Amyloidosis
Encyclopedia
In medicine
, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid
protein
s, which are abnormally deposited in organ
s and/or tissue
s 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.
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 protein
s 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.
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 enzyme
s called protease
s 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 oligomer
s. 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.
As of 2010, there were 27 human and nine animal fibril proteins classified, along with eight inclusion bodies
.
, 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
.
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 acid
s.
Another classification is primary or secondary.
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, which are abnormally deposited in organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
s and/or tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
s and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
, it takes on a particular aggregated insoluble form, similar to the beta-pleated sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, 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 transthyretinTransthyretin
Transthyretin is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine and retinol binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol...
is termed "ATTR." Deposition patterns vary between patients but are almost always composed of just one amyloidogenic protein. Deposition can be systemic
Systemic disease
Life-threatening disease redirects here.A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Although most medical conditions will eventually involve multiple organs in advanced stage Life-threatening disease redirects here.A systemic disease is one...
(affecting many different organ systems) or organ-specific. Many amyloidoses are inherited
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
, 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
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
(termed AL amyloidosis
AL amyloidosis
Amyloid Light-chain amyloidosis, primary systemic amyloidosis or just primary amyloidosis is the most common form of systemic amyloidosis in the US. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein fibers made of components of...
), or with continuous overproduction of acute phase protein
Acute phase protein
Acute-phase proteins are a class of proteins whose plasma concentrations increase or decrease in response to inflammation...
s in chronic inflammation (which can lead to AA amyloidosis
AA amyloidosis
AA amyloidosis is a form of amyloidosis associated with serum amyloid A protein , an acute-phase protein. It causes reactive systemic amyloidosis, as a "reaction" to inflammation, but also familial Mediterranean fever, which is an inheritable condition.-Presentation:The common feature to conditions...
).
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
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
, which is the directed degradation of proteins by cellular enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s called protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s 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 oligomer
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
s. 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)
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
and SAP (serum amyloid P
Serum Amyloid P component
Amyloid P component, serum is the identical serum form of amyloid P component , a 25kDa pentameric protein first identified as the pentagonal constituent of in vivo pathological deposits called "amyloid"...
, 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 AL amyloidosis Amyloid Light-chain amyloidosis, primary systemic amyloidosis or just primary amyloidosis is the most common form of systemic amyloidosis in the US. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein fibers made of components of... / multiple myeloma Multiple myeloma Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies... . Contains immunoglobulin light-chains (λ,κ) derived from plasma cells. |
||||||||||||||||||||||||||||||
| AA | SAA Serum amyloid A Serum amyloid A proteins are a family of apolipoproteins associated with high-density lipoprotein in plasma. Different isoforms of SAA are expressed constitutively at different levels or in response to inflammatory stimuli . These proteins are produced predominantly by the liver... |
AA amyloidosis AA amyloidosis AA amyloidosis is a form of amyloidosis associated with serum amyloid A protein , an acute-phase protein. It causes reactive systemic amyloidosis, as a "reaction" to inflammation, but also familial Mediterranean fever, which is an inheritable condition.-Presentation:The common feature to conditions... |
||||||||||||||||||||||||||||||
| Aβ | β amyloid/APP Amyloid precursor protein Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export... |
> | ||||||||||||||||||||||||||||||
| ATTR | transthyretin Transthyretin Transthyretin is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine and retinol binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol... |
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. | ||||||||||||||||||||||||||||||
| Aβ2M | β2 microglobulin Beta-2 microglobulin β2 microglobulin also known as B2M is a component of MHC class I molecules, which are present on all nucleated cells . In humans, the β2 microglobulin protein is encoded by the B2M gene.-Structure and function:... |
Not to be confused with Aβ, β2m is a normal serum protein, part of major histocompatibility complex Major histocompatibility complex Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells... (MHC) Class 1 molecules. Haemodialysis-associated amyloidosis Haemodialysis-associated amyloidosis Haemodialysis-associated amyloidosis is a form of amyloidosis associated with chronic renal failure.-Presentation:Long-term haemodialysis results in a gradual accumulation of β2 microglobulin, a serum protein, in the blood. It accumulates because it is unable to cross the dialysis filter.... |
