Amyloidosis

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Amyloidosis
Classification and external resources
Cardiac amyloidosis high mag.jpg
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
MeSH D000686

In medicine, amyloidosis refers to a variety of conditions wherein normally soluble proteins become insoluble and are deposited in the extracellular space of various organs or tissues, disrupting normal function.[1][2] The insoluble fibrous protein aggregates that develop in amyloidosis are known as amyloids. They result from a change in the protein's secondary structure, which causes the protein to take on a particular aggregated insoluble form, similar to the beta-pleated sheet.[3] Symptoms vary widely depending upon where in the body amyloid deposits accumulate. Amyloidosis may be inherited or acquired.[4] Senile systemic amyloidosis was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied.[5][6]

Classification[edit]

Historical classification systems were based on clinical factors. Until the early 1970s, the idea of a single amyloid substance predominated. Various descriptive classification systems were proposed based on the organ distribution of amyloid deposits and clinical findings. Most classification systems included primary (i.e., idiopathic) amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis (i.e., secondary to chronic inflammatory conditions). Some classification systems included myeloma-associated, familial, and localized amyloidosis.

The modern era of amyloidosis classification began in the late 1960s with the development of methods to solubilize amyloid fibrils. These methods permitted chemical amyloid studies. Descriptive terms such as primary amyloidosis, secondary amyloidosis, and others (e.g., senile amyloidosis), which are not based on etiology, provide little useful information and are no longer recommended.

Amyloid[edit]

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,[7] at least 36 have been associated in some way with a human disease.[8]

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 Serum amyloid A protein (SAA) is an acute-phase reactant that is deposited in the tissues in AA amyloidosis.
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.[9] Also found in Leptomeningeal amyloidosis. 105210
2M β2 microglobulin Not to be confused with , 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.[10]

Alternative classifications[edit]

An older, clinical, method of classification refers to amyloidoses as systemic or localised

Another classification is primary or secondary.

Signs and symptoms[edit]

There are numerous symptoms that are associated with this disease. The most common ones have to do with the heart, such as heart failure and arrhythmia. 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 well-known symptoms is macroglossia.[12]

Pathogenesis[edit]

Native cells have two different methods of making different proteins. Some proteins cells make the whole protein in one piece; for other proteins, cells make only protein fragments, and the fragments come and join together to form the whole protein. But such a protein can sometimes fall apart into the original protein fragments. This process of "flip flopping" happens frequently for certain protein types, especially the ones that cause amyloidosis.

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.[12]

Infectivity: The Evidence For Transmission of Amyloidosis[edit]

There is evidence that oral ingestion of amyloid fibers may lead to amyloidosis. This evidence is based on studies in cattle, chickens, mice, and cheetahs.[1] Thus, in a sense, amyloidosis may be considered a contagious disease, although whether this occurs or is important in the development of naturally occurring amyloidosis remains unknown. Nevertheless, because amyloid fibers can be detected in muscle in low amounts, it raises some concern about whether people could develop amyloidosis as a result of ingesting meat from an animal with the disease.[1] There is currently very little evidence in support of such a public health risk.

Diagnosis[edit]

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. Also, thioflavin T stain may be used.[13] 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.[13]

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.[13]

Treatment[edit]

Chemotherapy is the first line treatment in AL, with mephalan plus dexamethasone. In AA, symptoms may improve if the underlying condition is treated; eprodisate has been shown to slow renal impairment by inhibiting polymerisation of amyloid fibrils. In familial causes of amyloidosis a liver transplant can be curative.

Additional images[edit]

See also[edit]

References[edit]

  1. ^ a b c Murakami, T; Ishiguro N, Higuchi K (March 2014). "Transmission of Systemic AA Amyloidosis in Animals". Veterinary Pathology 51 (2): 363–371. doi:10.1177/0300985813511128. PMID 24280941. 
  2. ^ Kumar, Vinay (2009). Robbins & Cotran Pathologic Basis of Disease. Saunders. ISBN 1416031219. 
  3. ^ "Atlas of Pathology". 
  4. ^ Pavelka, Margit; Roth, Jürgen. Functional Ultrastructure: An Atlas of Tissue Biology and Pathology. Springer. p. 258. ISBN 3-211-83564-4. 
  5. ^ Coles LS, Young RD (2012). "Supercentenarians and transthyretin amyloidosis: the next frontier of human life extension". PREVENTATIVE MEDICINE 54 (Suppl): s9–s11. doi:10.1016/j.ypmed.2012.03.003. PMID 22579241. 
  6. ^ "Searching for the Secrets of the Super Old". Science. September 26, 2008. pp. 1764–65. Retrieved February 22, 2013. 
  7. ^ Mok KH, Pettersson J, Orrenius S, Svanborg C (March 2007). "HAMLET, protein folding, and tumor cell death". Biochem. Biophys. Res. Commun. 354 (1): 1–7. doi:10.1016/j.bbrc.2006.12.167. PMID 17223074. 
  8. ^ Pettersson-Kastberg J, Aits S, Gustafsson L, et al. (November 2008). "Can misfolded proteins be beneficial? The HAMLET case". Ann. Med. 41 (3): 1–15. doi:10.1080/07853890802502614. PMID 18985467. 
  9. ^ Hassan W, Al-Sergani H, Mourad W, Tabbaa R (2005). "Amyloid heart disease. New frontiers and insights in pathophysiology, diagnosis, and management". Tex Heart Inst J 32 (2): 178–84. PMC 1163465. PMID 16107109. 
  10. ^ Sipe JD, Benson MD, Buxbaum JN, et al. (September 2010). "Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis". Amyloid 17 (3–4): 101–104. doi:10.3109/13506129.2010.526812. PMID 21039326. 
  11. ^ a b c Table 5-12 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7.  8th edition.
  12. ^ a b [1], Karp, Judith E., ed. Amyloidosis Diagnosis and Treatment. Rochester: Humana, 2010. Online Source. .
  13. ^ a b c Dember LM (December 2006). "Amyloidosis-associated kidney disease". J. Am. Soc. Nephrol. 17 (12): 3458–71. doi:10.1681/ASN.2006050460. PMID 17093068. 

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