and the fragments come and join together to form the whole protein. But such a protein can sometimes fall apart into the original protein fragments. This process of "flip flopping" happens frequently for certain protein types, especially the ones that cause amyloidosis.
The fragments or actual proteins are at risk of mis-folding as they are synthesized, to make a bad protein. This causes proteolysis, which is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion; proteases come and digest the mis-folded fragments and proteins. The problem occurs when the proteins do not dissolve in proteolysis. This happens because the mis-folded proteins sometimes become robust enough that they are not dissolved by normal proteolysis. When the fragments do not dissolve, they get spit out of proteolysis and they aggregate to form oligomers. The reason they aggregate is that the parts of the protein that do not dissolve in proteolysis are the β-pleated sheets, which are extremely hydrophobic. They are usually sequestered in the middle of the protein, while parts of the protein that are more soluble are found near the outside. When they are exposed to water, these hydrophobic pieces tend to aggregate with other hydrophobic pieces. This ball of fragments gets stabilized by GAG's (glycosaminoglycans) and SAP (serum amyloid P), a component found in amyloid aggregations that is thought to stabilize them and prevent proteolytic cleavage. The stabilized balls of protein fragments are called oligomers. The oligomers can aggregate together and further stabilize to make amyloid fibrils.
Both the oligomers and amyloid fibrils can cause cell toxicity and impair organ function.
If diagnosis of one of the amyloidoses is suspected, a tissue sample of an affected organ, often abdominal wall fat, the rectum or a salivary gland, can be examined in biopsy for evidence of characteristic amyloid deposits. The tissue is treated with various stains. The most useful stain in the diagnosis of amyloid is Congo red, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy. Also, thioflavin T stain may be used. An abdominal wall fat biopsy is not completely sensitive and, sometimes, biopsy of an involved organ (such as the kidney) is required to achieve a diagnosis.
The nature of the amyloid protein can be determined by various ways: the detection of abnormal proteins in the bloodstream (on protein electrophoresis or light chain determination), binding of particular antibodies to the amyloid found in the tissue, or extraction of the protein and identification of its individual amino acids.
Treatment depends on the type of amyloidosis that is present. Chemotherapy is the first line treatment in AL, with mephalan plus dexamethasone. In AA, symptoms may improve if the underlying condition is treated; eprodisate has been shown to slow renal impairment by inhibiting polymerisation of amyloid fibrils. In some familial causes of amyloidosis a liver transplant may be curative.
|This section requires expansion. (August 2013)|
Amyloidosis, dystrophic calcification