|Classification and external resources|
In medicine, amyloidosis refers to a variety of conditions wherein normally soluble proteins become insoluble and are deposited in the extracellular space of various organs or tissues, disrupting normal function. The insoluble fibrous protein aggregates that develop in amyloidosis are known as amyloids. They result from a change in the protein's secondary structure, which causes the protein to take on a particular aggregated insoluble form, similar to the beta-pleated sheet. Symptoms vary widely depending upon where in the body amyloid deposits accumulate. Amyloidosis may be inherited or acquired. Senile systemic amyloidosis was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied.
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 solubilize amyloid fibrils. These methods permitted chemical amyloid studies. 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 in multiple myeloma (termed AL amyloidosis), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloidosis).
The names of the amyloid usually start with the letter "A". Following is a brief description of the more common types of amyloid:
An older, clinical, method of classification refers to amyloidoses as systemic or localised
- Systemic amyloidoses affect more than one body organ or system. Examples are: AL, AA and Aβ2m.
- Localised amyloidoses affect only one body organ or tissue type. Examples are: Aβ, IAPP, Atrial natriuretic factor (in isolated atrial amyloidosis), and Calcitonin (in medullary carcinoma of the thyroid)
Another classification is primary or secondary.
- Primary amyloidoses arise from a disease with disordered immune cell function such as multiple myeloma and other immunocyte dyscrasias.
- Secondary (reactive) amyloidoses are those occurring as a complication of some other chronic inflammatory or tissue destructive disease. Examples are reactive systemic amyloidosis and secondary cutaneous amyloidosis.
Signs and symptoms
There are numerous symptoms that are associated with this disease. The most common ones have to do with the heart, such as heart failure and arrhythmia. Also, the respiratory tract can be affected and cause hemoptysis. Usually, the spleen enlarges and sometimes ruptures. The gastrointestinal tract is usually affected and causes vomiting, hemorrhaging and diarrhea. Amyloidosis can also affect the body's motor functions and cause polyneuropathy.
Native cells have two different methods of making different proteins. Some proteins cells make the whole protein in one piece; for other proteins, 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 organ dysfunction.
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.
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 familial causes of amyloidosis a liver transplant can be curative.
|This section requires expansion. (August 2013)|
Amyloidosis, dystrophic calcification
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