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{{Amyloidosis}}
{{Amyloidosis}}
{{CMG}}
{{CMG}}; {{AE}}{{SHH}}{{Sab}}
 
== Overview ==
== Overview ==
[[Amyloid]] is an abnormal insoluble [[extracellular]] [[protein]] that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In systemic amyloidosis, [[amyloid]] gradually accumulate and [[amyloid]] deposition is widespread in the viscera, [[blood vessel]] walls, and in the different [[Connective tissue|connective tissues]]. [[AL amyloidosis|Primary (AL) amyloidosis)]] is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal [[Immunoglobulin|immunoglobulin (Ig)]] [[Light chain|light chains]] that usually produced by [[plasma cell]] clones. [[AA amyloidosis|Secondary amyloidosis]] is associated with chronic [[inflammation]] (such as [[tuberculosis]] or [[rheumatoid arthritis]]). Hereditary (or familial) amyloidosis are [[Autosome|autosomal]] [[Dominance relationship|dominant]] diseases that [[inherited]] variant [[Protein|proteins]] cause the production and deposition of [[amyloid]] fibrils. Some [[Neurodegenerative disease|neurodegenerative disorders]] such as [[Parkinson's disease]], [[Alzheimer's disease|Alzheimer]], and [[Huntington's disease]] may occur in localised amyloidosis. On microscopic pathology, typical green [[birefringence]] under [[Polarization|polarized]] light after [[Congo red]] staining (appears in red under normal light).


==Pathophysiology==
== Pathophysiology ==


[[Amyloid]] is a pathological extracellular deposit composed predominantly of amyloid fibrils with characteristic morphology and pathognomonic tinctorial properties, specifically the capacity to bind [[Congo Red dye]] and then display red-green dichroism when viewed in strong cross polarised light.  Amyloid fibrils are formed from normally soluble autologous precursor proteins that have undergone misfolding and aggregated into fibrils with a common cross Beta-sheet core structure.
*[[Amyloid]] is an abnormal insoluble [[extracellular]] [[protein]] that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes.<ref name="pmid26719234">{{cite journal |vauthors=Wechalekar AD, Gillmore JD, Hawkins PN |title=Systemic amyloidosis |journal=Lancet |volume=387 |issue=10038 |pages=2641–2654 |date=June 2016 |pmid=26719234 |doi=10.1016/S0140-6736(15)01274-X |url=}}</ref>
*These abnormal [[Amyloid|amyloids]] are derived from misfolding and aggregation of normally soluble [[Protein|proteins]].
*[[Amyloid]] deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.<ref name="pmid267192342">{{cite journal |vauthors=Wechalekar AD, Gillmore JD, Hawkins PN |title=Systemic amyloidosis |journal=Lancet |volume=387 |issue=10038 |pages=2641–2654 |date=June 2016 |pmid=26719234 |doi=10.1016/S0140-6736(15)01274-X |url=}}</ref>


The deposits are rich in [[proteoglycans]] and always contain the non-fibrillar normal plasma glycoprotein, [[serum amyloid P component]] (SAP), which binds specifically to all amyloid fibrils.
===Systemic Amyloidosis===


Amyloidosis is disease caused by amyloid deposits in the tissues. The deposits may be local or systemic in distribution and acquired or hereditary in aetiology. All patients with amyloidosis have amyloid deposits in their tissues when they first present clinically. In each individual, disease is always worse when there is more amyloid present, and arrest or regression of amyloid deposition is associated with clinical benefit. Only organs or tissues in which amyloid deposits are present are directly functionally compromised, even when the amyloid fibril precursor protein is ubiquitous.
*In systemic amyloidosis, [[amyloid]] gradually accumulates and [[amyloid]] deposition is widespread in the viscera, [[blood vessel]] walls, and different [[Connective tissue|connective tissues]].<ref name="pmid23227278">{{cite journal |vauthors=Baker KR, Rice L |title=The amyloidoses: clinical features, diagnosis and treatment |journal=Methodist Debakey Cardiovasc J |volume=8 |issue=3 |pages=3–7 |date=2012 |pmid=23227278 |pmc=3487569 |doi= |url=}}</ref><ref name="pmid16409147">{{cite journal |vauthors=Pepys MB |title=Amyloidosis |journal=Annu. Rev. Med. |volume=57 |issue= |pages=223–41 |date=2006 |pmid=16409147 |doi=10.1146/annurev.med.57.121304.131243 |url=}}</ref>


