Amyloidosis
Tissue-compromising amyloid deposits, derived from many different precursors, have been
identified in almost 40 distinct human amyloidoses. The diseases may be local (if precursor
synthesis is close to the site of deposition) or systemic (with tissue compromising amyloid
deposits at a distance from the synthesizing cells). 3 molecules are universally associated with
the fibrillar deposits: serum amyloid P (SAP), apolipoprotein E (ApoE) and heparan sulfate
proteoglycans (HSPGs) have been found in all the Congophilic deposits, regardless of precursor.
It has been hypothesized that the accessory molecules either protect the fibrils from
degradation, are “failed” physiologic chaperones (proteins that assist other proteins in folding
correctly) or are “pathologic” chaperones that enhance aggregation and deposition of the
precursors. It is now apparent that some proteins that form amyloid fibrils under physiologic
conditions are not associated with disease. Thus the capacity of individual (rather than all)
proteins to assume an amyloidogenic conformation may be evolutionarily conserved as a
functional domain across species and kingdoms (ex. in bacteria that form biofilms).
The secreted amyloidogenic precursors circulate complexed with their physiologic
partners (ex. homo-/heterodimers etc), with secreted chaperones or other. These interactions
tend to mitigate their tendencies to misfold and aggregate. The circulating pool of any
amyloidogenic precursor is influenced by the amount and rate of precursor synthesis and
secretion and the rate of tissue deposition.
Serum amyloid P: a plasma protein belonging to the pentraxin family (similar to CRP), it helps in
immune defense by binding pathogens and apoptotic cells. It is produced mainly in the liver (but
it’s not typically an acute-phase reactant). It binds to amyloid fibrils of all types and stabilizes
amyloid deposits; that’s why it’s found in all types of amyloidosis.
Amyloidogenesis
In systemic amyloidosis the deposits are predominantly extracellular and precursors are
synthesized as soluble polypeptide chains in the ER of the producing cell. Some molecules
displaying lesser degrees of misfolding (and therefore are not sent to proteasome for
degradation) are bound by other chaperones and are transported to the exterior of the cell,
resulting in a circulating physiologically soluble protein with amyloidogenic potential. Some
amyloidogenic proteins associated with neurodegenerative diseases (ex. Tau) may never transit
the conventional secretory pathway, forming pathogenic intracellular aggregates and spreading
from cell to cell by unconventional means.
The naturally slow-occurring fibrillogenesis can be speeded-up by preformed fibrillar
“seeds”, suggesting a process of nucleated polymerization. In the case of multimeric proteins
(ex. L-chain dimers or TTR tetramers) the soluble multimers first dissociate to monomers, which
denature, misfold, then aggregate. It is possible that the precursor can bind to its tissue target in
the native state and undergo the denaturation and/or proteolysis that predisposes to
aggregation in situ. Such aggregates could form the nucleus capable of binding other monomers
or oligomers that ultimately achieve the critical concentration required for local fibril formation.
The deposition in tissues is perhaps determined (among others) by tissue-specific
physicochemical conditions (ex. interstitial pH and ionic strength).
Histology
, Amyloid is homogeneous, amorphous, tissue-displacing material that stains with the dye Congo
red, emitting a characteristic apple-green fluorescence and birefringence under polarized light.
Although the deposits can result from inflammatory diseases, they are not considered
inflammatory in nature, as they don’t gather many inflammatory cells around them.
AA amyloidosis
It’s a reactive, acquired amyloidosis, by chronic inflammation or chronic infection. It was
formerly the most common form of amyloidosis diagnosed worldwide and it’s in areas where
there is a high frequency of chronic, indolent infections or genetic clusters of autoinflammatory
diseases and the most common form of amyloidosis in children. Amyloid fibrils composed by
fragments of (always smaller than) SAA.
SAA is produced primarily by the liver (acute-phase reactant) under the influence of IL-1,
TNF and IL-6 and regulated by NF-kB. Synthesis has also been seen in macrophages, endothelial
and smooth muscle cells. SAA is an apolipoprotein (a protein that binds to lipids to form
lipoproteins, which are responsible for transporting lipids) which circulates bound to HDL. It has
several identified functions, most of which are involved in the immune/inflammatory response.
