Amyloidosis is a condition caused by deposition of abnormal extracellular protein fibrils in tissues, which damages organs and impairs function. It can be hereditary or associated with chronic inflammatory diseases. The abnormal proteins form fibrils with a characteristic beta-pleated sheet structure that takes up Congo red stain. The kidney is most commonly involved, which can lead to proteinuria and renal failure. Cardiac involvement also carries a poor prognosis. Diagnosis requires biopsy of affected tissues with staining to identify the amyloid deposits. The prognosis depends on the type and extent of organ involvement.
2. • Definition
• History
• Properties of amyloid proteins
• Classification
• Pathogenesis
• Morphology
• Clinicopathological classification
• Morphology of affected organs and clinical features
• Diagnosis
• Prognosis
Layout
3. AMYLOIDOSIS
Is a condition associated with inherited and
inflammatory disorders in which
There is deposition of
Extracellular fibrillar proteins
Tissue damage & functional compromise
Aggregates of
MISFOLDED
proteins
Insoluble
4. HISTORICAL ASPECTS
• “amylim” a latin word means “starch”
• Matthias Schleiden a German Botanist was the first to use the term
“amyloid” in botany, for starch, referring to“starch-like”.
• German pathologist Rudolf Virchow in 1854 used the word
“Amyloid” to describe some deposits in nervous system which
showed the same color reaction with iodine and sulfuric acid, i.e. a
change from brown to blue, typical to starch.
• In 1959 amyloid deposits were found to be composed of fibrils,
other proteins and glycosoaminoglycans.
8. BIO CHEMICAL FORMS
MAJOR
AL Protein
Highly sulfated
glycosaminoglycans
Transthyretin (TTR) β2-Microglobulin Serum Amyloid P
( SAP)
Proteoglycans
AA Protein Aβ Amyloid
MINOR
Prion proteins(APrP)
9. Complete Ig light chains
(lambda/kappa light
chain)/amino terminal
fragment of light chains/both
Secreted by monoclonal
population of plasma cells
Plasma cell tumors
Non Immunoglobulin
Derived from SAA protein
which is synthesized from
liver
Acute phase protein
Chronic inflammation
Derivedfrom proteolysis of
Amyloid precursor protein
transmembrane
glycoprotein
Alzheimer disease
BIO CHEMICAL FORMS
MAJOR
AL Protein AA Protein Aβ Amyloid
10. Is a normal serum protein
Mutantformsare deposited in
familial amyloid
polyneuropathies
Normalform is deposited in
heart of aged patients (Senile
cardiac Amyloidosis)
A normal serum protein
Component of MHC class 1
Aβ2-m-Amyloid fibril
component
Long term hemodialysis
BIO CHEMICAL FORMS
MINOR
Transthyretin (TTR) β2-Microglobulin
Highly sulfated
glycosaminoglycans
Serum Amyloid P
( SAP)
Proteoglycans
Prion proteins(APrP)
12. Normal circumstances
Misfolded proteins are
degraded
Intracellularly Extracellularly
Amyloidosis
Control mechanism fails
Mutations which favor
misfolding
Proteasome
pathway
Macrophages
Accumulation and
Aggregation to form
fibrils
Abnormal folding of proteins/ Misfolded proteins
Basic Mechanism
13. Normal proteins, when produced in abnormal
numbers
Production of mutant proteins
Acquired mutation
Monoclonal B lymphocyte
proliferation
Immunoglobulin light
chains Incomplete
proteolysis
AL protein
Chronic Inflammation
Macrophages activation
IL1 &IL6
Increased SAA protein
Incomplete
proteolysis
AA protein
Eg : Transthyretin (TTR)
Mutation
Mutant TTR
Aggregation
ATTR protein
PATHOGENESIS
14. MECHANISM OF DAMAGE TO THE TISSUES
1. Pressure effect: leading to atrophy
2. Accumulation in vessel wall : Leading to ischemia and also increased
permeability
3. Direct cytotoxicity: eg, Amyloidogenic light chain accumulation n
cardiac cells
