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==Overview==
==Overview==
In 1639, Nicolaus Fontanus [[Autopsy|autopsied]] a young man who had [[ascites|ascitis]], [[jaundice]], [[liver abscess]] and [[splenomegaly]] and his report has been the first description of amyloidosis. and in 1959, Cohen and Calkins assessed an ultra-thin sections of amyloidotic tissues by [[Electron microscope|electron microscopic]] examination. Amyloidosis may be classified based on [[precursor]] of amyloidogenic [[protein]] into different subtypes, include AL amyloidosis ([[Light chain|Light chains]] of [[Immunoglobulin|immunoglobulines]]), AA amyloidosis ([[Serum amyloid A|Serum amyloid A protein]]), AF amyloidosis (Mutant [[transthyretin]], [[Apolipoprotein A1|A1-apolipoprotein,]] [[gelsolin]], [[fibrinogen]], etc.), ATTRwt amyloidosis (Wild-type [[transthyretin]]), and AH amyloidosis (ß2-microglobulin). Amyloidosis also may classified by their extension of organ involvement as systemic amyloidosis ([[AL amyloidosis|primary amyloidosis]], [[AA amyloidosis|secondary amyloidosis]], hereditary amyloidosis) and Organ-specific amyloidosis ([[cardiac amyloidosis]], [[Hepatic amyloidosis with intrahepatic cholestasis|hepatic amyloidosis]], [[renal amyloidosis]], etc.). [[Amyloid]] is an abnormal insoluble [[extracellular]] [[protein]] that deposits in the different tissues and causes organic dysfunction. These abnormal [[Amyloid|amyloids]] derived from misfolding and aggregation of normally soluble [[Protein|proteins]]. 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]]. In organ-specific amyloidoses, [[amyloid]] deposition occurs only in the origin organ or tissue of [[precursor]] [[protein]]. In microscopy pathology of amyloidosis, [[amyloid]] is detectable as typical green [[birefringence]] under [[Polarization|polarized]] light after [[Congo red]] staining, linear non-branching [[Fibril|fibrils]], distinct [[X-rays|X-ray]] diffraction pattern consistent with Pauling's model of a cross-beta fibril.
<br />


== Historical Perspective ==
== Historical Perspective ==
*In 1639, Nicolaus Fontanus [[Autopsy|autopsied]] a young man who had [[ascites|ascitis]], [[jaundice]], [[liver abscess]] and [[splenomegaly]] and his report has been the first description of amyloidosis.
*In 1639, Nicolaus Fontanus [[Autopsy|autopsied]] a young man who had [[ascites|ascitis]], [[jaundice]], [[liver abscess]] and [[splenomegaly]] and his report has been the first description of amyloidosis.
*In 1854, Rudolph Virchow introduced the term of [[amyloid]] as an macroscopic abnormality in some tissues.
*In 1854, Rudolph Virchow introduced the term of [[amyloid]] as an macroscopic abnormality in some tissues.
*In 1867, Weber reported the first case of amyloidosis associated with [[multiple myeloma]].<ref name="pmid218384133">{{cite journal |vauthors=Kyle RA |title=Amyloidosis: a brief history |journal=Amyloid |volume=18 Suppl 1 |issue= |pages=6–7 |date=June 2011 |pmid=21838413 |doi=10.3109/13506129.2011.574354001 |url=}}</ref>
*In 1867, Weber reported the first case of amyloidosis associated with [[multiple myeloma]].
*In 1922, Bennhold introduced [[Congo red|Congo red staining]] of [[amyloid]] that remains the [[Gold standard (test)|gold standard]] for [[diagnosis]].
*In 1922, Bennhold introduced [[Congo red|Congo red staining]] of [[amyloid]] that remains the [[Gold standard (test)|gold standard]] for [[diagnosis]].
*In 1959, Cohen and Calkins used ultra-thin sections of amyloidotic tissues and assessed by [[Electron microscope|electron microscopic]] examination, explained the presence of non-branching [[Fibril|fibrils]] with indeterminate length and variable width.<ref name="pmid10940217">{{cite journal |vauthors=Sipe JD, Cohen AS |title=Review: history of the amyloid fibril |journal=J. Struct. Biol. |volume=130 |issue=2-3 |pages=88–98 |date=June 2000 |pmid=10940217 |doi=10.1006/jsbi.2000.4221 |url=}}</ref><ref name="pmid218384133">{{cite journal |vauthors=Kyle RA |title=Amyloidosis: a brief history |journal=Amyloid |volume=18 Suppl 1 |issue= |pages=6–7 |date=June 2011 |pmid=21838413 |doi=10.3109/13506129.2011.574354001 |url=}}</ref>
*In 1959, Cohen and Calkins used ultra-thin sections of amyloidotic tissues and assessed by [[Electron microscope|electron microscopic]] examination, explained the presence of non-branching [[Fibril|fibrils]] with indeterminate length and variable width.<ref name="pmid218384133">{{cite journal |vauthors=Kyle RA |title=Amyloidosis: a brief history |journal=Amyloid |volume=18 Suppl 1 |issue= |pages=6–7 |date=June 2011 |pmid=21838413 |doi=10.3109/13506129.2011.574354001 |url=}}</ref>