In amyloidosis the link between physical presence of amyloid deposits and disease is irrefutably strong.  Pre-fibrillar protein aggregates are cytotoxic for cultured cells exposed under artefactual in vitro conditions but there is no evidence that this is pathophysiologically relevant to amyloidosis in vivo.  No clinical or pathological effects are detectable in any form of acquired or hereditary systemic amyloidosis until amyloid deposits are demonstrable, regardless of the length of time that the predisposition exists before amyloid develops.
====Primary Amyloidosis (AL)====


Clinical impairment progresses as amyloid deposits increase in size, and regression of amyloid is associated with clinical improvement and survival. If damaged organs are replaced there is no organ dysfunction, even in the face of unchanged abundance of amyloid fibril precursor proteins fully capable of aggregation and fibril formation, until new amyloid deposits form and accumulate to a critical mass. This usually takes years.  
*[[AL amyloidosis|Primary (AL) amyloidosis)]] is the most common type of amyloidosis.<ref name="pmid267192343">{{cite journal |vauthors=Wechalekar AD, Gillmore JD, Hawkins PN |title=Systemic amyloidosis |journal=Lancet |volume=387 |issue=10038 |pages=2641–2654 |date=June 2016 |pmid=26719234 |doi=10.1016/S0140-6736(15)01274-X |url=}}</ref>
*It results from aggregation and deposition of monoclonal [[Immunoglobulin|immunoglobulin (Ig)]] [[Light chain|light chains]] that are usually produced by [[plasma cell]] clones.
*Change in the [[secondary structure]] or [[tertiary structure]] of a monoclonal [[light chain]] results in abnormal folding of the [[light chain]] that abnormally form [[amyloid]] [[Fibril|fibrils]].
*This type of amyloidosis most frequently involve the [[kidney]] ([[nephrotic syndrome]]) and the [[heart]].
*In [[AL amyloidosis|primary (AL) amyloidosis]] survival rate depends on:
**Type of organ involvement ([[amyloid]] heart disease is the main prognostic factor)
**The severity of different organ involvement
**[[Hematology|Hematological]] response to treatment
*The median [[Survival analysis|survival]] of patients with [[AL amyloidosis]] is approximately 3.8 years.


There is usually no histological evidence of inflammation, or cell death or dysfunction, even in massively amyloid laden organs, and the organs continue to function until the amyloid deposits critically compromise structure and/or function.  For example, cardiac amyloid deposition impairs diastolic filling by stiffening the ventricle.
====Secondary Amyloidosis (AA)====


