Amyloidosis causes: Difference between revisions

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Revision as of 21:24, 22 August 2012

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Causes

Systemic amyloidosis

Primary/Hereditary amyloidosis

These rare hereditary disorders are usually due to point mutations in precursor proteins, and are also usually autosomal dominantly transmitted.The precursor proteins are;

Transthyretin-the most commonly implicated protein.
Lysozyme
Apolipoprotein B
Fibrinogen
Apolipoprotein A1
Gelsolin

Secondary 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 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.

Neurological amyloid

Alzheimer's disease (Aβ 39-43)
Parkinson's disease (alpha-synuclein)
Huntington's disease (huntingtin)
Transmissible spongiform encephalopathies caused by 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 type 2 diabetes mellitus

References

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@@ Line 39: / Line 39: @@
 '''Other'''
 * [[Amylin]] deposition can occur in the [[pancreas]] in some cases of [[Diabetes mellitus type 2|type 2 diabetes mellitus]]
-===Gross Pathology===
-{| 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"
-|-
-|
-|-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"
-|-
-|
-|-valign="top"
-|[[Image:skinamy.jpg|thumb|SKIN: AMYLOIDOSIS, PRIMARY; YELLOW LESIONS ]]
-|[[Image:tongueamy.jpg|thumb|TONGUE: PRIMARY AMYLOIDOSIS]]
-|[[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.]]
-|}
-{| align="row=3"
-|-
-|
-|-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===
-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]
-{| align=row
-|-
-|
-|-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?====
-Several important diseases are associated with [[amyloid]] deposits but are not amyloidosis.
-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]].
-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.
-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]].
-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.
-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.
-====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 ==