Amyloids are protein aggregates that have developed into a folded shape allowing numerous replicates of that protein to clump altogether, creating fibrils. Within in the body, the growth of many diseases have been related to amyloids. Amyloids that are pathogenic develop when originally normal proteins escape their healthy purpose and create plaques of fibrous outside cells that may interrupt the normal role of organs and tissues (UCL, 2018).
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Greater than 50 diseases have been related with these amyloids, recognized as amyloidosis, and can participate in a part in certain neurodegenerative disorders. Prions are infectious amyloid proteins where the infectious type is able to perform as a template to change additional non-infectious proteins into infectious ones. Healthy natural roles amyloids can in addition may have for example, the release of hormones in humans (Toyama and Weissman, 2011).
Several various polypeptides and proteins amyloids have been seen to result from. β-sheet arrangements which aggregate into long fibers that these polypeptide chains usually produce, though, similar polypeptides may fold into many unique conformations of amyloid. Various types of diseases due to prions could have been formed as a result of variety of the conformations (Ramirez-Alvarado, Merkel and Regan, 2000).
The beginning of the word amyloid was introduced into the scientific literature by the German botanist Matthias Schleiden (1804 – 1881). He used the term amyloid to describe the reaction produced in the iodine-sulphuric acid test in plants to test for starch.
In 1854, Rudolph Virchow presented and made popular the word amyloid in medical literature to describe a macroscopic abnormality in tissue that showed an iodine positive staining result. Later light microscopic investigations with polarizing optics revealed the characteristic birefringence of deposits of amyloid, a feature that amplified deeply following Congo red staining. In 1959, electron microscopic investigation of extremely thin pieces of amyloid tissues showed the existence of fibrils.
Employing the conditions of the Congo red stain and fibrillary morphology, at least 20 biochemically separate types of amyloid have been discovered, all distinctly related with a specific disease. Analysis with X-ray diffraction showed the fibrils to be arranged in the conformation of a beta pleated sheet, with a cross beta structure. Due to the similar dimensions and staining properties of the extracted fibrils from the tissues laden with amyloid and amyloid fibrils in tissue sections, they were assumed to be the same. But, the three dimensional association of amyloid P component (AP) and proteoglycans, seen in all types of amyloid, to the alleged protein only fibrils in tissues, was uncertain. Lately, it has been proposed that, amyloid fibrils are comprised of proteoglycans and AP in addition to amyloid proteins and therefore, look like connective tissue microfibrils (Sipe and Cohen, 2000).
Certain kinds of amyloidosis are genetic or acquired. They are classified into whether they are systemic or localized forms. The most seen cases of systemic forms are: inflammation (AA), light chain (AL), dialysis (Aβ2M), and hereditary and old age (ATTR) (Sipe et al., 2014)
Amyloidosis presentation is broad and depends on the site of amyloid accumulation. The most usual organs occupied are the heart and kidney (Feng, 2013).
Nephrotic syndrome can be caused from deposition of amyloid in the kidneys that is due to a decrease in the filtering ability of the kidney and therefore retains proteins. Kidneys are involved in about 90% of individuals with AA amyloidosis, with symptoms varying from urine containing protein to nephrotic syndrome and seldom kidney insufficiency. The deposition of amyloid in the heart may be both systolic and diastolic heart failure. The heart is typically safe in AA amyloidosis. The central nervous system is not normally affected by individuals with amyloidosis however they may acquire autonomic and sensory neuropathies. Liver buildup of amyloids may result in raised levels in blood alkaline phosphatase and aminotransferases, two liver injury biomarkers, seen in approximately one third of patients. 2.4% of AA amyloidosis and 8.5% of AL amyloidosis, malabsorption is present. Deposits of amyloid in the villi in the intestine, start to corrode the functional ability of the villi, is a possible mechanism for malabsorption (Ebert and Nagar, 2008).
The pathogenesis of amyloidosis is as follows. There are two unique pathways of creating protein by the cells in the body. Certain proteins are created from fragments of protein, others are made from a single piece or sequence of amino acids, and they come altogether to create the entire protein. However, some proteins may occasionally break up into the initial fragments that made up the protein. This procedure involving “flip flopping” occurs often for specific types of protein, particularly ones that lead to amyloidosis.
The actual or fragments that made up the protein are at danger of being misfolded as they are manufactured, to create an ill operating protein. This triggers proteolysis, which is the destruction of proteins by enzymes secreted by cells known as proteases or broken down by intramolecular digestion, here proteases come along and the misfolded proteins and fragments are digested. The issue happens if the proteins are not disappeared by proteolysis since the proteins that are misfolded occasionally develop into robust proteins strong enough to prevent them from not becoming destroyed by proteolysis. If the fragments are not broken down, they aggregate to become oligomers. The basis for why the proteins aggregate is because sections of the protein which are not destroyed in proteolysis are β-pleated sheets that are hydrophobic. They are normally concealed in the centre of the protein, whereas sections of the protein which are more hydrophilic are located close to the external surface. If the proteins encounter water, the parts that are hydrophobic are inclined to aggregate along with other parts are hydrophobic. This particular clump of proteins becomes stable by SAP (serum amyloid P) and GAGs (glycosaminoglycans), a constituent located in aggregates of amyloid which is considered to make the amyloid aggregate stable and preventing it from cleavage by proteolysis. Oligomers is what the stabilized spheres of protein pieces are named. These oligomers are able to aggregate together and become more stabilized to create fibrils of amyloid. Toxic to cells are both the amyloid fibrils and oligomers which can also disrupt with correct function of the organ (Gertz and Rajkumar, 2010).