There is no evidence of [[cytotoxicity]] in the [[myocardium]] and the heart muscle continues to contract excellently and propel the progressively reduced stroke volume until the end.  Similarly in hereditary transthyretin amyloidosis, amyloid fibrils may accumulate over years in the vitreous humour of the eye until fibril density impairs optical clarity and causes blindness. The amyloidogenic variant [[transthyretin]] in the eye is synthesized in the choroid plexus and by the ciliary epithelium directly overlying the retina, and continuously bathes the retina.  However replacement of the amyloid laden vitreous with optically clear medium restores perfect vision in every case.  The putative toxic pre-fibrillar aggregates evidently have no deleterious effect on retinal neurones, whereas accumulation of amyloid fibrils causes blindness and their removal cures it.
*[[AA amyloidosis|Secondary amyloidosis]] occurs as a reaction to an existing illness.
*[[AA amyloidosis|Secondary amyloidosis]] is associated with chronic [[inflammation]] (such as [[tuberculosis]] or [[rheumatoid arthritis]]).<ref name="pmid116772762">{{cite journal |vauthors=Khan MF, Falk RH |title=Amyloidosis |journal=Postgrad Med J |volume=77 |issue=913 |pages=686–93 |date=November 2001 |pmid=11677276 |pmc=1742163 |doi= |url=}}</ref>
*[[AA amyloidosis|Secondary or reactive amyloidosis (AA)]] comprises approximately 45% of the systemic amyloidoses.
*[[Pathogenesis]] of [[AA amyloidosis|secondary amyloidosis]] is multifactorial, including:
**[[Primary structure]] of the [[precursor]] protein
**Acute phase response
**Nonfibril [[Protein|proteins]] ([[amyloid]] P component, [[Apolipoprotein E|apo E]], [[Glycosaminoglycan|GAGs]], [[Proteoglycan|proteoglycans]] and [[basement membrane]] [[Protein|proteins]])
**[[Receptor (biochemistry)|Receptors]]
**[[Lipid metabolism]]
**[[Protease|Proteases]]


Finally there are many clinical situations in which the local physical presence of substantial amyloid deposits alone is the only possible cause of disease and [[death]], and where reduction or removal of the deposits relieves symptoms and signs and is life saving.
====Hereditary Amyloidosis====
<ref>Amyloid and amyloidosis. Gilles Grateau, Robert A. Kyle, Martha Skinner, 2005 ISBN 0-8493-3534-5</ref>


===Systemic amyloidosis===
*Hereditary amyloidosis is an [[Autosome|autosomal]] [[Dominance relationship|dominant]] disorder.<ref name="pmid11261421">{{cite journal |vauthors=Hund E, Linke RP, Willig F, Grau A |title=Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment |journal=Neurology |volume=56 |issue=4 |pages=431–5 |date=February 2001 |pmid=11261421 |doi=10.1212/wnl.56.4.431 |url=}}</ref>
====Primary/Hereditary amyloidosis====
*It can have a heterogeneous nature of presentation and can be complicated by significant disability and mortality.<ref name="pmid28978215">{{cite journal |vauthors=Gertz MA |title=Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges |journal=Am J Manag Care |volume=23 |issue=7 Suppl |pages=S107–S112 |date=June 2017 |pmid=28978215 |doi= |url=}}</ref>
These rare hereditary disorders are usually due to [[point mutations]] in precursor proteins, and are also usually [[autosomal dominant]]ly transmitted.The precursor proteins are;
*[[Inherited]] variant [[Protein|proteins]] cause the production and deposition of [[amyloid]] fibrils.<ref name="pmid116772762" />
* [[Transthyretin]]-the most commonly implicated protein.
*Hereditary amyloidosis is due to amyloidogenic [[Mutation|mutations]] and the subsequent deposition of [[Amyloid|amyloids]] which include:
* [[Lysozyme]]
**[[Transthyretin|Transthyretin (TTR)]] (most common [[inherited]] [[mutation]])
* [[Apolipoprotein B]]
**[[Fibrinogen]]
* [[Fibrinogen]]
**[[Apolipoprotein A1]]
* [[Apolipoprotein A1]]
**[[Apolipoprotein A2]]
* [[Gelsolin]]
**[[Lysozyme]]
**[[Gelsolin]] [[Gene|genes]]


====Secondary amyloidosis====
===Organ-specific Amyloidosis===
These are far more common than the primary amyloidoses.
* ''AL amyloidosis'' ([[immunoglobulin light chains]] are the precursor protein, overproduced in [[multiple myeloma]]).  This is sometimes, confusingly and erroneously, called 'primary amyloidosis'.
* ''AA amyloidosis'' (the precursor protein is [[serum amyloid A protein]] (SAA), an [[acute-phase protein]] due to chronic [[inflammation]]).  In contrast to AL amyloid, this has previously been termed 'secondary amyloidosis'.  These occur with a wide variety of diseases associated with chronic inflammation, such as [[rheumatoid arthritis]], [[familial Mediterranean fever]] or chronic infection.
* ''Dialysis related amyloidosis'' (the precursor protein is [[beta-2-microglobulin]] which is not removed with [[dialysis]], and thus accumulates in patients with [[end stage renal failure]] on dialysis).