== Classification ==
== PClassification ==


=== Amyloidosis may be classified based on [[precursor]] of amyloidogenic [[protein]] into different subtypes, include: ===
=== Amyloidosis may be classified based on [[precursor]] of amyloidogenic [[protein]] into different subtypes, include: ===
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== 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.
*
*These abnormal [[Amyloid|amyloids]] 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.
===Systemic Amyloidosis===
*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]].<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>
====Primary Amyloidosis (AL)====
*[[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.
*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]] (usually [[proteinuria]] with the [[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 organs involvement
**[[Hematology|Haematological]] response to treatment
*The median [[Survival analysis|survival]] of patients with [[AL amyloidosis]] is aproximately 3.8 years.
For more information about primary amyloidosis click [[AL amyloidosis|'''here''']].


====Secondary Amyloidosis (AA)====
*[[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)]] is approximately 45% of all systemic amyloidosis.
*[[Pathogenesis]] of [[AA amyloidosis|secondary amyloidosis]] is multifactorial that include:
**[[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]]
For more information about secondary amyloidosis click '''[[AA amyloidosis|here]]'''.
====Hereditary Amyloidosis====
*Hereditary (or familial) amyloidosis are [[Autosome|autosomal]] [[Dominance relationship|dominant]] diseases that [[inherited]] variant [[Protein|proteins]] cause the production and deposition of [[amyloid]] fibrils.<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>
*Hereditary amyloidosis are due to amyloidogenic [[Mutation|mutations]] and subsequently deposition of [[Amyloid|amyloids]], include:
**[[Transthyretin|Transthyretin (TTR)]] (most common [[inherited]] [[mutation]])
**[[Fibrinogen]]
**[[Apolipoprotein A1]]
**[[Apolipoprotein A2]]
**[[Lysozyme]]
**[[Gelsolin]] [[Gene|genes]]
===Organ-specific Amyloidosis===
*In this type of amyloidoses, [[amyloid]] deposition occurs only in the origin organ or tissue of [[precursor]] [[protein]].
*Some [[Neurodegenerative disease|neurodegenerative disorders]] such as [[Parkinson's disease]], [[Alzheimer's disease|Alzheimer]], and [[Huntington's disease]] may occur in localised amyloidosis.
*Localised amyloidoses can accure due to deposition of [[intracellular]] and/or [[extracellular]] [[amyloid]].
**[[Huntington's disease]]: [[intracellular]] [[protein]] deposition
**[[Parkinson's disease]]: [[intracellular]] [[protein]] deposition
**[[Alzheimer's disease]]: [[intracellular]] ([[Tau protein]] [[Fibril|fibrils]]) and [[extracellular]] ([[amyloid]] β fibrils) deposition
===Microscopic Pathology===
In microscopy pathology of amyloidosis, [[amyloid]] is detectable as:<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><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>
*Typical green [[birefringence]] under [[Polarization|polarized]] light after [[Congo red]] staining (appears in 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
*
*


==Epidemiology and Demographics==
== Natural History, Complications and Prognosis ==
===Incidence===
 
*The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide.<ref name="pmid1167727622">{{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>
 
===Prevalence===
 
*The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
*In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
*The prevalence of [disease/malignancy] is estimated to be [number] cases annually.
 