SAP scanning: amyloid fibrils have a high affinity for SAP. This technique allows an
estimation of the amount of AA fibrils on different tissues, as the patient is injected with
radiolabeled SAP.
Clinical: renal disease is the most common (glomerular or interstitial deposits) and
myopathy. Other target-organs are: liver, spleen, adrenal glands, heart and abdominal fat.
Vascular deposition may be seen. May lead to hepatomegaly, nephropathy and nephrotic
syndrome. Heart failure with left ventricular hypertrophy and peripheral and autonomic
neuropathy are less frequent
Causes
-chronic inflammation (RA, FMF, Castleman)
-chronic infections (TB, leprosy, chronic osteomyelitis)
Diagnosis: SAA serum concentration is not useful since only a minority of patients with
very high levels develop tissue amyloid deposits. Definite diagnosis is by biopsy (kidney,
abdominal fat) with Congo red stain and antibodies to known amyloid precursors (ex. specific
for AA). For amyloidosis myopathy, characteristic net-like pattern on MRI.
large kidneys on u/s! This and early diabetic nephropathy: ↑ kidney size
Treatment: treat the underlying disease. TCZ is the most effective agent for therapy of
inflammation-associated AA as it is supposed to reduce SAA production by the liver.
Aβ2M amyloidosis
Mostly found in dialysis patients. Amyloid deposition is directly related to the duration of
dialysis (20% after 2 years, 50% at 9 years, 100% after 13 years, with comparable increases seen
in patients undergoing peritoneal dialysis). These percentages reflect older techniques and
modern day rates are lower. It is hypothesized that aggregation of the β2M molecule is
enhanced or accelerated by the characteristics of the dialysis regimens and the proinflammatory
properties of some of the membranes.
β2M is produced by all nucleated cells, serving as the light chain binding partner of the
heavy chain of MHC-I as well as several other proteins involved in immune and inflammatory
responses, allowing them to transit the secretory pathway for expression on the cell surface. It is
continuously shed from cell surfaces and circulates in low levels in the blood and it’s filtered by
the glomerulus and almost completely reabsorbed and catabolized by proximal tubular
epithelial cells. In ESKD, production exceeds excretion.
Tissue-compromising amyloid deposits, derived from many different precursors, have been
identified in almost 40 distinct human amyloidoses. The diseases may be local (if precursor
synthesis is close to the site of deposition) or systemic (with tissue compromising amyloid
deposits at a distance from the synthesizing cells). 3 molecules are universally associated with
the fibrillar deposits: serum amyloid P (SAP), apolipoprotein E (ApoE) and heparan sulfate
proteoglycans (HSPGs) have been found in all the Congophilic deposits, regardless of precursor.
It has been hypothesized that the accessory molecules either protect the fibrils from
degradation, are “failed” physiologic chaperones (proteins that assist other proteins in folding
correctly) or are “pathologic” chaperones that enhance aggregation and deposition of the
precursors. It is now apparent that some proteins that form amyloid fibrils under physiologic
conditions are not associated with disease. Thus the capacity of individual (rather than all)
proteins to assume an amyloidogenic conformation may be evolutionarily conserved as a
functional domain across species and kingdoms (ex. in bacteria that form biofilms).
The secreted amyloidogenic precursors circulate complexed with their physiologic
partners (ex. homo-/heterodimers etc), with secreted chaperones or other. These interactions
tend to mitigate their tendencies to misfold and aggregate. The circulating pool of any
amyloidogenic precursor is influenced by the amount and rate of precursor synthesis and
secretion and the rate of tissue deposition.
Serum amyloid P: a plasma protein belonging to the pentraxin family (similar to CRP), it helps in
immune defense by binding pathogens and apoptotic cells. It is produced mainly in the liver (but
it’s not typically an acute-phase reactant). It binds to amyloid fibrils of all types and stabilizes
amyloid deposits; that’s why it’s found in all types of amyloidosis.
Amyloidogenesis
In systemic amyloidosis the deposits are predominantly extracellular and precursors are
synthesized as soluble polypeptide chains in the ER of the producing cell. Some molecules
displaying lesser degrees of misfolding (and therefore are not sent to proteasome for
degradation) are bound by other chaperones and are transported to the exterior of the cell,
resulting in a circulating physiologically soluble protein with amyloidogenic potential. Some
amyloidogenic proteins associated with neurodegenerative diseases (ex. Tau) may never transit
the conventional secretory pathway, forming pathogenic intracellular aggregates and spreading
from cell to cell by unconventional means.