=== Organ-specific amyloidosis ===
*In this type of amyloidosis, [[amyloid]] deposition occurs only in the organ of origin or tissue of [[precursor]] [[protein]].
In almost all of the organ-specific pathologies, there is '''significant debate''' as to whether the amyloid plaques are the causal agent of the disease or instead a downstream consequence of a common [[idiopathic]] agent. The associated proteins are indicated in parentheses.
*[[Neurodegenerative disease|Neurodegenerative disorders]], such as [[Parkinson's disease]], [[Alzheimer's disease]], and [[Huntington's disease]], may occur in localized amyloidosis.


'''Neurological amyloid'''
*Localized amyloidoses can develop due to the deposition of [[intracellular]] and/or [[extracellular]] [[amyloid]].
* [[Alzheimer's disease]] ([[Amyloid beta|Aβ 39-43]])
**[[Huntington's disease]]: [[intracellular]] [[protein]] deposition
* [[Parkinson's disease]] ([[alpha-synuclein]])
**[[Parkinson's disease]]: [[intracellular]] [[protein]] deposition
* [[Huntington's disease]] ([[huntingtin]])
**[[Alzheimer's disease]]: [[intracellular]] ([[Tau protein]] [[Fibril|fibrils]]) and [[extracellular]] ([[amyloid]] β fibrils) deposition
* [[Transmissible spongiform encephalopathy|Transmissible spongiform encephalopathies]] caused by [[prion|prion protein]] (PrP) were sometimes classed as amyloidoses, as one of the four pathological features in diseased tissue is the presence of [[amyloid plaques]].  These diseases include
** [[Creutzfeldt-Jakob disease]] (PrP in [[cerebrum]])
** [[Kuru]] (diffuse PrP deposits in brain)
** [[Fatal Familial Insomnia]] (PrP in [[thalamus]])
** [[Bovine spongiform encephalopathy]] (PrP in [[cerebrum]] of cows)
'''Cardiovascular amyloid'''
* [[Cardiac amyloidosis]]
* See the chapter on [[CMR in Cardiac Amyloidosis]]
** Senile cardiac amyloidosis-may cause [[heart failure]]
* [[Congophilic angiopathy]]
'''Other'''
* [[Amylin]] deposition can occur in the [[pancreas]] in some cases of [[Diabetes mellitus type 2|type 2 diabetes mellitus]]


===Gross Pathology===
==Genetics==
{| align="row=3"
|-
|
|-valign="top"
|[[Image:LA Amyloid.jpg|thumb|Amyloidosis Lesion In Left Atrium: Gross natural color view of a diagnostic lesion]]
|[[Image:LA Amyloid 2.jpg|thumb|Amyloidosis Lesion In Left Atrium: Gross natural color close-up]]
|[[Image:Amyloidosis LA nodules.jpg|thumb|Amyloidosis, left atrium, endocardial nodules]]
|}


{| align="row=3"
==== Hereditary Amyloidosis ====
|-
|
|-valign="top"
|[[Image:Amyloidosis endocardial nodules.jpg|thumb|Amyloidosis, left atrium, endocardial nodules]]
|[[Image:Amyloidosis and LVH.jpg|thumb|Amyloidosis and left ventricular hypertrophy]]
|[[Image:kidneyamy.jpg|thumb|URINARY SYSTEM: Kidney, amyloidosis]]
|}


