Transcript of Immunopathology 6
- 1. AMYLOIDOSIS
- 2. Amyloidosis is a group of diseases having in common the
deposition of similar-appearing proteins. Amyloid is a pathologic
proteinaceous substance, deposited between cells in various tissues
and organs of body in a wide variety of clinical settings.
- 3. Chemical Nature of Amyloid: Of 15 bio-chemically distinct
forms of amyloid proteins, Three most common are :(1) AL (amyloid
light chain) protein: derived from plasma cells and contains
immunoglobulin light chains.(2) AA (amyloid-associated) protein:
non immunoglobulin protein synthesized by liver.(3) -amyloid
protein (A) : derived from a transmembrane glycoprotein.
- 4. Several other biochemically distinct proteins have been
found in amyloid deposits:o Transthyretin (TTR) is a normal serum
protein that binds and transports thyroxine and retinol, hence the
name trans-thy-retin.o 2-microglobulin (A2m) a component of MHC
class I molecules.o Calcitonin: derived from C-cell (
parafollicular cell ) of thyroid gland.
- 5. Classification of Amyloidosis: Systemic (Generalized)
Amyloidosis: primary amyloidosis:o Immunocyte dyscrasias with
amyloidosis: as in Multiple myeloma and other monoclonal B-cell
proliferations [ AL protein ]. secondary amyloidosis:o Chronic
inflammatory conditions such as T.B, bronchiectasis, and
osteomyelitis [ AA protein ].o Hemodialysis-associated amyloidosis
in Chronic renal failure[ 2-microglobulin( A2m )].
- 6. Hereditary amyloidosis:o Familial Mediterranean fever [ AA
protein ].o Familial amyloidotic neuropathies [ ( ATTR )
Transthyretin amyloid ]. Systemic senile amyloidosis: [ (ATTR)
Transthyretin amyloid ]. Localized Amyloidosis: Senile cerebral
Alzheimer disease [ -amyloid protein (A) ]. Medullary carcinoma of
thyroid [ Calcitonin ].
- 7. Pathogenesis: Amyloidosis results from abnormal folding of
proteins, which are deposited as fibrils in extracellular tissues
and disrupt normal function. Misfolded proteins are often unstable.
The proteins that form amyloid fall into two general categories:
(1) normal proteins that have an inherent tendency to fold
improperly, and do so when they are produced in increased
amounts.
- 8. (2) mutant proteins that are structurally unstable and prone
to misfolding and subsequent aggregation. Normally, misfolded
proteins are degraded intracellularly in proteasomes ; or
extracellularly by macrophages. It appears that in amyloidosis,
these quality control mechanisms fail, so that, too much of a
misfolded protein accumulates outside cells.
- 9. Morphology: Macroscopically : the affected organs are often
enlarged and firm and have a waxy appearance. Microscopically:o The
most commonly used staining technique employs the dye Congo red,
which under ordinary light imparts a pink or red color to amyloid
deposits.o Under polarized light, the Congo red-stained amyloid
shows a green birefringence.o By electron microscopy, amyloid is
made up of nonbranching fibrils ( -pleated sheet ).
- 10. Specific Organs- Morphology:Kidney: renal amyloidosis is
the major cause of death. Histologically:- the amyloid is deposited
primarily in glomeruli, but interstitial peritubular tissue,
arteries, and arterioles are also affected.
- 11. Spleen:o Amyloidosis of spleen may be inapparent grossly or
may cause moderate to marked splenomegaly .o two patterns of
deposition are seen: the deposit is largely limited to splenic
follicles, producing tapioca-like granules on gross inspection,
designated as sago spleen. in red pulp the amyloid appears to spare
follicles and instead involves walls of splenic sinuses.o Fusion of
early deposits gives rise to large, maplike areas of amyloidosis,
designated as lardaceous spleen.
- 12. Liver:o The deposits may be in apparent grossly or may
cause moderate to marked hepatomegaly.o The amyloid appears first
in space of Disse and then progressively encroaches on adjacent
hepatic parenchymal cells and sinusoids.o In time, pressure
atrophy, and disappearance of hepatocytes occur, causing total
replacement of large areas of liver parenchyma.o Normal liver
function is usually preserved despite sometimes quite severe
involvement of liver.
- 13. Heart:o the deposits begin in focal subendocardial
accumulations and within myocardium between the muscle fibers.o
Expansion of these myocardial deposits eventually causes pressure
atrophy of myocardial fibers Other Organs:o Nodular depositions in
tongue may cause macroglossia.o Depositions of amyloid in carpal
ligament of wrist, resulting in compression of median nerve (carpal
tunnel syndrome).
- 14. Clinical Correlation: Clinical manifestations at first are
nonspecific, such as weakness, weight loss, light headache, or
syncope. more specific findings appear later and relate to renal,
cardiac, and gastrointestinal involvement. Renal involvement :o
proteinuria and is important cause of nephrotic syndrome .o
Progressive obliteration of glomeruli in advanced cases ultimately
leads to renal failure and uremia.
- 15. Cardiac amyloidosis :o congestive heart failure.o
conduction disturbances and arrhythmias, which may be fatal.o
Occasionally restrictive cardiomyopathy , and chronic constrictive
pericarditis . Gastrointestinal amyloidosis:o may be asymptomatic.o
Amyloidosis of tongue may cause sufficient enlargement and
inelasticity to hamper speech and swallowing.o Depositions in
stomach and intestine may lead to malabsorption, diarrhea, and
disturbances in digestion.
- 16. Diagnosis of amyloidosis: depends on demonstration of
amyloid deposits in tissues. The most common sites biopsied are
kidney, rectal or gingival tissues in patients suspected of having
systemic amyloidosis. In suspected cases of immunocyte-associated
amyloidosis:o serum and urine protein electrophoresis , and
immunoelectrophoresis should be performed.o Bone marrow aspirates
in such cases often show plasmacytosis, even in absence of overt
multiple myeloma.
- 17. prognosis: for patients with generalized amyloidosis is
poor. Those with immunocyte-derived amyloidosis (not including
multiple myeloma) have a median survival of 2 years after
diagnosis. Patients with myeloma-associated amyloidosis have a
poorer prognosis. The outlook for patients with reactive systemic
amyloidosis is some what better and depends on control of
underlying condition. New therapeutic strategies aimed at
correcting protein misfolding and inhibiting fibrillogenesis are
being developed.
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