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1. AMYLOIDOSIS
By..
Carmel jerone raj s MSC

4. Physical and chemical nature of amyloid
Amyloid is composed of 2 main types of complex proteins.
1. Fibril proteins comprise about 95% of amyloid.
2. Non-fibrillar components constitute the remaining 5% of amyloid.
Chemical analysis of fibril proteins of amyloid are heterogeneous
nature.

5. Fibril Proteins
•By electron microscopy, The fibrils are delicate,
randomly dispersed, non-branching, each measuring
7.5-10 nm in diameter and having indefinite length.
•By X-ray crystallography and infra-red spectroscopy, the
fibrils are shown to have cross- β -pleated sheet
configuration which produces 1000 A° periodicity that
gives the characteristic staining properties of amyloid
with Congo red.

6. • in 1970s while currently 20 biochemically different proteins are known to
form amyloid fibrils in humans in different clinicopathologic settings.
Thus these proteins can be categorised as under:
1. AL (amyloid light chain) protein
2. AA (amyloid associated) protein
3. Other proteins

7. AL protein
AL amyloid fibril protein is derived from immunoglobulin light chain.
AA protein
AA fibril protein is composed of protein with molecular weight of
8.5kD which is derived from larger precursor protein in the serum
called SAA (serum amyloid-associated protein).
SAA fibril protein is found in secondary amyloidosis which includes
the largest group of diseases associated with amyloidosis.

8. OTHER PROTEINS
. Apart from the two major forms of amyloid fibril proteins, a few other
forms of proteins are found in different clinical states..
•1. Transthyretin (TTR);
 It is a serum protein synthesised in the liver and transports thyroxine.
It was earlier called AFp (amyloid familial pre - albumin) since it
precedes albumin (pre-albumin) on serum electrophoresis but is not
related to serum albumin.

9. 2. Aβ 2 -microglobulin (Aβ 2 M):
This form of amyloid is seen in cases of long-term haemodialysis (for
8-10 years). As the name suggests, β 2 Microglubulon is a small
protein which is a normal component of major histocompatibility
complex (MHC) and has β -pleated sheet structure.
there is high serum concentration of β 2 M protein in these patients.

10. 3. β -amyloid protein (Aβ ).
• Aβ is distinct from Aβ 2 Micro globulin and is seen in cerebral
plaques as well as cerebral blood vessels in Alzheimer’s disease.
• Aβ is derived from amyloid beta precursor protein (AβPP)
which is a transmembrane glycoprotein. The normal function of
βPP is probably cell-to-matrix signalling.

11. 4. Immunoglobulin heavy chain amyloid (AH).
 AH is derived from truncated heavy chain of immunoglobulin and is
an uncommon form of systemic amyloidosis.
5. Amyloid from hormone precursor proteins.
 It includes examples such as amyloid derived from pro-
calcitonin(ACal), islet amyloid polypeptide (AIAPP, Amylin), pro-insulin
(AIns), prolactin (APro), atrial natriuretic factor(AANF), and lactoferrin
(ALac).

12. 6. Amyloid of prion protein (APrP).
 It is derived from precursor prion protein which is a plasma membrane
glycoprotein. Prion proteins are proteinaceous infectious particles lacking in RNA
or DNA. Amyloid in prionosis occurs due to abnormally folded isoform of the PrP.
7. Miscellaneous heredofamilial forms of amyloid.
 This group includes a variety of amyloid proteins reported recently. These are
amyloid derived from: apolipoprotein I(AApoAI), gelsolin (AGel), lysozyme (ALys),
fibrinogen α-chain (AFib), lysozyme (ALys), cystatin C (ACys)

13. II. Non-fibrillar Components
Non-fibrillar components comprise about 5% of the amyloid material. These
include the following
1. Amyloid P (AP)-component. It is synthesised in the liver and is present in all
types of amyloid. It is derived from circulating serum amyloid P-component
2. Apolipoprotein-E (apoE). It is a regulator of lipoprotein metabolism and is
found in all types of amyloid. One allele,apoE4, increases the risk of Alzheimer
precursor protein (APP) deposition in Alzheimer’s disease but not in all other
types of amyloid deposits.

14. 3. Sulfated glycosaminoglycans(GAGs). These are constituents of matrix
proteins; particularly associated is heparan sulfate in all types of tissue amyloid.
4. α-1 anti-chymotrypsin. It is seen in cases of AA deposits only but not seen
in primary amyloidosis.
5. Protein X. This protein has been shown to be present in cases of prionoses.
6. Other components. Besides above, components of complement, proteases,
and membrane constituents may be seen.

