View source for Secondary amyloidosis pathophysiology

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{{Secondary amyloidosis}}
{{CMG}}; {{AE}} {{Sahar}} {{SHH}} {{Sab}}
== Overview ==
AA [[amyloid]] is an abnormal insoluble [[extracellular]] [[protein]] derived from the spontaneous aggregation of fibrils composed of misfolded [[proteins]], called amyloid precursors. In secondary amyloidosis, the [[amyloid]] precursor is SAA, an [[acute phase reactant]], encoded by SAA 1&2 [[genes]]. In secondary amyloidosis, intermediate products of SAA [[metabolism]] tend to aggregate and form protofilaments that accumulate within [[extracellular space]] and form the insoluble [[amyloid]] deposits. Secondary amyloidosis is associated with chronic [[inflammation]] (such as [[tuberculosis]] or [[rheumatoid arthritis]]).
== Pathophysiology ==
*AA [[amyloid]] is an abnormal insoluble [[extracellular]] [[protein]] derived from the spontaneous aggregation of fibrils composed of misfolded [[proteins]], called [[amyloid]] precursors.<ref name="JayaramanGantz2017">{{cite journal|last1=Jayaraman|first1=Shobini|last2=Gantz|first2=Donald L.|last3=Haupt|first3=Christian|last4=Gursky|first4=Olga|title=Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis|journal=Proceedings of the National Academy of Sciences|volume=114|issue=32|year=2017|pages=E6507–E6515|issn=0027-8424|doi=10.1073/pnas.1707120114}}</ref><ref name="KisilevskyRaimondi2016">{{cite journal|last1=Kisilevsky|first1=Robert|last2=Raimondi|first2=Sara|last3=Bellotti|first3=Vittorio|title=Historical and Current Concepts of Fibrillogenesis and In vivo Amyloidogenesis: Implications of Amyloid Tissue Targeting|journal=Frontiers in Molecular Biosciences|volume=3|year=2016|issn=2296-889X|doi=10.3389/fmolb.2016.00017}}</ref>
*In secondary amyloidosis, the amyloid precursor is SAA, an [[acute phase reactant]], encoded by SAA 1&2 [[genes]].
*Normally, SAA increased during the [[inflammatory process]] and then taken up by [[macrophages]] and degraded within [[Lysosome|lysosomal]] compartments.
*In [[patients]] with secondary amyloidosis, intermediate products of SAA [[metabolism]] tend to aggregate and form protofilaments.
*These protofilaments with other [[protein]] materials accumulate within [[extracellular space]] and form the insoluble [[amyloid]] deposits.
*[[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>
*This algorithm explains the simplified [[pathogenesis]] of secondary amyloidosis.
<br>
{{familytree/start |summary=Sample 1}}
{{familytree | | | | | E04 | | | | |E04=[[Infection]]/[[Inflammation]]}}
{{familytree | | | | | |!| | | | }}
{{familytree | | | | | E05 | | | | |E05=Increased production of [[IL-1]]/[[IL-6]]/[[TNF-α]]}}
{{familytree | | | | | |!| | | | }}
{{familytree | | | | | C05 | | | | |C05=Upregulation of [[hepatic]] serum amyloid A production}}
{{familytree | | | | | |!| | | | | | }}
{{familytree | | | | | C04 | | | | |C04=SAA production uptake by [[macrophages]]}}
{{familytree | | | | | |!| | | | }}
{{familytree | | | | | D05 | | | | |D05=C-terminal cleavage of SAA}}
{{familytree | | | | | |!| | | | }}
{{familytree | | | | | F01 | | | | |F01=β-sheet configuration of SAA}}
{{familytree | | | | | |!| | | | }}
{{familytree | | | | | G05 | | | | |G05=Fibril deposition in [[extracellular space]]}}