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Amyloidosis is diagnosed by requiring a tissue biopsy. Evidence of characteristic amyloid deposits is what the biopsy is assessed for. Various stains the tissue is treated with. Congo red is the most useful stain in the diagnosis of amyloid, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy (Dember, 2006).
The histological staining technique Congo red is the gold standard technique for the diagnosis of amyloidosis. Amyloid forms nonpolar hydrogen bonds with Congo red dye and red changing to apple green birefringence happens once examined under polarized light as a result of the arrangement of the molecules of the dye on the linear pattern of amyloid fibrils. The Congo red non-polar hydrogen bonding with amyloid is enhanced by the high pH. In the polarization aspect of the Congo red dye and amyloid is that the appearance of green polarization colour primarily depends on near-perfect parallel alignment of the dye particles. Amyloid differs from other materials which are stained by Congo red in that amyloid deposits bind the dye molecules in a more orderly and parallel fashion (Graham and Holland, 2005).
The amyloid protein type can be determined in various ways: the detection in the bloodstream of abnormal proteins (light chain determination or on protein electrophoresis), binding to the amyloid by of particular antibodies found in the tissue (immunohistochemistry), or protein extraction and identification of its individual amino acids. AA amyloidosis can be identified by Immunohistochemistry, the majority of the time, but not so much with cases of AL amyloidosis. Laser microdissection with mass spectrometry is the best dependable technique of diagnosing the various amyloidosis forms of amyloidosis.
The most common form of amyloidosis is AL and the search for plasma cell dyscrasia, which is caused by memory B cells releasing aberrant immunoglobulins or immunoglobulins portions is where diagnosis begins. Familial transthyretin-associated amyloidosis or people with family history of idiopathic neuropathies or heart failure who have no evidence of plasma cell dyscrasias, ATTR is suspected. Isoelectric focusing can be used to identify ATTR, which separates mutated forms of transthyretin. On clinical grounds AA is suspected in people with chronic infections or disease of inflammation. Immunohistochemistry staining can be used to identify AA.
The classification used for amyloidosis nowadays is with using an abbreviation of the protein that makes the majority of deposits, prefixed with the letter A. Here are some of the types of amyloid diseases using their classification: AL (amyloid light chain), AA (Serum amyloid A protein (SAA)), Aβ (β amyloid/APP, found in Alzheimer disease brain lesions), and ATTR (transthyretin is a protein that is mostly produced in the liver that is involved in the transport of retinol binding protein and thyroxine) (Falk, Comenzo and Skinner, 1997).
The type of amyloidosis that is present will depend on what treatment is followed. A strong dose of a chemotherapy drug, melphalan, with accompanying stem cell transplantation has demonstrated potential in initial research and is advised for AL amyloidosis stage I and II. AA symptoms can be reduced, if the primary disease is sorted, eprodisate has been seen to reduce renal impairment by stopping amyloid fibril polymerization. ATTR can be treated with a liver transplant which is a cure as transthyretin mutated forms can develop into amyloids which are synthesized in the liver (Rosenzweig and Landau, 2011).
A recent vast increase there has been in the understanding and treatment of patients with amyloidosis. Among physicians there has been an increased clinical awareness about this disorder, the investigations required to pursue its diagnosis, and the therapeutic options currently available is necessary for the benefit to impact on patients.
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- Ebert, E. and Nagar, M. (2008). Gastrointestinal Manifestations of Amyloidosis. The American Journal of Gastroenterology, 103(3), pp.776-787.
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- Gertz, M. and Rajkumar, S. (2010). Amyloidosis. Totowa, NJ: Springer Science+Business Media, LLC.
- Ramirez-Alvarado, M., Merkel, J. and Regan, L. (2000). A systematic exploration of the influence of the protein stability on amyloid fibril formation in vitro. Proceedings of the National Academy of Sciences, 97(16), pp.8979-8984.
- Rosenzweig, M. and Landau, H. (2011). Light chain (AL) amyloidosis: update on diagnosis and management. Journal of Hematology & Oncology, 4(1), p.47.
- Sipe, J., Benson, M., Buxbaum, J., Ikeda, S., Merlini, G., Saraiva, M. and Westermark, P. (2014). Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid, 21(4), pp.221-224.
- Sipe, J. and Cohen, A. (2000). Review: History of the Amyloid Fibril. Journal of Structural Biology, 130(2-3), pp.88-98.
- Toyama, B. and Weissman, J. (2011). Amyloid Structure: Conformational Diversity and Consequences. Annual Review of Biochemistry, 80(1), pp.557-585.
- UCL (2018). National Amyloidosis Centre. [online] Centre for Amyloidosis and Acute Phase Proteins. Available at: https://www.ucl.ac.uk/amyloidosis/national-amyloidosis-centre [Accessed 17 Oct. 2018].
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