{| align="row=3"
* Hereditary amyloidosis involves [[Mutation|mutations]] in the following genes:<ref name="pmid8464497">{{cite journal |vauthors=Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CC, Terry CJ |title=Human lysozyme gene mutations cause hereditary systemic amyloidosis |journal=Nature |volume=362 |issue=6420 |pages=553–7 |date=April 1993 |pmid=8464497 |doi=10.1038/362553a0 |url=}}</ref>
|-
** LYZ gene
|
** Fibrinogen A alpha polypeptide gene
|-valign="top"
** FGA gene
|[[Image:skinamy.jpg|thumb|SKIN: AMYLOIDOSIS, PRIMARY; YELLOW LESIONS ]]
** APOA1 gene
|[[Image:tongueamy.jpg|thumb|TONGUE: PRIMARY AMYLOIDOSIS]]
** Lysozyme gene
|[[Image:thyroidgland.jpg|thumb|THYROID GLAND: AMYLOIDOSIS OF THE THYROID This illustration shows the outer aspect and cut surface of localized amyloidosis of the thyroid gland (amyloid tumor).  The gland is enlarged and bosselated and exhibits a salmon color on cross section.]]
** B2M gene
|}


{| align="row=3"
==== Primary Localized Cutaneous Amyloidosis ====
|-
|
|-valign="top"
|[[Image:lower respiratory tract.jpg|thumb|LOWER RESPIRATORY TRACT: NODULAR PARENCHYMAL AMYLOIDOSIS This nodule of amyloid shells taken out from the lung as an irregular, tan, waxy mass.]]
|[[Image:liveramy.jpg|thumb|LIVER: Amyloidosis]]
|[[Image:liverbiliaryamy.jpg|thumb|LIVER-BILIARY TRACT: Liver, amyloidosis]]
|[[Image:kidneybladderamy.jpg|thumb|KIDNEY-BLADDER-URINARY: AMYLOIDOSIS OF URINARY BLADDER <small>(Courtesy of Dr. George M. Farrow, Rochester, MN.)]]
|}


===Microscopic Pathology===
* Primary localized cutaneous amyloidosis is inherited in autosomal dominant manner.<ref name="pmid18179886">{{cite journal |vauthors=Arita K, South AP, Hans-Filho G, Sakuma TH, Lai-Cheong J, Clements S, Odashiro M, Odashiro DN, Hans-Neto G, Hans NR, Holder MV, Bhogal BS, Hartshorne ST, Akiyama M, Shimizu H, McGrath JA |title=Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis |journal=Am. J. Hum. Genet. |volume=82 |issue=1 |pages=73–80 |date=January 2008 |pmid=18179886 |pmc=2253984 |doi=10.1016/j.ajhg.2007.09.002 |url=}}</ref>
Amyloid can be diagnosed on histological examination of affected tissue.


Images shown below are courtesy of Professor Peter Anderson and published with permission. [http://www.peir.net © PEIR, University of Alabama at Birmingham, Department of Pathology]
* Primary localized cutaneous amyloidosis involves mutations in the following genes:<ref name="pmid181798862">{{cite journal |vauthors=Arita K, South AP, Hans-Filho G, Sakuma TH, Lai-Cheong J, Clements S, Odashiro M, Odashiro DN, Hans-Neto G, Hans NR, Holder MV, Bhogal BS, Hartshorne ST, Akiyama M, Shimizu H, McGrath JA |title=Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis |journal=Am. J. Hum. Genet. |volume=82 |issue=1 |pages=73–80 |date=January 2008 |pmid=18179886 |pmc=2253984 |doi=10.1016/j.ajhg.2007.09.002 |url=}}</ref>
** OSMR gene


