Amyloidosis

In medicine, amyloidosis refers to a variety of conditions in which amyloid proteins are abnormally deposited in organs and/or tissues. A protein is described as being amyloid if, due to an alteration in its secondary structure, it takes on a particular aggregated insoluble form similar to the beta-pleated sheet. Symptoms vary widely depending upon the site of amyloid deposition. Amyloidosis may be inherited or acquired.

Classification of amyloid
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 over production of immunoglobulin light chains in multiple myeloma (termed AL amyloid), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloid).

Out of the approximately 60 amyloid proteins that have been identified so far, at least 36 have been associated in some way with a human disease.

Pathogenesis
When a native cell creates a protein, it could either make the actual protein or protein fragments. These fragments could come and join together to form the actual protein. This protein can sometimes regress into the protein fragments. This process of "flip flopping" happens frequently in certain proteins, especially the ones that cause this disease. 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). These 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.

Classification
The names of the amyloid usually start with the letter "A". Following is a brief description of the more common types of amyloid:

As of 2010, there were 27 human and nine animal fibril proteins classified, along with eight inclusion bodies.

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, arrhythmia, and an irregular heart beat. 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. The amyloidosis can also affect the motor functions and cause polyneuropathy. When the amyloid fibrils and oligomers get to the skin they can cause skin lesions and petechiae. One of the most famous symptoms is macroglossia.

Diagnosis
If the diagnosis of amyloidosis is suspected, a biopsy (tissue sample)of abdominal wall fat, the rectum or a salivary gland can be examined 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. Alternatively, the 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.

Alternative classifications
An older, clinical, method of classification refers to the 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.