4. Prefibrillar oligomers: are found be more injurious than actual
fibrils. In Alzheimer's and ATTR Amyloidosis
15. GENERALISED/SYSTEMIC AMYLOIDOSIS
Familial Amyloidotic Neuropathy Transthyretin ATTR
Systemic senile amyloidosis Transthyretin ATTR
CATEGORY
PRECURSOR
PROTEIN
FIBRIL
PROTEIN
ASSOCIATED DISEASES
CLASSIFICATION (Based on the clinicopathologic features)
Primary Amyloidosis ( immunocyte
dyscrasias with amyloidosis
Ig Light chains AL Multiple myeloma & other
plasma cell dyscrasias
Secondary Amyloidosis ( Reactive systemic
amyloidosis
SAA AA Chronic inflammation
Hemodialysis associated Amyloidosis β2-microglobulin Aβ2-m Chronic renal failure
LOCALISED AMYLOIDOSIS
Senile cerebral APP Aβ Alzheimer disease
Endocrine: Thyroid Calcitonin Acal Medullary Ca Thyroid
Islet of Langerhans Islet Amyloid
Peptide
AIAPP Type 2 Diabetes
HEREDITARY AMYOIDOSIS
Familial Mediterranean fever SAA AA
17. • Chronic renal failure
• β2-microglobulin is increased in the serum of these patients and
gets Deposited in synovium, joints & tendon sheath
β2-microglobulin
not filtered by
dialysis membranes
Hemodialysis associated Amyloidosis
Deposition of A β2
microglobulin
• With recent advances and new dialysis filters the incidence
has decreased.
18. Familial Amyloidotic NeuropathyFamilial Mediterranean fever
Heredofamilial amyloidosis
Autosomal recessive
Autoinflammatory syndrome
Excessive production of IL1 in
response to inflammation
Characterized by attacks of fever
with serosal inflammation
Wide spread amyloidosis
AA proteins
Autosomal dominant
Deposition of amyloid in peripheral
and autonomic nerves
Fibrils are made up of mutant TTRs
19. • Limited to a single tissue or organ
• Can be only microscopic foci or may be evident grossly as
nodular masses
• The common sites: lung, larynx, skin, bladder, tongue etc.
• Microscopic findings: Lymphocytes and plasma cells can be seen
in the periphery of amyloid deposits.
• Some cases , the amyloid consists of AL protein
Localised amyloidosis
21. GROSS EXAMINATION
• May or may not be visible
• If the deposits are too much, then the organ is enlarged, grey,
waxy and firm.
22. MICROSCOPIC EXAMINATION
Hematoxylin & Eosin
• Extracellular
• Closely adjacent to basement membranes.
• With further accumulation, it encroaches
on cells and destroy them
• Can be perivascular or vascular
• Amorphous, eosinophilic, glassy/hyaline.
• Should be differentiated from collagen, fibrin.
23. SPECIAL STAINS
Congo Red Stain
Ordinary light
Amyloid appears red/pink
Polarizing microscopy
Apple Green Birefringence
Cross beta pleated sheet conformation is the reason for this
special staining property!
30. 1.KIDNEY
• Most common
• Most serious
• Found most commonly in secondary amyloidosis .
• Accounts for one third cases of primary amyloidosis
31. • Gross examination:
• Can be normal size/ enlarged
• may be contracted/shrunken (due to the narrowing of vessels
resulting in ischemia)
• Cut surface: Pale and waxy/ transluscent
32. Microscopy
Can involve any part of kidney! But glomerular lesions predominates.
Glomeruli: They
appear as
amorphous material
in mesangium and
capillary loops
Tubules : deposits near
basement membrane.
Later seen in connective
tissue between
them/interstitium
Vessels: deposits in
the walls of arterioles
leading to narrowing
of lumen
33. Clinical features of Renal amyloidosis
• Can present with proteinuria.
• May be severe enough to result in Nephrotic syndrome
Increased
deposition in
glomeruli and
interstitium
Glomerular
ischemia and
atrophy of
tubules
Chronic Renal
failure
34. 2.LIVER
• Involved in most cases of systemic amyloidosis.