The naturally slow-occurring fibrillogenesis can be speeded-up by preformed fibrillar
“seeds”, suggesting a process of nucleated polymerization. In the case of multimeric proteins
(ex. L-chain dimers or TTR tetramers) the soluble multimers first dissociate to monomers, which
denature, misfold, then aggregate. It is possible that the precursor can bind to its tissue target in
the native state and undergo the denaturation and/or proteolysis that predisposes to
aggregation in situ. Such aggregates could form the nucleus capable of binding other monomers
or oligomers that ultimately achieve the critical concentration required for local fibril formation.
The deposition in tissues is perhaps determined (among others) by tissue-specific
physicochemical conditions (ex. interstitial pH and ionic strength).
Histology
, Amyloid is homogeneous, amorphous, tissue-displacing material that stains with the dye Congo
red, emitting a characteristic apple-green fluorescence and birefringence under polarized light.
Although the deposits can result from inflammatory diseases, they are not considered
inflammatory in nature, as they don’t gather many inflammatory cells around them.
AA amyloidosis
It’s a reactive, acquired amyloidosis, by chronic inflammation or chronic infection. It was
formerly the most common form of amyloidosis diagnosed worldwide and it’s in areas where
there is a high frequency of chronic, indolent infections or genetic clusters of autoinflammatory
diseases and the most common form of amyloidosis in children. Amyloid fibrils composed by
fragments of (always smaller than) SAA.
SAA is produced primarily by the liver (acute-phase reactant) under the influence of IL-1,
TNF and IL-6 and regulated by NF-kB. Synthesis has also been seen in macrophages, endothelial
and smooth muscle cells. SAA is an apolipoprotein (a protein that binds to lipids to form
lipoproteins, which are responsible for transporting lipids) which circulates bound to HDL. It has
several identified functions, most of which are involved in the immune/inflammatory response.
SAP scanning: amyloid fibrils have a high affinity for SAP. This technique allows an
estimation of the amount of AA fibrils on different tissues, as the patient is injected with
radiolabeled SAP.
Clinical: renal disease is the most common (glomerular or interstitial deposits) and
myopathy. Other target-organs are: liver, spleen, adrenal glands, heart and abdominal fat.
Vascular deposition may be seen. May lead to hepatomegaly, nephropathy and nephrotic
syndrome. Heart failure with left ventricular hypertrophy and peripheral and autonomic
neuropathy are less frequent
Causes
-chronic inflammation (RA, FMF, Castleman)
-chronic infections (TB, leprosy, chronic osteomyelitis)
Diagnosis: SAA serum concentration is not useful since only a minority of patients with
very high levels develop tissue amyloid deposits. Definite diagnosis is by biopsy (kidney,
abdominal fat) with Congo red stain and antibodies to known amyloid precursors (ex. specific
for AA). For amyloidosis myopathy, characteristic net-like pattern on MRI.
large kidneys on u/s! This and early diabetic nephropathy: ↑ kidney size
Treatment: treat the underlying disease. TCZ is the most effective agent for therapy of
inflammation-associated AA as it is supposed to reduce SAA production by the liver.
Aβ2M amyloidosis
Mostly found in dialysis patients. Amyloid deposition is directly related to the duration of
dialysis (20% after 2 years, 50% at 9 years, 100% after 13 years, with comparable increases seen
in patients undergoing peritoneal dialysis). These percentages reflect older techniques and
modern day rates are lower. It is hypothesized that aggregation of the β2M molecule is
enhanced or accelerated by the characteristics of the dialysis regimens and the proinflammatory
properties of some of the membranes.
β2M is produced by all nucleated cells, serving as the light chain binding partner of the
heavy chain of MHC-I as well as several other proteins involved in immune and inflammatory
responses, allowing them to transit the secretory pathway for expression on the cell surface. It is
continuously shed from cell surfaces and circulates in low levels in the blood and it’s filtered by
the glomerulus and almost completely reabsorbed and catabolized by proximal tubular
epithelial cells. In ESKD, production exceeds excretion.