{| align=row
== Associated Conditions ==
|-
Conditions associated with amyloidosis include:<ref name="pmid8757765">{{cite journal |vauthors=Hofstra RM, Sijmons RH, Stelwagen T, Stulp RP, Kousseff BG, Lips CJ, Steijlen PM, Van Voorst Vader PC, Buys CH |title=RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia |journal=J. Invest. Dermatol. |volume=107 |issue=2 |pages=215–8 |date=August 1996 |pmid=8757765 |doi=10.1111/1523-1747.ep12329651 |url=}}</ref>
|
|-valign="top"
|[[Image:Aldehyd Fuchsin.jpg|thumb|Heart: Amyloidosis, aldehyde fuchsin stain]]
|[[Image:Amyloidosis Kongored.jpg|thumb|Heart: Perivascular amyloid, amyloidosis, congo red showing birefringence]]
|[[Image:Perivas Amyloid.jpg|thumb|Heart: Perivascular amyloid, amyloidosis (Hematoxylin and eosin staining)]]
|[[Image:Amyloidosis, lymph node, polarizer.jpg|thumb|Congo red stain, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy]]
|}


====What is not Amyloidosis?====
* MEN2A


Several important diseases are associated with [[amyloid]] deposits but are not amyloidosis.  
== Gross Pathology ==
On gross pathology, the organs affected by amyloidosis can be characterized by the following features:
*Porcelain like or waxy appearance
*Enlargement
===Images===
[[File:Amyloidosis (4867136708).jpg|300px|left|thumb|Nodular deposits of amyloid on the pleural surfaces.<ref>By Yale Rosen from USA - Amyloidosis, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=31127928</ref>]]
[[File:Amyloidosis, Node, Gross.jpg|400px|center|thumb|Cut section of an inguinal lymph node showing firm and waxy consistency.<ref>By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377537238/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629764</ref>]]
[[File:Amyloidosis, Node, Lugol's Reaction.jpg|300px|left|thumb|A slice of the affected node (left) has turned black after treatment with Lugol's solution. A piece of normal myometrium (right) treated similarly with no reaction is also shown.<ref>By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377538012/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629740</ref>]]
<br style="clear:left">


The neuropathology of [[Alzheimer’s disease]] by definition includes intra-cerebral ABeta amyloid deposits, but it is not known whether these deposits are responsible for the neuronal cell death that causes cognitive decline; non-fibrillar ABeta aggregates may be more directly involved.  In contrast, by analogy with the notable friability of systemic blood vessels containing AL amyloid deposits, it seems likely that the cerebrovascular ABeta amyloid deposits in cerebral [[amyloid angiopathy]] are responsible for [[cerebral hemorrhage]].  
==Microscopic Pathology==
On microscopic histopathological analysis, amyloidosis is characterized by:<ref name="pmid116772762" /><ref name="pmid119640392">{{cite journal |vauthors=Röcken C, Shakespeare A |title=Pathology, diagnosis and pathogenesis of AA amyloidosis |journal=Virchows Arch. |volume=440 |issue=2 |pages=111–122 |date=February 2002 |pmid=11964039 |doi=10.1007/s00428-001-0582-9 |url=}}</ref>


Most patients with type 2 diabetes have amyloid deposits in the islets of Langerhans, which may exacerbate islet dysfunction, but amyloid is not the original cause of their diabetes.  Cerebral amyloid deposits of the prion protein are present in many forms of transmissible spongiform encephalopathy but are absent in others, including [[bovine spongiform encephalopathy]] in cows and fatal familial insomnia in humans, and amyloid is thus not essential for pathogenesis of TSE.
*Green [[birefringence]] under [[Polarization|polarized]] light after [[Congo red]] staining (appears red under normal light)
 
*Linear non-branching [[Fibril|fibrils]] (indefinite length with an approximately same diameter)
Many other diseases are associated with, and possibly caused by, protein misfolding and aggregation.  Some of these aggregates share the amyloid cross Beta-sheet fold, for example in [[Huntington’s disease]] and related poly-glutamine repeat hereditary neurodegenerative diseases, and in [[Parkinson’s disease]].
*Distinct [[X-rays|X-ray]] diffraction pattern consistent with Pauling's model of a cross-beta fibril
 