{{familytree | | | | | |!| | | | }}
{{familytree | | | | | H05 | | | | |H05=Binding of [[glycosaminoglycan]], serum amyloid P, and [[lipid]] components}}
{{familytree | | | | | |!| | | | }}
{{familytree | | | | | K05 | | | | |K05=Resistant to proteolysis}}
{|
! colspan="2" style="background:#DCDCDC;" align="center" + |The above algorithm is adopted from International Journal of Nephrology and Renovascular Disease<ref>{{cite journal |vauthors=Rumjon A, Coats T, Javaid MM |title=Review of eprodisate for the treatment of renal disease in AA amyloidosis |journal=Int J Nephrol Renovasc Dis |volume=5 |issue= |pages=37–43 |date=2012 |pmid=22427728 |pmc=3304340 |doi=10.2147/IJNRD.S19165 |url=}}</ref>
|- 
|}

== Associated Conditions ==
*[[Conditions]] associated with AA amyloidosis include:<ref name="BlankHegenbart2018">{{cite journal|last1=Blank|first1=Norbert|last2=Hegenbart|first2=Ute|last3=Dietrich|first3=Sascha|last4=Brune|first4=Maik|last5=Beimler|first5=Jörg|last6=Röcken|first6=Christoph|last7=Müller-Tidow|first7=Carsten|last8=Lorenz|first8=Hanns-Martin|last9=Schönland|first9=Stefan O.|title=Obesity is a significant susceptibility factor for idiopathic AA amyloidosis|journal=Amyloid|volume=25|issue=1|year=2018|pages=37–45|issn=1350-6129|doi=10.1080/13506129.2018.1429391}}</ref><ref name="van der HilstYamada2008">{{cite journal|last1=van der Hilst|first1=J. C. H.|last2=Yamada|first2=T.|last3=Op den Camp|first3=H. J. M.|last4=van der Meer|first4=J. W. M.|last5=Drenth|first5=J. P. H.|last6=Simon|first6=A.|title=Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis|journal=Rheumatology|volume=47|issue=11|year=2008|pages=1651–1654|issn=1462-0324|doi=10.1093/rheumatology/ken371}}</ref><ref name="PapaDoglio2017">{{cite journal|last1=Papa|first1=Riccardo|last2=Doglio|first2=Matteo|last3=Lachmann|first3=Helen J.|last4=Ozen|first4=Seza|last5=Frenkel|first5=Joost|last6=Simon|first6=Anna|last7=Neven|first7=Bénédicte|last8=Kuemmerle-Deschner|first8=Jasmin|last9=Ozgodan|first9=Huri|last10=Caorsi|first10=Roberta|last11=Federici|first11=Silvia|last12=Finetti|first12=Martina|last13=Trachana|first13=Maria|last14=Brunner|first14=Jurgen|last15=Bezrodnik|first15=Liliana|last16=Pinedo Gago|first16=Mari Carmen|last17=Maggio|first17=Maria Cristina|last18=Tsitsami|first18=Elena|last19=Al Suwairi|first19=Wafaa|last20=Espada|first20=Graciela|last21=Shcherbina|first21=Anna|last22=Aksu|first22=Guzide|last23=Ruperto|first23=Nicolino|last24=Martini|first24=Alberto|last25=Ceccherini|first25=Isabella|last26=Gattorno|first26=Marco|title=A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry|journal=Orphanet Journal of Rare Diseases|volume=12|issue=1|year=2017|issn=1750-1172|doi=10.1186/s13023-017-0720-3}}</ref>
{| class="wikitable"
|+
| colspan="2" style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Associated Conditions'''
|-
! style="background: #DCDCDC; padding: 5px; text-align: center;" |'''Conditions'''
|'''Examples'''
|-
| style="background: #DCDCDC; padding: 5px; text-align: left;" |'''Chronic infections'''
|
*[[Tuberculosis]]
*[[Leprosy]]
*Whipple Disease
*[[Osteomyelitis]]
*[[Chronic pyelonephritis]]
*[[Subacute bacterial endocarditis]]
*Chronic cutaneous ulcers
|-
| style="background: #DCDCDC; padding: 5px; text-align: left;" |'''Monogenic [[Periodic fever syndrome|periodic fever syndromes]]'''
