3. tion
Amyloid is defined as the deposition of
insoluble protein fibrils, forming histologically
a homogeneous, extracellular eosinophilic
mass.
Congo Red +++
Displays green birefringence under
polarized light
Amyloidosis constitutes a
heterogeneous group of distinct
diseases which differ in their
pathogenesis and clinical course.
4. Amyloid fibril protein occurs in tissue deposits as
rigid, non-branching fibrils 7-to 10 nm in dm
When analysed by X-ray
diffraction, the fibrils
exhibit a characteristic
cross Beta diffraction
pattern
7. A biochemical approach is the basis of the
classification.
The current WHO classification is based upon the
type of amyloid fibril, referred as Precursor Protein.
Which by convention is designated A and followed
by a suffix that is an abbreviated form of the parent
or precursor protein name.
Similarly when the amyloid
fibrils are derived from acute
phase reactant- Serum AA
protein, the amyloid fibril is
AA and the disease is AA
amyloidosis.
For example, when amyloid fibrils are derived
from immunoglobulin light chain, the amyloid
fibril is AL and the disease is AL amyloidosis.
8. There are than 20 types of precursor proteins are
known associated with various clinical forms of
amyloidosis.
They are associated with variety of
-Inflammatory
-Immune
-Infectious
-Hereditary conditions
9. Amyloid protein Precursor Systemic(S) or
Localized (L)
Syndrome
AL/AH Immunoglobulin
light/heavy chain
S, L Primary,
Myeloma
assosiated.
AA Serum AA
protein
S Sporadic,
secondary,
reactive, familial
ATTR Transthyretin S, ? L Familial, Senile,
Systemic
AFib Fibrinogen A a
chain
S Familial
10. AApoAI, II, IV Apolipoprotein
AI. AII, AIV
S, L Familial,
sporadic(aging)
AGEL Gelsolin S Familial
ALys Lysosome S Familial
ACys Cystatin C S Familial
Ab2M B2 Microglobulin S, ? L Dialysis
associated
11. Precursor protein is Immunoglobulin light
chain (AL) or a few times heavy chain
(AH).
Associated with hepatic, cardiac and
GIT involvement.
The most common clinical presentation is
proteinuria with or without renal
insufficiency
12. AA amyloidosis arises in the context of an acute
phase response seen in inflammatory arthritis,
periodic fevers, chronic infections and
malignancies.
This protein is derived from acute phase reactant
Serum Amyloid A or SAA
13.
14. Patients of an age range 11 to 87 years
(median 55) are affected.
In younger patients a hereditary
component must be considered.
Familial Mediterranean fever remains an
important cause around mediterranean
and in its immigrant population.
Protein urea and nephrotic syndrome are
most common presenting symptoms.
15. Diverse group of autosomal dominant diseases much
less frequent than AL or AA amyloidosis.
In keeping with the current classification , these are
named after the precursor amyloid fibril protein.
Among these diseases are amyloidosis derived from
1) Fibrinogen A a-chain (Afib)
2) Transthyretin (ATTR)
3) Apolipoprotein AI (AApoA1)
4) Apolipoprotein AII (AApoAII)
5) Gelsolin (Agel)
6) Lysozyme (Alys)
7) Cystatin (Acys)
16. Dialysis associated amyloidosis (AB2M) is
a type of systemic amyloidosis
developing in patients undergoing long-term
hemodialysis.
The amyloid precursor protein is B2-
microglobulin, which is a sub unit of class
I histocompatibilty antigens.
The protein is not effectively removed
during dialysis.
17. Clinical manifestation of the disease are
zero at 5 years but increase to 50% at 12
years.
There can be Peripheral
Osteoarthropathy, Spondyloarthropathy,
Ischemic colitis and Heart failure.
18.
19. • Enlarged kidneys
• Pale, waxy appearing cut surfaces
• Increase in the weight of kidney
20. • Amyloid deposits can be found
in any of the renal
compartments.
• Glomerular amyloid formations
begin in the mesangium.
• And then extends to the
capillary walls.
In H/E sections, amyloid appears
as eosinophilic, amorphous,
hyaline material.
21. Amyloid deposition in glomeruli may
occur in following patterns:
• 1) Segmental.
• 2) Diffuse mesangial.
• 3) Nodular.
• 4) Pure basement membrane pattern
22. • Early segmental deposits are small and confined to
mesangium without creating nodularity
• It is very easy to miss this early form
23. • In the diffuse form
• The mesangium is uniformly expanded by weakly
PAS positive acelluar deposits.
24. • In the nodular form
• Mesangium is asymmetrically expanded by large
masses of amyloid that compress the capillary
spaces.
25. • Rarely cresents can be seen
Highlighting the fact that capillary wall rupture has
occured
26. • Renal vessels are often involved with arteriolar
deposits being most frequent followed by deposits in
arteries, PTCs and veins.
