Familial ATTR amyloidosis pathophysiology: Difference between revisions

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===Pathogenesis===
===Pathogenesis===
*[[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>
*It is understood that amyloidosis is the result of deposition of [[Amyloid]].<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>
*Amyloid is an abnormal insoluble [[extracellular]] [[protein]] which may cause organic dysfunction and a wide variety of clinical syndromes.
*These abnormal [[Amyloid|amyloids]] are derived from misfolding and aggregation of normally soluble [[Protein|proteins]].
*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>
*[[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>
*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>
 
*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>
==Genetics==
*[[Inherited]] variant [[Protein|proteins]] cause the production and deposition of [[amyloid]] fibrils.<ref name="pmid116772762" />
 
*Hereditary amyloidosis is due to amyloidogenic [[Mutation|mutations]] and the subsequent deposition of [[Amyloid|amyloids]] which include:
* Familial ATTR amyloidosis is transmitted in [[Autosome|autosomal]] [[Dominance relationship|dominant]] pattern but it can have a heterogeneous nature of presentation.<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><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><ref name="pmid116772762" />
**[[Transthyretin|Transthyretin (TTR)]] (most common [[inherited]] [[mutation]])
 
* Genes involved in the pathogenesis of Familial ATTR amyloidosis include:
** [[Transthyretin|Transthyretin (TTR)]] (most common [[inherited]] [[mutation]])
**[[Fibrinogen]]
**[[Fibrinogen]]
**[[Apolipoprotein A1]]
**[[Apolipoprotein A1]]
Line 47: Line 50:
**[[Lysozyme]]
**[[Lysozyme]]
**[[Gelsolin]] [[Gene|genes]]
**[[Gelsolin]] [[Gene|genes]]
*The exact pathogenesis of [disease name] is not completely understood.
OR
*It is understood that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
*The progression to [disease name] usually involves the [molecular pathway].
*The pathophysiology of [disease/malignancy] depends on the histological subtype.
==Genetics==
[Disease name] is transmitted in [mode of genetic transmission] pattern.
OR
Genes involved in the pathogenesis of [disease name] include:
*[Gene1]
*[Gene2]
*[Gene3]
OR
The development of [disease name] is the result of multiple genetic mutations such as:
*[Mutation 1]
*[Mutation 2]
*[Mutation 3]


==Associated Conditions==
==Associated Conditions==
Conditions associated with [disease name] include:
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>


*[Condition 1]
* MEN2A
*[Condition 2]
*[Condition 3]


==Gross Pathology==
==Gross Pathology==
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
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">


==Microscopic Pathology==
==Microscopic Pathology==
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
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>
 
*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)
*Distinct [[X-rays|X-ray]] diffraction pattern consistent with Pauling's model of a cross-beta fibril
===Images===
[[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>]]
[[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">


==References==
==References==

Latest revision as of 22:57, 29 October 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR


[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Pathogenesis

  • It is understood that amyloidosis is the result of deposition of Amyloid.[1]
  • Amyloid is an abnormal insoluble extracellular protein which may cause organic dysfunction and a wide variety of clinical syndromes.
  • 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]

Genetics

  • Familial ATTR amyloidosis is transmitted in autosomal dominant pattern but it can have a heterogeneous nature of presentation.[3][4][5]

Associated Conditions

Conditions associated with amyloidosis include:[6]

  • 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.[7]
Cut section of an inguinal lymph node showing firm and waxy consistency.[8]
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.[9]


Microscopic Pathology

On microscopic histopathological analysis, amyloidosis is characterized by:[5][10]

  • 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.[11]
Amyloidosis (black arrows) in a lymph node after staining with Congo Red.[12]
Green birefringence under polarized light.[13]


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. ↑ 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.
  4. ↑ Gertz MA (June 2017). "Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges". Am J Manag Care. 23 (7 Suppl): S107–S112. PMID 28978215.
  5. ↑ 5.0 5.1 Invalid <ref> tag; no text was provided for refs named pmid116772762
  6. ↑ 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.
  7. ↑ By Yale Rosen from USA - Amyloidosis, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=31127928
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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.
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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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