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| __NOTOC__ | | __NOTOC__ |
| {{Amyloidosis}} | | {{Amyloidosis}} |
| {{CMG}} | | {{CMG}}; {{AE}} {{SHH}} |
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| == Overview == | | == Overview == |
| | Hereditary amyloidosis can be caused by [[genetic mutations]] in different genes. Causes of acquired amyloidosis can include [[tuberculosis]], [[Familial mediterranean fever|familial Mediterranean fever]], [[rheumatoid arthritis]], [[multiple myeloma]], [[ankylosing spondylitis]], and [[psoriatic arthritis]]. |
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| [[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.
| | ==Causes== |
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| 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.
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| 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.
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| 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.
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| 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.
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| 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.
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| 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.
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| 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.
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| <ref>Amyloid and amyloidosis. Gilles Grateau, Robert A. Kyle, Martha Skinner, 2005 ISBN 0-8493-3534-5</ref>
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| ===Systemic amyloidosis=== | |
| ====Primary/Hereditary amyloidosis====
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| 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;
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| * [[Transthyretin]]-the most commonly implicated protein.
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| * [[Lysozyme]]
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| * [[Apolipoprotein B]]
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| * [[Fibrinogen]]
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| * [[Apolipoprotein A1]]
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| * [[Gelsolin]]
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| ====Secondary amyloidosis====
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| These are far more common than the primary amyloidoses.
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| * ''AL amyloidosis'' ([[immunoglobulin light chains]] are the precursor protein, overproduced in [[multiple myeloma]]). This is sometimes, confusingly and erroneously, called 'primary amyloidosis'.
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| * ''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.
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| * ''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).
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| === Organ-specific amyloidosis ===
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| 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.
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| '''Neurological amyloid'''
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| * [[Alzheimer's disease]] ([[Amyloid beta|Aβ 39-43]])
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| * [[Parkinson's disease]] ([[alpha-synuclein]])
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| * [[Huntington's disease]] ([[huntingtin]])
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| * [[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
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| ** [[Creutzfeldt-Jakob disease]] (PrP in [[cerebrum]])
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| ** [[Kuru]] (diffuse PrP deposits in brain)
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| ** [[Fatal Familial Insomnia]] (PrP in [[thalamus]])
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| ** [[Bovine spongiform encephalopathy]] (PrP in [[cerebrum]] of cows)
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| '''Cardiovascular amyloid'''
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| * [[Cardiac amyloidosis]]
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| * See the chapter on [[CMR in Cardiac Amyloidosis]]
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| ** Senile cardiac amyloidosis-may cause [[heart failure]]
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| * [[Congophilic angiopathy]]
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| '''Other'''
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| * [[Amylin]] deposition can occur in the [[pancreas]] in some cases of [[Diabetes mellitus type 2|type 2 diabetes mellitus]]
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| ===Gross Pathology===
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| {| align="row=3"
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| |[[Image:LA Amyloid.jpg|thumb|Amyloidosis Lesion In Left Atrium: Gross natural color view of a diagnostic lesion]]
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| |[[Image:LA Amyloid 2.jpg|thumb|Amyloidosis Lesion In Left Atrium: Gross natural color close-up]]
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| |[[Image:Amyloidosis LA nodules.jpg|thumb|Amyloidosis, left atrium, endocardial nodules]]
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| |}
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| {| align="row=3"
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| |[[Image:Amyloidosis endocardial nodules.jpg|thumb|Amyloidosis, left atrium, endocardial nodules]]
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| |[[Image:Amyloidosis and LVH.jpg|thumb|Amyloidosis and left ventricular hypertrophy]]
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| |[[Image:kidneyamy.jpg|thumb|URINARY SYSTEM: Kidney, amyloidosis]]
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| |}
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| {| align="row=3"
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| |[[Image:skinamy.jpg|thumb|SKIN: AMYLOIDOSIS, PRIMARY; YELLOW LESIONS ]]
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| |[[Image:tongueamy.jpg|thumb|TONGUE: PRIMARY AMYLOIDOSIS]]
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| |[[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.]]
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| |}
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| {| align="row=3"
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| |[[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.]]
