Amyloidosis causes: Difference between revisions
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== Overview == | == Overview == | ||
==Causes== | |||
===Systemic amyloidosis=== | ===Systemic amyloidosis=== | ||
====Primary/Hereditary amyloidosis==== | ====Primary/Hereditary amyloidosis==== | ||
Revision as of 21:24, 22 August 2012
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Amyloidosis Microchapters |
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Amyloidosis causes On the Web |
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American Roentgen Ray Society Images of Amyloidosis causes |
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
Gross Pathology
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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. © PEIR, University of Alabama at Birmingham, Department of Pathology
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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.