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) β-amyloid protein (Aβ) :
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 β2-microglobulin (Aβ2m) 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[ β2-microglobulin( Aβ2m )].

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 [ β-amyloid
protein (Aβ) ].
 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 ( β-pleated sheet ).

11. 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.

12.  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.

13.  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.

14.  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).

15. 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.

16.  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.

17. 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.

18. 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.

19. THANK YOU