Gross : Enlarged, pale & waxy
35. Microscopy
Initially appears
in space of
Disse
In between the cords
of hepatocytes
( RIBBON like pink
staining )
Shrunken
/atrophic
hepatocytes
Compression of
cords
eosinophilic hyaline material (1) present within and between the
hepatic tissue (2). There is marked distortion of lobular
36. 3.SPLEEN
Gross : Moderate to marked splenomegaly. Two patterns seen:
Moderate enlargement.
C/S: transluscent waxy nodules resembling sago
grains
Moderate to marked enlargement
C/S: map like areas resembling Lard!
LARDACEOUS SPLEEN/DIFFUSESAGO SPLEEN /NODULARSAGO SPLEEN /NODULAR
37. Microscopy
Micro: involves periarteolar lymphoid
sheath (white pulp) and hence they
form discrete deposits
Micro: Deposits start in the walls of
splenic sinuses,which progresses till
they form large diffuse masses.
SAGO SPLEEN /NODULAR LARDACEOUS SPLEEN/DIFFUSE
38. 4.HEART
• Commonly associated with systemic amyloidosis
• Rarely as localized type ( Senile Cardiac
Amyloidosis)
Clinical Features:
• Can result in Cardiac Failure.
• Subendocardial deposition can interfere with conduction system
leading to arrhythmias .
39. Gross :
May be enlarged.
Pale , translucent and waxy.
Nodules/Plaques of amyloid can
be seen in the epi/endocardium
40. Microscopically
Seen in the coronary vessels or surrounding them.
Around the myocardial fibes ( Ring Fibers).
Left atrium/interatrial septum in Senile Cardiac Amyloidosis.
41. Other organs
• Brain- Alzheimer disease, amyloid plaques.
• Gastrointestinal tract- Malabsorption, diarrhea. Involvement of tongue can
cause macroglossia.
• Respiratory tract involved focally or diffuse from larynx to bronchioles.
• Vascular amyloidosis- vascular fragility and increased bleeding tendency.
• Peripheral and autonomic nerves- Familial amyloidotic neuropathies
Macroglossia Bleeding under the skinAmyloid plaques -Alzheimer disease
42. DIAGNOSIS OF AMYLOIDOSIS
• Diagnosis of systemic amyloidosis is confirmed by tissue diagnosis/
histopathological examination.
• Abdominal fat pad aspiration is the preferred method for diagnosis.
• Rectal and Gingival biopsy or labial/salivary gland biopsy may be taken
for systemic amyloidosis.
• Localised amyloidosis: biopsy of the involved tissue and confirmation
by staining.
43. • Immunohistochemistry the most commonly used method for amyloid
typing.
• In suspected AL amyloidosis electrophoresis and immunoelectrophoresis.
44. • Scintigraphy with radiolabelled serum amyloid (SAP-SERUM
AMYLOID P component, I123 labelled) – rapid and specific, measures
the extent of amyloidosis.
• Technetium scan: Tc 99m pyrophosphate binds avidly to many types of
amyloid -strongly positive in patients with severe disease.
Recent advances in amyloidosis
45. PROGNOSIS
• Generalised /systemic amyloidosis: the prognosis is poor.
• Myeloma associated amyloidosis has poorer outcomes with median
survival rates of 2years.
• Survival time depends on the type of predominantly involved organ.
• Cardiac involvement is the major determinant of survival prognosis –
major cause of death.
Transthyretin- transfer protein (transfers thyroxine and retinol)
Proteins are made up of chains of amino acids and these chains fold into 3D structures
Sometimes present with carpel tunnel syndrome because of macroglobulin deposition.
Function of the liver is generally not impaired
The basis for the test is injection of a small amount of radio-labelled SAP which binds on amyloid deposits throughout the body. The deposited radio labeled SAP transmits a radioactive signal. This signal is picked up by a detector, gamma camera. All body parts where radioactive signal is detected will contain amyloid deposits
