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Amyloidosis
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What is amyloidosis?
Condition associate with a number of inherited and inflammatory
disorders in which extracellular deposits of fibrillar proteins are
responsible for tissue damage and functional compromise.
Starch like appearance due to the presence of abundent
charged sugar groups.
Along with fibrillar deposit, proteoglycan, glycosaminoglycan
( heparan sulphate & dermatan sulphate), and plasma protein
(serum amyloid P component- SAP) are seen.
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Under the microscope
Under light microscope and H & E stain appears as amorphous,
eosinophilic, hyaline, extracellular substance.
To differentiate from other hyaline materials :
Congo red stain- imparts a pink or red xolour to tissu
deposits under ordinary light and green birefringence under
polarizing microscopy.
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Properties
Physical properties
Continuous, non branching fibrils with a diameter of approx.
7.5 – 10 nm
X-ray crystallography and infrared spectroscopy demonstrate a
characteristic cross-ẞ-pleated sheet conformation.
ß-pleated appearance seen irrespective of clinical setting and is
responsible for the distinctive Congo red staining and
birefrigence of amyloid.
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Chemical properties
95% amyloid material composed of fibril protein
Rest 5% by P component and GAGs.
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Types of Amyloid Bodies
1. AL type (amyloid light chain protein):
made up of complete immunoglobulin light chains, the amino
terminal fragments of light chains, or both
Mostly composed of λ and sometimes κ light chains.
These are produced from free Ig chains secreted by a
monoclonal population of plasma cells.
Its depositions is associated with certain forma of plasma cell
tumours.
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2. AA type (amyloid associated):
Derived by proteolysis from a larger percursor in the serum
called the serum amyloid-associated (SAA) protein, synthesized
in liver and circulated bound to HDL.
These are associated with chronic inflammation, and is often
called secondary amyloidosis.
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3. Aß type (ß-amlkoid protein):
It constitutes the core of cerebral plaques found in Alzheimer
disease and in the wall of cerebral blood vessels with such
individuals.
Derived by proteolysis from a large transmembrane glycoprotein
called amyloid precursor protein.
Some other types are
Transerythrin
ß2-microglobulin
Prion proteins
Serum amyloid P component, proteoglycans, and GAGs.
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Pathogenesis of Amyloidosis
Amyloidosis results from abnormal folding of proteins, which
become insoluble, aggregate, and deposits as fibrils in
extracellular tissues.
Normally misfolded proteins are degraded intracellularly in
proteasomes and extracellularly by macrophages
In amyloidosis these mechanisms fail.
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Proteins that form amyloid can either be :-
a) Normal protein that have and inherent tendency to fold
improperly, associate and forms fibrils
b) mutant proteins that are prone to misfolding or subsequent
aggregation.
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Classification of Amyloidosis
Based on no. of organs involved:
a) Systemic amyloidosis. b)Localized amyloidosis
Based on occurrence :-
a) Primary amyloidosis. b) Secondary amyloidosis
c) Hereditary or familial amyloidosis
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Primary amyloidosis
It is systemic in distribution
AL type
The most common type of amyloidosis.
Caused due to clonal proliferation of plasma cells that synthesize an
Ig that is prone to its misfolding and form amyloid.
E.g. In multiple myeloma
Malignant plasma cells produces abnormal amounts of Ig (monoclonal
gammopathy) along with unpaired κ and λ light chains (Bence-Jones
Proteins).
But the amyloidogenic potential of any particular light chain is largely
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Reactive Systemic Amyloidosis
(Secondary amyloidosis)
It is systemic in distribution
Amyloids are of AA type.
Occurs secondary to chronic inflammation.
Causes :- a) Defect in the monocyte derived enzymes which
normally degrade SAA (Serum amyloid-associated) proteins.
b) Genetically abnormal structure of SAA, which render it
resistant to degradation by macrophages
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★ SAA proteins are produced by liver cells. Its production is
simulated by cytokines like IL-6 and IL-1 that are produced during
an inflammation.
Conditions associated with secondary amyloidosis are :-
Rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel
disease (Crohn disease and ulcerative colitis), in heroin abusers,
carcinoma and Hodgkin lymphoma.
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Heredofamilial amyloidosis
Familial Mediterranean fever
It is an autoinflammatory syndrome associated with excessive production
of cytokine IL-1 .
It is and autosomal recessive condition
Amyloid fibril proteins are of AA types
Mainly found in individuals of Armenian, Sephardic Jewish and Arabic
origin.
Clinical characteristics:- attack of fever with inflammation of serosal
surface, including peritoneum, pleura, and synovial membrane.
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Autosomal dominant disorders :-
Amyloid deposition in peripheral and autonomic nerves.
Amyloid fibrils are made up of TTRs
Found in different parts of the world
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Haemodialysis-Associated
amyloidosis
Occurs in individuals undergoing long term haemodialysis for renal
failure
Amyloid deposition of ẞ2-microglobulin
These proteins are found in high concentration in serum in
individuals with renal failure as these fail to be filtered by dialysis
membrane
ẞ2-microglobulin accumulate in the carpel ligament causing carpel
tunnel syndrome by compressing the median nerve
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Localized amyloidosis
Limited to a single organ or tissue
May produce nodular masses in kungs, larynx, skin, urinary
bladder, tongue and region about the eye.
Infiltrates of lymphocytes and plasma cells are seen along the
periphery of the nodular masses
Amyloid consists of AL type
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Endocrine Amyloid
It is a localized amyloidosis
In medullary carcinoma of thyroid, islet tumour of pancrease,
pheochromocytomas, and undifferentiated carcinomas of the
stomach, and in islet of Langerhans in type II diabetes mellitus.
Amyloid proteins are derived from polypeptide hormones
( medullary carcinoma) or from unique proteins (islet amyloid
polypeptide).
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Amyloid of aging
(Senile systemic amyloid)
Systemic deposition of amyloid in elderly patient ( 70-80 years of
age)
Associated with restrictive cardiomyopathy and arrhythmias.
Amyloid are of TTR type
Also known as Senile cardiac amyloidosis, because of dominant
involvement and dysfunction of the heart.