||||||||||||||||||||||||||||||
| AIAPP | amylin Amylin Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:... |
Found in the pancreas of patients with type 2 diabetes Diabetes mellitus type 2 Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and... . |
||||||||||||||||||||||||||||||
| APrP | prion protein | In prion Prion A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection... diseases, misfolded prion proteins deposit in tissues and resemble amyloid proteins. Some examples are Creutzfeldt–Jakob disease (humans), BSE or "mad cow disease" Bovine spongiform encephalopathy Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of... (cattle), and scrapie Scrapie Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie... (sheep and goats). |
||||||||||||||||||||||||||||||
| AGel | GSN Gelsolin Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency... |
Finnish type amyloidosis Finnish type amyloidosis Finnish type amyloidosis is a form of amyloidosis associated with gelsolin. Lattice corneal dystrophy type II is a part of the clinical picture in this amyloidosis, unlike LCDI, in which pathology is limited by corneal tissue.-Presentation:... > |- |
ACys | CST3 Cystatin C Cystatin C or cystatin 3 , a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease... |
> | AApoA1 | APOA1 | > | AFib | FGA Fibrinogen alpha chain Fibrinogen alpha chain is a protein that in humans is encoded by the FGA gene.-Interactions:Fibrinogen alpha chain has been shown to interact with Tissue plasminogen activator.-Further reading:... |
> | ALys | LYZ | > | ? | OSMR | Primary cutaneous amyloidosis Primary cutaneous amyloidosis Primary cutaneous amyloidosis is a form of amyloidosis associated with oncostatin M receptor. This type of amyloidosis has been divided into the following types:* Macular amyloidosis* Lichen amyloidosis* Nodular amyloidosis... > |- |
ABri ADan |
ITM2B ITM2B Integral membrane protein 2B is a protein that in humans is encoded by the ITM2B gene.ITM2B or BRI2 is a gene located on chromosom 13. The gene is connected to Familial Danish Disease and Familial British Disease causing amyloid and pre-filbrillar effects similar to those seen in Alzheimers... |
Danish-type > |- |
APro | prolactin Prolactin Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen... |
Prolactinoma Prolactinoma A prolactinoma is a benign tumor of the pituitary gland that produces a hormone called prolactin. It is the most common type of pituitary tumor... > |- |
AKer | keratoepithelin | > | AANF | atrial natriuretic factor | > | ACal | calcitonin Calcitonin Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found... |
> |
As of 2010, there were 27 human and nine animal fibril proteins classified, along with eight inclusion bodies
Inclusion bodies
Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...
.
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, arrhythmiaCardiac dysrhythmia
Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
, and an irregular heartbeat. Also, the respiratory tract can be affected and cause hemoptysis
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
. Usually, the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
enlarges and sometimes ruptures. The gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
is usually affected and causes vomiting, hemorrhaging and diarrhea. Amyloidosis can also affect the body's motor functions and cause polyneuropathy
Polyneuropathy
Polyneuropathy is a neurological disorder that occurs when many peripheral nerves throughout the body malfunction simultaneously. It may be acute and appear without warning, or chronic and develop gradually over a longer period of time. Many polyneuropathies have both motor and sensory...
.
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
Macroglossia
Macroglossia is the medical term for unusual enlargement of the tongue. Severe enlargement of the tongue can cause cosmetic and functional difficulties including in speaking, eating, swallowing and sleeping.- Amyloid Disorders :...
.
Diagnosis
If diagnosis of amyloidosis is suspected, a tissue sample of abdominal wall fat, the rectumRectum
The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long...
or a salivary gland
Salivary gland
The salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into maltose...
, can be examined in biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
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
Congo red
Congo red is the sodium salt of 3,3'-bis. It is a secondary diazo dye...
, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy
Microscopy
Microscopy is the technical field of using microscopes to view samples and objects that cannot be seen with the unaided eye...
. Alternatively, thioflavin T
Thioflavin
Thioflavin can refer to either of two dyes used for histology staining and biophysical studies of protein aggregation.Thioflavin T is a benzothiazole salt obtained by the methylation of dehydrothiotoluidine with methanol in the presence of hydrochloric acid...
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
Protein electrophoresis
Protein electrophoresis is a method for analysing the proteins in a fluid or an extract. The electrophoresis may be performed with a small volume of sample in a number of alternative ways with or without a supporting medium: SDS polyacrylamide gel electrophoresis Protein electrophoresis is a method...
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 acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s.
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, IAPPAmylinAmylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...
, Atrial natriuretic factor (in isolated atrial amyloidosisIsolated atrial amyloidosisIsolated atrial amyloidosis is a form of amyloidosis affecting the atria of the heart.It is associated with accumulation of atrial natriuretic factor.It may cause arrythmias....
) and CalcitoninCalcitoninCalcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
(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 myelomaMultiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
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.