===Images===
However intracellular and intranuclear protein aggregates have very different pathogenetic effects than extracellular amyloid deposits, and are in radically different locations for drug intervention.  They are also not associated with the non-fibrillar components of amyloid deposits, the proteoglycans and SAP.  These intracellular protein aggregates are thus not amyloid and the diseases with which they are associated are not amyloidosis.  Although there may be informative similarities and parallels, especially in protein misfolding and aggregation studied in vitro, to conflate such widely different processes is misleading and potentially dangerous when extrapolated to development of therapeutic interventions.
[[File:Small bowel duodenum with amyloid deposition congo red 10X.jpg|300px|left|thumb|Small bowel duodenum with amyloid deposition Congo red.<ref>By Michael Feldman, MD, PhDUniversity of Pennsylvania School of Medicine - http://www.healcentral.org/healapp/showMetadata?metadataId=38717, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=870218</ref>]]
 
[[File:Amyloidosis, Node, Congo Red.jpg|300px|center|thumb|Amyloidosis (black arrows) in a lymph node after staining with Congo Red.<ref>By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559787/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629716</ref>]]
Other protein misfolding diseases, such as the serpinopathies, are even more remote from amyloidosis, with intracellular deposition of protein aggregates that do not share the typical amyloid cross-Beta fold and where much of the pathogenesis of disease is related to loss of normal serpin function rather than adverse effects of the aggregates.
[[File:Amyloidosis, lymph node, polarizer.jpg|300px|left|thumb|Green [[birefringence]] under [[Polarization|polarized]] light.<ref>By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559955/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629705</ref>]]
 
<br style="clear:left">
====What is SAP?====
 
SAP is a highly conserved constitutive normal trace plasma protein with specific avid calcium dependent binding to all amyloid fibrils that causes its remarkable selective concentration and persistence in amyloid deposits of all types.  
 
SAP is intrinsically resistant to proteolysis and is further stabilised by its tight binding to amyloid fibrils, which in turn stabilises the fibrils and protects them from proteolysis.  
 
SAP knockout mice show delayed and reduced deposition of experimentally induced reactive systemic amyloid. SAP is therefore a valid therapeutic target, and in vivo inhibition of SAP binding and/or depletion of circulating SAP should reduce amyloid burden.


== References ==
== References ==
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[[Category:Disease]]
[[Category:Rheumatology]]
[[Category:Cardiology]]
[[Category:Mature chapter]]
[[Category:Metabolic disorders]]
[[Category:Inborn errors of metabolism]]
[[Category:Endocrinology]]

Latest revision as of 19:03, 29 October 2019

Amyloidosis Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]Sabawoon Mirwais, M.B.B.S, M.D.[3]

Overview

Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In systemic amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera, blood vessel walls, and in the different connective tissues. Primary (AL) amyloidosis) is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that usually produced by plasma cell clones. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis). Hereditary (or familial) amyloidosis are autosomal dominant diseases that inherited variant proteins cause the production and deposition of amyloid fibrils. Some neurodegenerative disorders such as Parkinson's disease, Alzheimer, and Huntington's disease may occur in localised amyloidosis. On microscopic pathology, typical green birefringence under polarized light after Congo red staining (appears in red under normal light).

Pathophysiology

  • Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes.[1]
  • These abnormal amyloids are derived from misfolding and aggregation of normally soluble proteins.
  • Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.[2]

Systemic Amyloidosis

Primary Amyloidosis (AL)

Secondary Amyloidosis (AA)

Hereditary Amyloidosis

Organ-specific Amyloidosis

Genetics

Hereditary Amyloidosis

  • Hereditary amyloidosis involves mutations in the following genes:[9]
    • LYZ gene
    • Fibrinogen A alpha polypeptide gene
    • FGA gene
    • APOA1 gene
    • Lysozyme gene
    • B2M gene

Primary Localized Cutaneous Amyloidosis

  • Primary localized cutaneous amyloidosis is inherited in autosomal dominant manner.[10]
  • Primary localized cutaneous amyloidosis involves mutations in the following genes:[11]
    • OSMR gene

Associated Conditions

Conditions associated with amyloidosis include:[12]

