2. AMYLOIDOSIS
• Amyloid is a pathologic proteinaceous
substance, deposited between cells in various
tissues and organs of the body in a wide
variety of clinical settings.
• Amyloidosis is not a single disease; rather it is
a group of diseases having in common the
deposition of similar-appearing proteins.
3. AMYLOIDOSIS
• It is a condition associated with a number of
inherited and inflammatory disorders in which
extracellular deposits of fibrillar proteins are
responsible for tissue damage and functional
compromise.
• These abnormal fibrils are produced by the
aggregation of misfolded proteins (which are
soluble in their normal folded configuration).
4. • The fibrillar deposits bind a wide variety of:
– Proteoglycans
– Glycosaminoglycans
– Plasma proteins, notably serum amyloid P
component (SAP)
- Approximately 95% of the amyloid material
consists of fibril proteins
- The remaining 5% is P component and other
glycoproteins.
Chemical Nature of Amyloid
5. Structure of an amyloid fibril, depicting beta-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis
Extra reading: Beta-sheets are he second form of regular secondary structure in proteins consisting of beta strands connected laterally by five or more hydrogen bonds, forming a
generally twisted, pleated sheet (the most common form of regular secondary structure in proteins is the alpha helix)
6.
7. Physical Nature of Amyloid
• By electron microscopy, amyloid is seen to be
made up largely of nonbranching fibrils of
indefinite length.
• This structure is identical in all types of
amyloidosis.
• The fibers have characteristic cross-β-pleated
sheets and are responsible for the distinctive
staining and birefringence of Congo red-
stained amyloid.
8. Amyloidosis,
Most common Forms :
(1) AL (amyloid light chain) is derived from
plasma cells and contains immunoglobulin
light chains
(2) AA (amyloid-associated) is a unique
nonimmunoglobulin protein synthesized by
the liver
(3) Aβ amyloid is found in the cerebral lesion of
Alzheimer disease
9. Other biochemical forms of Amyloid
• Transthyretin (TTR): is deposited familial amyloid
polyneuropathies and in the heart of aged individuals
(senile systemic amyloidosis).
11. Classification of Amyloidosis.
• Amyloid may be classified based on its constituent
chemical fibrils into categories such as AL, AA, and
ATTR (as described in the previous slides)
• Or it can be divided into :
– Systemic, (generalized) pattern is subclassified into:
• primary amyloidosis, when associated with B- cell dyscrasias
• secondary amyloidosis, when it occurs as a complication of an
underlying chronic inflammatory or tissue destructive process.
• Hereditary or familial amyloidosis constitutes a separate group.
– Localized
12.
13. Immunocyte Dyscrasias with Amyloidosis
(Primary Amyloidosis)
• Usually systemic and is of AL type.
• Is the most common form of amyloidosis.
• The malignant B cells characteristically synthesize
abnormal amounts of a single specific
immunoglobulin (monoclonal gammopathy).
14. Reactive/ Secondary Systemic Amyloidosis
• The amyloid deposition is systemic and is composed
of AA protein.
• It is secondary to an associated inflammatory
condition like rheumatoid arthritis, and inflammatory
bowel disease. It may also occur in association with
tumors, like renal cell carcinoma.
15. Amyloid of Aging
• Senile systemic amyloidosis: systemic deposition of
amyloid in elderly patients (heart) was previously
called senile cardiac amyloidosis.
• Those who are symptomatic present with a
restrictive cardiomyopathy and arrhythmias.
• The amyloid in this form is composed of the normal
TTR molecule.
16.
17. Pathogenesis
• Amyloidosis results from abnormal folding of
proteins, which are deposited as fibrils in
extracellular tissues and disrupt normal
function.
18. Pathogenesis cont.
• The proteins that form amyloid fall into two
general categories:
(1) normal proteins that have an inherent
tendency to fold improperly and form fibrils,
and do so when they are produced in
increased amounts
(2) mutant proteins that are structurally
unstable and prone to misfolding and then
form fibrils.
21. • Light microscope: amyloid appears as
amorphous, eosinophilic, hyaline, extracellular
substance that gradually encroaches on and
produces pressure atrophy of adjacent cells.
• On congo red stain: amyloid gives a pink or
red color under ordinary light and an apple
green birefringence under polarizing light.
22. Morphology
• Primary amyloidosis cannot reliably be
distinguished from the secondary amyloidosis
but more often it involves the heart, kidney
and, gastrointestinal tract, skin and tongue.
• Secondary amyloidosis usually involves
kidneys, liver, spleen and lymph nodes as well
as many other tissues.
24. Morphology cont.
• Histologic diagnosis of amyloid is based on its
characteristic staining with dye Congo red,
which under ordinary light imparts a pink or
red color to amyloid deposits. Under polarized
light, the Congo red-stained amyloid shows a
green birefringence
26. Morphology in Kidney
Most common organ involved.
Histologically the amyloid is deposited in the
1) Glomeruli, with progression there is hyalinization
of the glomeruli.
2) Peritubular region extending into interstitium.
3) Blood vessels: hyaline thickening of the arteriolar
wall and narrowing of lumen, eventually causing
ischemia with tubular atrophy and interstitial
fibrosis.
27. Morphology in Spleen
May cause splenomegaly. There are two patterns
of deposition.
1) Deposit is in the splenic follicles, producing
tapioca-like granules on gross inspection, called
sago spleen.
2) Deposit in splenic sinuses and connective tissue of
the red pulp. Fusion of deposits gives rise to large,
areas of amyloidosis, designated the lardaceous
spleen.
Tapioca: granular preparation of cassava starch
28. Morphology in Liver
• May cause hepatomegaly.
• The amyloid appears first in the space of Disse and
then progressively encroaches on adjacent hepatic
parenchymal cells and sinusoids.
• In time due to pressure atrophy, there disappearance
of hepatocytes, causing replacement of large areas of
liver by amyloid.
30. Morphology in Heart
• May be enlarged and firm. Histologically the deposits
are subendocardial and within the myocardium
between the muscle fibers.
• Expansion of these myocardial deposits eventually
causes pressure atrophy of myocardial fibers.
• When they are subendocardial, the conduction
system may be damaged, causing
electrocardiographic abnormalities.
31.
32. Clinical Correlation
. Variable presentation: no clinical manifestations, or it
may cause death.
.The symptoms depend on the magnitude of the
deposits and on the organs affected.
. At first nonspecific symptoms such as weakness,
weight loss, light-headedness, or syncope. Specific
findings appear later and most often relate to renal,
cardiac, and gastrointestinal involvement.
33. Clinical Correlation
1) Renal involvement: proteinuria, can cause of the
nephrotic syndrome. Progressive obliteration of
glomeruli in advanced cases leads to renal failure
and uremia
2) Cardiac amyloidosis: insidious congestive heart
failure. The most serious complications are
conduction disturbances and arrhythmias, which
may prove fatal.
34. Clinical Correlation
3) Gastrointestinal amyloidosis: may be
asymptomatic. Amyloidosis of the tongue may
cause enlargement and hamper speech and
swallowing.
Depositions in the stomach and intestine may
lead to malabsorption, diarrhea, and
disturbances in digestion.
35.
36. Diagnosis
• The diagnosis of amyloidosis depends on demonstration of
amyloid deposits in tissues.
• The most common sites biopsied are the kidney or rectal or
gingival tissues in patients suspected of having systemic
amyloidosis.
