Amyloidosis

Amyloidosis
Classification and external resources
Micrograph showing amyloid deposition (red fluffy material) in the heart (cardiac amyloidosis). Congo red stain.
ICD-10	E85
ICD-9	277.3
DiseasesDB	633
eMedicine	med/3377 med/3888
MeSH	D000686

In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. 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, i.e. where in the body these "bad proteins" are found in significant numbers. 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 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).

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. Such a 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). 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.

Classification

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

Official abb.	Amyloid type/Gene	Description	OMIM
AL	amyloid light chain	AL amyloidosis / multiple myeloma. Contains immunoglobulin light-chains (λ,κ) derived from plasma cells.	254500
AA	SAA	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).	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
ABri ADan	ITM2B	Cerebral amyloid angiopathy, British-type Danish-type	176500 117300
APro	prolactin	Prolactinoma
AKer	keratoepithelin	Familial corneal amyloidosis
AANF	atrial natriuretic factor	Senile amyloid of atria of heart
ACal	calcitonin	Medullary carcinoma of the thyroid

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 heartbeat. 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.

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 diagnosis of amyloidosis is suspected, a tissue sample of 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. Alternatively, 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 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.

Additional images

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  Small bowel duodenum with amyloid deposition congo red 10X

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  Amyloidosis, dystrophic calcification

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  Small bowel duodenum with amyloid deposition 20X

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  Amyloidosis, Node, Congo Red

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  Amyloidosis, blood vessels, H&E

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  Amyloidosis, lymph node, H&E

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  Amyloidosis, lymph node, polarizer

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  Cardiac amyloidosis. H&E stain.

See also

• Proteopathy

External links

• Stanford University Amyloid Center
• AL Amyloidosis on Wikilite.com
• Amyloidosis at the Open Directory Project