  • MEN2A

Gross Pathology

On gross pathology, the organs affected by amyloidosis can be characterized by the following features:

  • Porcelain like or waxy appearance
  • Enlargement

Images

Nodular deposits of amyloid on the pleural surfaces.[13]
Cut section of an inguinal lymph node showing firm and waxy consistency.[14]
A slice of the affected node (left) has turned black after treatment with Lugol's solution. A piece of normal myometrium (right) treated similarly with no reaction is also shown.[15]


Microscopic Pathology

On microscopic histopathological analysis, amyloidosis is characterized by:[6][16]

  • Green birefringence under polarized light after Congo red staining (appears red under normal light)
  • Linear non-branching fibrils (indefinite length with an approximately same diameter)
  • Distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril

Images

Small bowel duodenum with amyloid deposition Congo red.[17]
Amyloidosis (black arrows) in a lymph node after staining with Congo Red.[18]
Green birefringence under polarized light.[19]


References

  1. ↑ Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  2. ↑ Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  3. ↑ Baker KR, Rice L (2012). "The amyloidoses: clinical features, diagnosis and treatment". Methodist Debakey Cardiovasc J. 8 (3): 3–7. PMC 3487569. PMID 23227278.
  4. ↑ Pepys MB (2006). "Amyloidosis". Annu. Rev. Med. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
  5. ↑ Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  6. ↑ 6.0 6.1 6.2 Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
  7. ↑ Hund E, Linke RP, Willig F, Grau A (February 2001). "Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment". Neurology. 56 (4): 431–5. doi:10.1212/wnl.56.4.431. PMID 11261421.
  8. ↑ Gertz MA (June 2017). "Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges". Am J Manag Care. 23 (7 Suppl): S107–S112. PMID 28978215.
  9. ↑ Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CC, Terry CJ (April 1993). "Human lysozyme gene mutations cause hereditary systemic amyloidosis". Nature. 362 (6420): 553–7. doi:10.1038/362553a0. PMID 8464497.
  10. ↑ Arita K, South AP, Hans-Filho G, Sakuma TH, Lai-Cheong J, Clements S, Odashiro M, Odashiro DN, Hans-Neto G, Hans NR, Holder MV, Bhogal BS, Hartshorne ST, Akiyama M, Shimizu H, McGrath JA (January 2008). "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis". Am. J. Hum. Genet. 82 (1): 73–80. doi:10.1016/j.ajhg.2007.09.002. PMC 2253984. PMID 18179886.
  11. ↑ Arita K, South AP, Hans-Filho G, Sakuma TH, Lai-Cheong J, Clements S, Odashiro M, Odashiro DN, Hans-Neto G, Hans NR, Holder MV, Bhogal BS, Hartshorne ST, Akiyama M, Shimizu H, McGrath JA (January 2008). "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis". Am. J. Hum. Genet. 82 (1): 73–80. doi:10.1016/j.ajhg.2007.09.002. PMC 2253984. PMID 18179886.
  12. ↑ Hofstra RM, Sijmons RH, Stelwagen T, Stulp RP, Kousseff BG, Lips CJ, Steijlen PM, Van Voorst Vader PC, Buys CH (August 1996). "RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia". J. Invest. Dermatol. 107 (2): 215–8. doi:10.1111/1523-1747.ep12329651. PMID 8757765.
  13. ↑ By Yale Rosen from USA - Amyloidosis, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=31127928
  14. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377537238/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629764
  15. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377538012/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629740
  16. ↑ Röcken C, Shakespeare A (February 2002). "Pathology, diagnosis and pathogenesis of AA amyloidosis". Virchows Arch. 440 (2): 111–122. doi:10.1007/s00428-001-0582-9. PMID 11964039.
  17. ↑ By Michael Feldman, MD, PhDUniversity of Pennsylvania School of Medicine - http://www.healcentral.org/healapp/showMetadata?metadataId=38717, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=870218
  18. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559787/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629716
  19. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559955/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629705

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