|<br />
*[[TNF receptor associated periodic syndrome|TNF Receptor associated periodic syndrome]] ([[TRAPS]])
*[[CAPS|Cryopyrin-associated periodic fever syndrome]]
*[[Mevalonate kinase deficiency]]
*[[Familial mediterranean fever]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: left;" |'''Conditions predisposing to recurrent infections'''
|
*[[Cystic fibrosis]]
*[[Bronchiectasis]]
*[[Kartagener syndrome]]
*[[Epidermolysis bullosa]]
*[[IV drug abusers|Injected drug abuse]]
*[[Jejuno-ileal bypass]]
*[[Paraplegia]]
*[[Sickle cell anemia]]
*[[Immunodeficiency]]
*[[Common variable immunodeficiency]]
*[[Cyclic neutropenia]]
*[[Hyperimmunoglobulin M syndrome]]
*[[Hypogammaglobulinemia]]
*[[X-linked agammaglobulinemia|Sex-linked agammaglobulinemia]]
*[[Human Immunodeficiency Virus|Human immunodeficiency virus]]/[[AIDS]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: left;" |'''Neoplasia''' 
|
*[[Adenocarcinoma]]
*[[Basal cell carcinoma]]
*[[Carcinoid tumors|Carcinoid tumor]]
*[[Castleman disease]]
*[[Gastrointestinal stromal tumor]]
*[[Hairy cell leukemia]]
*[[Hepatic adenoma]]
*[[Hodgkin disease]]
*[[Mesothelioma]]
*[[Renal cell carcinoma]]
*[[Sarcoma]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: left;" |'''Inflammatory Arthritis''' 
|
*Adult-onset Still disease
*[[Ankylosing spondylitis]]
*[[Juvenile idiopathic arthritis]]
*[[Psoriatic arthropathy]]
*[[Reiter's syndrome|Reiter syndrome]]
*[[Rheumatoid arthritis]]
*[[Gout]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: left;" |'''Systemic [[Vasculitis]]'''
|
*Antineutrophil cytoplasmic antibody-associated vasculitis
*[[Behcet disease]]
*[[Giant cell arteritis]]
*[[Polyarteritis nodosa]]
*[[Polymyalgia rheumatica]]
*[[Systemic lupus erythematosus]]
*[[Takayasu arteritis]]
*[[Inflammatory Bowel Disease]]
*[[Ulcerative colitis]]
*[[Crohn disease]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: left;" |'''Others'''
|
*[[Atrial myxoma]]
*Inflammatory abdominal aortic aneurism
*[[Retroperitoneal fibrosis]]
*[[SAPHO syndrome|SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome]]
*[[Sarcoidosis]]
*[[Sinus histiocytosis with massive lymphadenopathy]]
|-
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== 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>]]
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==Microscopic Pathology==
On microscopic [[histopathological]] analysis, aa 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

On electron microscopy, [[amyloid]] fibrils have the following characteristics:<ref name="CloseNeumann2018">{{cite journal|last1=Close|first1=William|last2=Neumann|first2=Matthias|last3=Schmidt|first3=Andreas|last4=Hora|first4=Manuel|last5=Annamalai|first5=Karthikeyan|last6=Schmidt|first6=Matthias|last7=Reif|first7=Bernd|last8=Schmidt|first8=Volker|last9=Grigorieff|first9=Nikolaus|last10=Fändrich|first10=Marcus|title=Physical basis of amyloid fibril polymorphism|journal=Nature Communications|volume=9|issue=1|year=2018|issn=2041-1723|doi=10.1038/s41467-018-03164-5}}</ref>
*10 to 15 nm diameter
*Straight, rigid, and nonbranching
*Composed of twisted protofilaments
===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>]]
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== References ==
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