===Mortality rate===
 
*The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries.<ref name="pmid164091472">{{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>


=== Age===
*In amyloidosis, insoluble fibrils of amyloid are deposited in body organs, causing organ dysfunction and eventually death.<ref name="pmid232272782">{{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>
*In AL amyloidosis untreated individuals have the worst prognosis. In this group of patients median survival is one to two years.<ref name="pmid11677276">{{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>


*In amyloidosis, the mean age of presentation is 55-60 years.<ref name="pmid214940832">{{cite journal |vauthors=Shin YM |title=Hepatic amyloidosis |journal=Korean J Hepatol |volume=17 |issue=1 |pages=80–3 |date=March 2011 |pmid=21494083 |pmc=3304630 |doi=10.3350/kjhep.2011.17.1.80 |url=}}</ref>
In patients with amyloidosis the most frequent complications include:<ref name="pmid26155101">{{cite journal |vauthors=Jerzykowska S, Cymerys M, Gil LA, Balcerzak A, Pupek-Musialik D, Komarnicki MA |title=Primary systemic amyloidosis as a real diagnostic challenge - case study |journal=Cent Eur J Immunol |volume=39 |issue=1 |pages=61–6 |date=2014 |pmid=26155101 |pmc=4439975 |doi=10.5114/ceji.2014.42126 |url=}}</ref>


===Race===
*Heart failure
*Nephrotic syndrome
*Hepatomegaly
*Peripheral neuropathy


*Hereditary amyloidosis subtypes include a substitution of an amino acid that is detected in approximately 4% of the black population.<ref name="pmid116772763">{{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>
In primary (AL) amyloidosis survival rate depends on:<ref name="pmid22909024">{{cite journal |vauthors=Desport E, Bridoux F, Sirac C, Delbes S, Bender S, Fernandez B, Quellard N, Lacombe C, Goujon JM, Lavergne D, Abraham J, Touchard G, Fermand JP, Jaccard A |title=Al amyloidosis |journal=Orphanet J Rare Dis |volume=7 |issue= |pages=54 |date=August 2012 |pmid=22909024 |pmc=3495844 |doi=10.1186/1750-1172-7-54 |url=}}</ref>
*[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].


===Gender ===
*Type of organ involvement (amyloid heart disease is the main prognostic factor)
*The severity of different organs involvement
* Haematological response to treatment


*Men are more commonly affected by amyloidosis than women.<ref name="pmid21494083">{{cite journal |vauthors=Shin YM |title=Hepatic amyloidosis |journal=Korean J Hepatol |volume=17 |issue=1 |pages=80–3 |date=March 2011 |pmid=21494083 |pmc=3304630 |doi=10.3350/kjhep.2011.17.1.80 |url=}}</ref>
*The median survival of patients with AL amyloidosis is aproximately 3.8 years.<ref name="pmid21483018">{{cite journal |vauthors=Merlini G, Seldin DC, Gertz MA |title=Amyloidosis: pathogenesis and new therapeutic options |journal=J. Clin. Oncol. |volume=29 |issue=14 |pages=1924–33 |date=May 2011 |pmid=21483018 |pmc=3138545 |doi=10.1200/JCO.2010.32.2271 |url=}}</ref>
*In primary (AL) amyloidosis 27% of patients dying within 1 year from diagnosis.
* The major determinant of outcome in amyloidosis is the extent of cardiac involvement.
**Cardiac amyloidosis is the cause of death in 75% of the patients who died, including sudden death in 25%.