• These deposits may be subtle or may replace the
vessel wall completely, occluding the lumen.
• In rare cases vessels walls are the only site for
amyliod deposition.
27. The tubules may show non specific
findings.
Interstitial and peri-tubular amyloidosis is
seen in 50 %of cases.
Medullay amyloid deposits are more
frequent.
A multinucleated giant cell reaction
may accompany amyloid deposits.
28. • Amyloid do not stain by silver staining
• Occasionally may stain with silver stains and
show spicules (Jones silver).
29. • Congo red is the gold standard procedure.
• Congo Red-Positive material must polarize and
produce apple green birefringence to be
considered diagnostic.
• To demonstrate small amount of amyloid, sections
should be cut to a thickness of 9 to 10um.
31. Methyl violet and Sulphonated Alcian
blue stains are less specific.
32. Typing of amyloid deposits is important because of
the difference in their treatment strategies.
Typing of the amyloid deposits can be performed
with various techniques.
The most definitive method used is IF or IHC staining
of tissue using antibodies that are directed against
known amyloid proteins.
33. • The typical antibody panel should include
• Amyloid P component
• Kappa & lambda Ig light chains
• Amyloid A protein
• Transthyretin
• Fibrinogen
• Beta-2 microglobulin
Stains for AA and
Apolipoprotein AI ,
AII, may be included
depending upon the
differential diagnosis.
• This panel allowed definitive
typing of amyloid in 90% of kidney biopsies
34.
35.
36. • Commercial antibodies are raised against the
constant regions of the Ig light chains.
• A subset of AL, in which amyloid fibrils
are derived from a truncated light chain
“containing only variable regions”
will be nonreactive with commercial antibodies
• Therefore, negative light chain staining does not rule
out AL amyloidosis.
40. Amyloid infiltration through the basement membrane with
resulting feathery spikes with basement membrane material
and delicate amyloid fibrils are shown in this case.
41. A proposed histopathologic classification
Renal amyloidosis was divided into 6 classes
Similar to the classification of SLE
42. The diagnosis of amyloid can be made
with certainty in majority of cases using a
combined apprach, including Light
microscope, histochemical, and
ultrastructural techniques.
It is important to identify the precursor
protein using ancillary diagnostic
techniques i.e. IF, IHC.
43. Nodular glomerular amyloidosis can be
confused with other nodulat
glomerulopathies i.e. ????
Diabetic nephropathy.
Light chain deposition
disease.
Heavy chain deposition
disease.
Ultrastructural
features can
differentiate
these entities.
51. Other infiltrative glomerular processes
must be ruled out.
Fibriallary and immunotactoid
glomerulopathies may be associated with
expanded mesangium and other feature
of amyloidosis.
The negative Congo Red stain and
ultrastructural finding differentiate these
diseases.
52. The overall prognosis in amyloidosis is
poor.
AL amyloidosis has the worst prognosis.
Prognosis largely depends on systemic
involvement.
Cardiac, hepatic and GIT involvent are
important negative predictor of survival
especially in AL amyloidosis.
53. From management point of view there
are three important categories.
AL AMYLOIDOSIS
Management is
targeted at the control
of underlying plasma
cell dyscrasia.
Treatment with high-dose
melphalan and
autologous blood stem
transplantation has led
an improvent in overall
survival.
AA AMYLOIDOSIS
Contol of the acute phase
response is currently the
standard of care.
Disease-modifying anti-rheumatic
drugs,
alkylating agents, anti-
TNF therapies, antibiotics,
steroids and surgeries are
being used.
HERIDITORY AMYLOIDOSIS
Since most of the
abnormal proteins are
being produced by liver,
liver transplant is currently
being offered to affected
patients. In severe
disease, combined liver,
kidney and heart
transplant is considered.
54. Best outcomes have been observed with
AA amyloidosis with 92% 5-year survival
rate.
In AL amyloidosis the 5-years survical rate
is 63%.
In AL amyloidosis the renal transplantation
is most clearly indicated for patients
without systemic manifestations of
Myeloma.
In AA amyloisdosis good control of acute
phase response is essential.
Editor's Notes
renal biopsy showing glomeruli with massive distension of the mesangial areas by amyloid.
The wall of an arteriole is also laden with amyloid
Amyloid deposits highlight with the trichrome staining like areas of mesangial acellular widening
glomeruli showing distension of the mesangium and capillary loops by amyloid deposits.
glomerulus showing distension of the mesangium and capillary loops by amyloid deposits
Glomerular crescent in a glomerulus with amyloid deposits, trichrome
Vascular deposits frequently coexist with glomerular amyloid
May mimic hyalinosis and even fibrinoid necrosis
small renal artery stained with congo red and examined by light microscropy
congo red and examined by polarization microscopy
The characteristic "apple-green" birefringence of amyloid is apparent in a renal vessel
IHC can detect deposits of amyloid that are congo-red negative