15. classification
Over the years, amyloidosis has been classified in a numbe of ways:
Based on cause, into primary (with unknown cause and the deposition
is in the disease itself) and secondary (as a complication of some
underlying known disease) amyloidosis.
Based on extent of amyloid deposition, into systemic (generalised)
involving multiple organs and localized amyloidosis involving one or
two organs or sites.etc

17. Normal kidney

19. SYSTEMIC AMYLOIDOSIS
• Primary Systemic (AL) Amyloidosis
Primary amyloidosis consisting of AL fibril proteins is
systemic or generalized in distribution. About 30% cases of AL
amyloid have some form of plasma cell dyscrasias, most
commonly multiple myeloma (in about 10% cases).
The remaining 70% cases of AL amyloid.

20. Majority of these cases too have a single type of abnormal
immunoglobulin in their serum (monoclonal) and that these
patients have some degree of plasmacytosis in the bone marrow.
In North America and Europe and is seen in individuals past the
age of 40 years. Primary amyloidosis is often severe in the heart,
kidney, bowel, skin, peripheral nerves, respiratory tract, skeletal
muscle, and other organs.

21. 2. Secondary/Reactive (AA) Systemic Amyloidosis
 Secondary or reactive amyloidosis occurs typically as a complication
of chronic infectious (e.g. tuberculosis)
Non-infectious chronic inflammatory conditions associated with
tissue destruction (e.g. autoimmune disorders such as rheumatoid
arthritis)
Secondary amyloidosis is typically distributed in solid abdominal
viscera like the kidney, liver, spleen and adrenals.

22. Secondary reactive amyloidosis is seen less frequently in
developed countries due to containment of infections before
they become chronic but this is the more common type of
amyloidosis in underdeveloped and developing countries of
the world.
 Secondary systemic amyloidosis can occur at any age
including children.

23. AA amyloid occurs spontaneously in some birds and animals;
it can also be experimentally induced in animals.
3. Haemodialysis-Associated (Ab2M) Amyloidosis
Patients on long-term dialysis for more than 10 years for
chronic renal failure may develop systemic amyloidosis
derived from β 2 –macroglobulin.

25. B. LOCALISED AMYLOIDOSIS
1. Senile cardiac amyloidosis (ATTR).
Senile cardiac amyloidosis is seen in 50% of people above the age of 70 years.
The deposits are seen in the heart and aorta. The type of amyloid in these cases
is ATTR but without any change in the protein structure of TTR.
2. Senile cerebral amyloidosis (Aβ, APrP).
Some of the important diseases associated with cerebral amyloidosis and the
corresponding amyloid proteins are: Alzheimer’s disease (Aβ), Down’s syndrome
(Aβ)

26. •3. Endocrine amyloidosis (Hormone precursors).
Some endocrine lesions are associated with microscopic deposits of
amyloid. The examples are as follows:
Medullary carcinoma of the thyroid (from procalcitonine ACal).
 Islet cell tumour of the pancreas (from islet amyloid polypeptide i.e.
AIAPP or Amylin).
 Type 2 diabetes mellitus (from pro-insulin, i.e. AIns).
 Pituitary amyloid (from prolactin i.e. APro).

27. 4. Localized tumour forming amyloid (AL).
 Sometimes , isolated tumour like formation of amyloid deposits
are seen.
e.g. in lungs, larynx, skin, urinary bladder, tongue, eye.
. In most of these cases, the amyloid type is AL.

28. STAINING CHARACTERISTICS OF AMYLOID

29. Symptoms of Amyloidosis
Changes in skin color
Feeling of fullness
Joint pain
Low red blood cell count (anemia)
Shortness of breath
Swelling of the tongue
Weak hand grip
Weakness , Weight loss.

30. Diagnosing Amyloidosis
A thorough physical exam and a detailed and accurate account of
your medical history are crucial in helping your doctor diagnose
amyloidosis.
There is no blood test to detect amyloidosis. Sophisticated laboratory
techniques called electrophoresis or free light chain assays may reveal
early evidence of some amyloid proteins.
A biopsy is needed to confirm a diagnosis of amyloidosis and
determine the specific type of protein involved in the disease.

31. Amyloidosis Treatment
There is no cure for amyloidosis. Your doctor will prescribe
treatments to suppress the development of the amyloid-forming
protein , and
Specific treatment depends on what type of amyloidosis you have
and how many organs are affected.

32. . Chemotherapy medicines alone are used to treat other patients with
primary AL amyloidosis.
Secondary (AA) amyloidosis is treated by controlling the underlying
disorder and with powerful anti-inflammatory medicines
called steroids, which fight inflammation.
Liver transplant may stop the disease in those with hereditary
amyloidosis.