==Case Studies==
==Case Studies==

Revision as of 17:08, 24 October 2019

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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]

Overview


Historical Perspective

PClassification

Amyloidosis may be classified based on precursor of amyloidogenic protein into different subtypes, include:

Type Amyloidogenic protein/ fibril Clinical syndrome
AL (primary amyloidosis) Light chains of immunoglobulines (most common type) Monoclonal gammopathy
AA (secondary amyloidosis) Serum amyloid A protein Chronic inflammatory diseases
AF Mutant transthyretin, A1-apolipoprotein, gelsolin, fibrinogen, etc. Familial polyneuropathy/cardiomyopathy/nephropathy
ATTRwt Wild-type transthyretin Senile restrictive cardiomyopathy _ Transthyretin-related amyloidosis wild-type
AH ß2-microglobulin Long-term hemodialysis

Amyloidosis also may classified by their extension of organ involvement as below:

Classification subtypes Causes Important clinical findings
Systemic amyloidosis Primary amyloidosis (AL)
Secondary amyloidosis (AA)
Hereditary amyloidosis
Organ-specific amyloidosis Renal amyloidosis
Cardiac amyloidosis
Hepatic amyloidosis
Amyloid neuropathy
Gastrointestinal amyloidosis

Natural History, Complications and Prognosis

  • In amyloidosis, insoluble fibrils of amyloid are deposited in body organs, causing organ dysfunction and eventually death.[2]
  • In AL amyloidosis untreated individuals have the worst prognosis. In this group of patients median survival is one to two years.[3]

In patients with amyloidosis the most frequent complications include:[4]

  • Heart failure
  • Nephrotic syndrome
  • Hepatomegaly
  • Peripheral neuropathy

In primary (AL) amyloidosis survival rate depends on:[5]

  • Type of organ involvement (amyloid heart disease is the main prognostic factor)
  • The severity of different organs involvement
  • Haematological response to treatment
  • The median survival of patients with AL amyloidosis is aproximately 3.8 years.[6]
  • In primary (AL) amyloidosis 27% of patients dying within 1 year from diagnosis.
  • The major determinant of outcome in amyloidosis is the extent of cardiac involvement.
    • Cardiac amyloidosis is the cause of death in 75% of the patients who died, including sudden death in 25%.

Case Studies

Case #1

  1. ↑ Kyle RA (June 2011). "Amyloidosis: a brief history". Amyloid. 18 Suppl 1: 6–7. doi:10.3109/13506129.2011.574354001. PMID 21838413.
  2. ↑ Baker KR, Rice L (2012). "The amyloidoses: clinical features, diagnosis and treatment". Methodist Debakey Cardiovasc J. 8 (3): 3–7. PMC 3487569. PMID 23227278.
  3. ↑ Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
  4. ↑ Jerzykowska S, Cymerys M, Gil LA, Balcerzak A, Pupek-Musialik D, Komarnicki MA (2014). "Primary systemic amyloidosis as a real diagnostic challenge - case study". Cent Eur J Immunol. 39 (1): 61–6. doi:10.5114/ceji.2014.42126. PMC 4439975. PMID 26155101.
  5. ↑ Desport E, Bridoux F, Sirac C, Delbes S, Bender S, Fernandez B, Quellard N, Lacombe C, Goujon JM, Lavergne D, Abraham J, Touchard G, Fermand JP, Jaccard A (August 2012). "Al amyloidosis". Orphanet J Rare Dis. 7: 54. doi:10.1186/1750-1172-7-54. PMC 3495844. PMID 22909024.
  6. ↑ Merlini G, Seldin DC, Gertz MA (May 2011). "Amyloidosis: pathogenesis and new therapeutic options". J. Clin. Oncol. 29 (14): 1924–33. doi:10.1200/JCO.2010.32.2271. PMC 3138545. PMID 21483018.
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