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.[1] Symptoms vary
widely depending upon the site of amyloid deposition. Amyloidosis may be inherited
or acquired.[2]

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 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:
Official Amyloid
Description
abb. type/Gene
amyloid light AL amyloidosis / multiple myeloma. Contains
AL
chain immunoglobulin light-chains (λ,κ) derived from plasma cells.
AA SAA AA amyloidosis
Aβ β amyloid/APP Found in Alzheimer disease brain lesions.
A mutant form of a normal serum protein that is deposited in
the genetically determined familial amyloid
ATTR transthyretin polyneuropathies. TTR is also deposited in the heart in senile
systemic amyloidosis.[6] Also found in Leptomeningeal
amyloidosis.
Not to be confused with Aβ, β2m is a normal serum protein,
Aβ2M β2 microglobulin part of major histocompatibility complex (MHC) Class 1
molecules. Haemodialysis-associated amyloidosis
AIAPP amylin Found in the pancreas of patients with type 2 diabetes.
In prion diseases, misfolded prion proteins deposit in tissues
and resemble amyloid proteins. Some examples are
APrP prion protein
Creutzfeldt–Jakob disease (humans), BSE or "mad cow
disease" (cattle), and scrapie (sheep and goats).
AGel GSN Finnish type amyloidosis
ACys CST3 Cerebral amyloid angiopathy, Icelandic-type
AApoA1 APOA1 Familial visceral amyloidosis
AFib FGA Familial visceral amyloidosis
ALys LYZ Familial visceral amyloidosis
? OSMR Primary cutaneous amyloidosis
ABri Cerebral amyloid angiopathy, British-type
ITM2B
ADan Danish-type
APro prolactin Prolactinoma
AKer keratoepithelin Familial corneal amyloidosis
atrial natriuretic
AANF Senile amyloid of atria of heart
factor
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 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
The major way that this disease is discovered is through a biopsy of the kidney, gastrointestinal
tract or the salivary glands. Once medical professionals have this biopsy, they stain it with a
variety of different stains. The most common stain is the Congo Red Dye Test. In this test the
normal skin and tissue turns a light red color but the amyloid tissue turns a dark red. Under
polarized light the amyloid proteins glow green with this red dye test. Also, they can test it with
Thioflavin T, which makes the amyloid fibrils glow in the dark and they need a specific
microscope to see this type of stain. The problem with these stains is that they only show that a
person has amyloidosis, not what type of amyloidosis. To find out the certain types of
amyloidosis, they need to go through more stains, such as the potassium permanganate stain
which shows up in the AA but not the AL (The AA and Al versions are the most similar forms of
this disease). Other than biopsy, one can look at a urine or blood sample. If the sample has
protein in it then the doctors can determine what type of protein it is and if it is amyloid or not.
They do this through immunofixation and nephelometry.
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