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| |[[Image:liveramy.jpg|thumb|LIVER: Amyloidosis]]
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| |[[Image:liverbiliaryamy.jpg|thumb|LIVER-BILIARY TRACT: Liver, amyloidosis]]
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| |[[Image:kidneybladderamy.jpg|thumb|KIDNEY-BLADDER-URINARY: AMYLOIDOSIS OF URINARY BLADDER <small>(Courtesy of Dr. George M. Farrow, Rochester, MN.)]]
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| |}
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| ===Microscopic Pathology===
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| Amyloid can be diagnosed on histological examination of affected tissue.
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| 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]
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| {| align=row
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| |[[Image:Aldehyd Fuchsin.jpg|thumb|Heart: Amyloidosis, aldehyde fuchsin stain]]
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| |[[Image:Amyloidosis Kongored.jpg|thumb|Heart: Perivascular amyloid, amyloidosis, congo red showing birefringence]]
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| |[[Image:Perivas Amyloid.jpg|thumb|Heart: Perivascular amyloid, amyloidosis (Hematoxylin and eosin staining)]]
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| |[[Image:Amyloidosis, lymph node, polarizer.jpg|thumb|Congo red stain, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy]]
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| |}
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| ====What is not Amyloidosis?====
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| Several important diseases are associated with [[amyloid]] deposits but are not amyloidosis.
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| 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]].
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| 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.
| | === Causes of Hereditary Amyloidosis === |
| | [[Mutation|Genetic mutations]] responsible for the development of amyloidosis can involve 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> |
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| 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]].
| | *LYZ [[gene]] |
| | *[[FAP (gene)|Fibrinogen A alpha polypeptide gene]] |
| | *FGA [[gene]] |
| | *APOA1 [[gene]] |
| | *[[Lysozyme]] [[gene]] |
| | *B2M [[gene]] |
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| 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.
| | === Causes of Acquired Amyloidosis === |
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| 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.
| | * Most common causes of acquired amyloidosis include:<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> |
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| ====What is SAP?====
| | **[[Tuberculosis]] (50%) |
| | **[[Familial mediterranean fever|Familial Mediterranean fever]] (26 - 40%) |
| | **[[Rheumatoid arthritis]] (20 - 25%) |
| | **[[Multiple myeloma]] (10 - 15%) |
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| 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.
| | * Less common causes of acquired amyloidosis include:<ref name="pmid26351592">{{cite journal |vauthors=Meira T, Sousa R, Cordeiro A, Ilgenfritz R, Borralho P |title=Intestinal Amyloidosis in Common Variable Immunodeficiency and Rheumatoid Arthritis |journal=Case Rep Gastrointest Med |volume=2015 |issue= |pages=405695 |date=2015 |pmid=26351592 |pmc=4553190 |doi=10.1155/2015/405695 |url=}}</ref><ref name="pmid24558615">{{cite journal |vauthors=Kadiroğlu AK, Yıldırım Y, Yılmaz Z, Kayabaşı H, Avcı Y, Yıldırım MS, Yılmaz ME |title=A rare cause of secondary amyloidosis: common variable immunodeficiency disease |journal=Case Rep Nephrol |volume=2012 |issue= |pages=860208 |date=2012 |pmid=24558615 |pmc=3914192 |doi=10.1155/2012/860208 |url=}}</ref><ref name="pmid26161016">{{cite journal |vauthors=Lim AY, Lee JH, Jung KS, Gwag HB, Kim DH, Kim SJ, Lee GY, Kim JS, Kim HJ, Lee SY, Lee JE, Jeon ES, Kim K |title=Clinical features and outcomes of systemic amyloidosis with gastrointestinal involvement: a single-center experience |journal=Korean J. Intern. Med. |volume=30 |issue=4 |pages=496–505 |date=July 2015 |pmid=26161016 |pmc=4497337 |doi=10.3904/kjim.2015.30.4.496 |url=}}</ref> |
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| 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.
| | **[[Ankylosing spondylitis]] |
| | | **[[Psoriatic arthritis]] |
| 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.
| | **[[Crohn's disease]] |
| | **[[Osteomyelitis]] |
| | **[[Common variable immunodeficiency]] |
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| == References == | | == References == |
| {{reflist|2}} | | {{reflist|2}} |
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| | [[Category:Disease]] |
| | [[Category:Rheumatology]] |
| | [[Category:Cardiology]] |
| | [[Category:Endocrinology]] |
| | [[Category:Needs causes]] |
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| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |