Amyloidosis: Notes On Amyloidosis by Dr. Ashish Jawarkar Contact

1
AMYLOIDOSIS
Notes on Amyloidosis By Dr. Ashish Jawarkar
Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
OVERVIEW
1. Definition
2. Properties
a. Physical
b. Chemical
3. Appearance
4. Pathogenesis
5. Classification
a. Localized
b. Systemic
c. Hereditary
6. Types in detail
7. Organ wise morphology
8. Summary chart

* DEFINITION
Deposition of a
1. pathologic
2. acellular proteinaceous substance
3. in extracellular space
in various tissues and organs, in many different clinical settings.
* PROPERTIES
Physical properties
1. 7.5 to 10 nm in diameter
2. continuous, non branching fibrils
3. randomly arranged

Chemical properties
Protein
(95%)
Types of protein
component
AL
AA
amyloid protein
Transthyretin (TTR)
2 microglobulin
(A 2 m)
Prions
Glycoprotein (P protein)
5%
Made up of complete immunoglobulin light chains ( chains) secreted

by plasma cells.
Found in plasma cell tumors
Made from proteolysis of SAA (serum amyloid associated protein)
synthesized in liver
Circulates in association with HDL
Deposited in inflammatory states as a part of acute phase response
Hence also known as acute phase protein
Derived from larger protein known as Amyloid Precussor protein
Constitutes core of cerebral plaques found in Alzheimers
Also deposited in walls of cerebral blood vessels
Protein that is bound to thyroxin and retinol and helps in transporting
them
Normal TTR is deposited in heart tissue with age (k/a Senile systemic
amyloidosis)
Mutant TTR is deposited in Familial amyloidotic polyneuropathy
Its a component of MHC class I
A 2 m is deposited in patients on
Misfolded proteins accumulate in CNS in prion disease

* APPEARANCE
LIGHT MICROSCOPY
Stains
Appearance
H&E STAIN:
Amorphous
Eosinophilic
Hyaline
Homogenous
Extracellular
Acellular substance
Produces atrophy of adjacent cells
Deposition of amyloid in splenic blood vessel wall
CONGO RED STAIN:On H&E pink red

On polarizing microscopy apple green birefringence
Deposition of amyloid in lymph node congo red LM

Amylod depositon in glomerulus congo red polarizing microscopy
THIOFLAVIN:
Amyloid deposited in wall of cerebral blood vessel in alzheimers

Thioflavin S stain

TOLUIDINE BLUE:
Perimyocytic amyloid deposition in semi-thin plastic-embedded

myocardium. This micrograph illustrates perimyocytic amyloid deposits
(pale purple-blue) surrounding and distorting individual myocytes (dark
purple-blue).
The toluidine blue sections are used to map the areas to be examined in
ultrathin sections in electron microscopy.
ALCIAN BLUE:
Microscopy of cardiac tissue from autopsy demonstrates amyloid

deposition between cardiac myocytes as homogeneous light pink
material (left). Sulfated Alcian blue staining shows extensive amyloid
deposition as green amorphous material (right)

METHYL VIOLET/
CRYSTAL VIOLET:
Metachromatic rose-pink staining amyloid in glomerulus

SIRIUS RED STAIN
Amyloid deposition in nerve fibre

X RAY CRYSTALLOGRAPHY
Cross beta pleated sheet configuration
INFRARED SPECTROSCOPY
Infrared spectra of amyloids from isotope-labeled amyloid- proteins

10
ELECTRON MICROSOCOPY

11
* PATHOGENESIS
Abnormally folded proteins
1. Normal proteins prone that misfold due to systemic conditions
2. mutant proteins that are prone to misfolding and aggregation
escape degradation in proteosomes / by macrophages

1. either due to abnormal enzymes in proteosomes
2. due to structure of proteins that resist degradation
deposition in extracellular sites
Example:
Deposition of amyloid in chronic inflammatory conditions
Liver cells
IL-1 & IL-6 produced by inflammatory cells
SAA (Serum Amyloid associated protein)

Degraded in
Proteosomes/
Macrophages
If there is a defect in
End products
enzymes of proteosomes/
Macrophages
defective structure
of SAA
Deposition of abnormal/
Non degraded SAA in
Extracellular sites
Amyloidosis

12
* CLASSIFICATION
Hereditary
1 Familial Mediterranean
fever
Non hereditary
Generalised
1 Systemic senile amyloidosis
Localised
1 Senile cerebral amyloidosis
2 Familial amyloidotic
polyneuropathy
1 Primary amyloidosis
(immunocyte dyscrasias)
2 Endocrine system related

a. Medullary Ca thyroid
b. Islets of langerhans
c. pheochromocytoma
d. undifferentiated Ca
stomach
2 Secondary amyloidosis
(reactive systemic
amyloidosis)
3 Hemodialysis associated
amyloidosis
3 Isolated atrial amyloidosis

13
* EACH TYPE IN DETAIL

(i) PRIMARY AMYLOIDOSIS (AL TYPE) (IMMUNOCYTE DYSCRASIAS)
Most common form
Associated with plasma cell dyscrasias
Monoclonal plasma cells synthesize either or chains, that gives a M spike on electrophoresis
Due to small molecular size bence jones protein is found in urine
Amyloid deposits are seen in the kidney of this patient. The entire filtering apparatus pictured here is inundated with amyloid deposits.

14
(ii) SECONDARY AMYLOIDOSIS (AA TYPE)

1. Secondary to infective conditions like TB, bronchiectasis, chronic osteomyelitis
2. Inflammatory conditions like Rheumatoid arthritis, Ankylosing spondylitis, inflammatory
bowel disease, Crohns and ulcerative colitis
3. skin popping in heroin abusers
4. non immunocyte derived tumors like renal cell carcinomas and Hodgkins
AA-amyloidosis of the splenic vessels in rheumatoid arthritis

15
(iii) HEMODIALYSIS ASSOCIATED AMYLOIDOSIS (a 2 MICROGLOBULIN)

In patients with renal disease, 2 microglobulin is present in high concentrations
Also this protein is not filtered through the dialysis membranes
It gets deposited in synovium / tendons / joints
May lead to carpal tunnel syndrome
A cell block prepared from the knee synovial fluid of a patient with dialysis-related beta-2 microglobulin
amyloidosis showed amorphous material that stained with Congo red. This material also showed
characteristic apple-green birefringence with polarized light microscopy.

16
(iv) FAMILIAL MEDITERRANEAN FEVER (AA PROTEIN)

FAMILIAL MEDITERRANEAN FEVER is a hereditary genetically restricted disease
commonly found among Jews originating from North African countries, Armenians, Turks and
Arabs.
FMF is recognized by two independent manifestations:
1.) acute, short-lived painful, bouts of stomach pain (peritonitis) or pleuritis with fever
2) nephropathic amyloidosis, which can lead to terminal renal failure even at a young
age.
The cause is a lack of pyrin, a neutrophil protein which slows down neutrophils when
enough have reached an area
Lacking pyrin, neutrophils mob body cavities every once in a while.
Colchicine, famous for its ability to slow down neutrophils (as in acute gout), controls the
attacks and prevents the dread complication of secondary amyloidosis.

17
(v) FAMILIAL AMYLOIDOTIC POLYNEUROPATHY (mutant aTTR)

Familial amyloid neuropathies(FAP) are a group of familial systemic amyloidoses with
involvement of peripheral nerves. The most common FAP is caused by an autosomal dominant
mutation of the transthyretin gene on 18q11.
The mutant protein is deposited in the form of amyloid and damages peripheral nerves,
the heart, kidneys, gastrointestinal tract, and other organs.
In nerves, amyloid damages first and most severely small fibers, causing loss of pain and
temperature sensation and autonomic dysfunction.
Transthyretin is produced in the liver. Liver transplantation arrests the progression of the
disease.
Familial amyloid neuropathy. Amyloid deposition in nerve. Sirius red stain

18
(vi) SENILE SYSTEMIC AMYLOIDOSIS/SENILE CARDIAC AMYLOIDOSIS)

(NORMAL aTTR)
Elderly patients
Present with restrictive cardiomyopathy and arrythmias
CARDIAC (HEART) AMYLOIDOSIS]. . Amyloidosis is an insoluble extracellular deposition of abnormal fibrillar

substance composed of specific protein fragments. Cardiac amyloidosis is usually seen in two clinical settings, either as
part of systemic amyloidosis or isolated senile cardiac amyloidosis not involving any other organs. The systemic
amyloidosis is generally seen in patients with underlying plasma cell dyscrasia, with abnormal plasma cells producing
monoclonal immunoglobulin light chain, usually lambda light chain. The senile cardiac amyloidosis is due to
deposition of a mutant form of transthyretin. Amyloid appears as light-pink hyaline extracellular deposits (left arrow)
displacing cardiac myocytes (right arrowhead).

19
(vii) DEPOSITION OF AMYLOID IN ENDOCRINE DISORDERS / TUMORS

PRODUCING HORMONES
a. MEDULLARY CARCINOMA OF THYROID (a CAL) (CALCITONIN)
Amyloid deposition in medullary ca thyroid
MTC can be remembered by the 3 Ms: aMyloid. Median node dissection. MEN 2A & MEN 2B
b. IN PATIENTS WITH DIABETES MELLITUS (a IAPP) (islet associated polypeptide)
The amyloid is deposited in the Islets of Langhans, the endocrine pancreas

20
(viii) ISOLATED ATRIAL AMYLOIDOSIS (a ANF) (atrial natriuretic factor)

Deposition of atrial natriuretic factor
(ix) SENILE CEREBRAL AMYLOIDOSIS (a protein)

Cerebral amyloid angiopathy (CAA) is a fundamental part of the pathology of many
disorders causing dementia and/or cerebral haemorrhage. In Alzheimer's disease (AD), CAA is
due to the deposition of amyloid alpha protein (Abeta) within the adventitia and media of
leptomeningeal and brain parenchymal arteries.
Although virtually all cases of AD show CAA to a greater or lesser extent, the brain
distribution of CAA is not uniform with the occipital lobe being the most commonly and most
severely affected region.
In vessels affected by CAA, local muscle and elastic elements are lost and replaced by
amyloid fibrils, thereby weakening the overall structure of the vessel. Consequently, CAA
predisposes towards cerebral infarction and cerebral haemorrhage,

21
* ORGAN WISE MORPHOLOGY

Gross:
1. The affected organ is enlarged
2. painting with iodine imparts yellow color which turns blue after application of sulphuric
acid
Section of myocardium stained with iodine

22
Microscopy:
KIDNEY
Early
1. subtle thickening of mesangial matrix
2. widening of
a. basement membrane
b. peritubular interstitium
c. walls of arteries
Late
1. depositions cause capillary narrowing and distortion of vascular tuft
2. glomerulus becomes a confluent mass of amyloid
SPLEEN
Two patterns
Deposition in follicles
(SAGO SPLEEN) (tapioca /sabudana )
Deposition in walls of sinuses

In red pulp
resembling Pig fat (lard)
Known as LARDACEOUS SPLEEN
Later fusion of both areas gives the

Appearance of map like areas in the spleen

23
Sago spleen
Lardaceous spleen

24
The amyloid material is diffusely spread throughout the splenic parenchyma.

LIVER
Early deposition in space of Disse
Late deposition in liver parenchyma
Sinusoids
Vessel walls
Kupfer cells
Hepatic amyloidosis

25
HEART
1. Subendocardial deposits
2. in between myocardial fibres
GIT
Initially around blood vessels
Amyloidosis of esophagus
TONGUE
MACROGLOSSIA
Macroglossia
amorphous eosinophilic hyaline deposits

26
* SUMMARY CHART


Amyloidosis: Notes On Amyloidosis by Dr. Ashish Jawarkar Contact

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Amyloidosis: Notes On Amyloidosis by Dr. Ashish Jawarkar Contact

Uploaded by

Copyright:

Available Formats

1

Notes on Amyloidosis By Dr. Ashish Jawarkar

Notes on Amyloidosis By Dr. Ashish Jawarkar

Made up of complete immunoglobulin light chains ( chains) secreted

Notes on Amyloidosis By Dr. Ashish Jawarkar

Deposition of amyloid in splenic blood vessel wall

CONGO RED STAIN:On H&E pink red

Deposition of amyloid in lymph node congo red LM

Notes on Amyloidosis By Dr. Ashish Jawarkar

Amylod depositon in glomerulus congo red polarizing microscopy

Amyloid deposited in wall of cerebral blood vessel in alzheimers

Notes on Amyloidosis By Dr. Ashish Jawarkar

Perimyocytic amyloid deposition in semi-thin plastic-embedded

Microscopy of cardiac tissue from autopsy demonstrates amyloid

Notes on Amyloidosis By Dr. Ashish Jawarkar

Metachromatic rose-pink staining amyloid in glomerulus

Amyloid deposition in nerve fibre

Notes on Amyloidosis By Dr. Ashish Jawarkar

Infrared spectra of amyloids from isotope-labeled amyloid- proteins

Notes on Amyloidosis By Dr. Ashish Jawarkar

Notes on Amyloidosis By Dr. Ashish Jawarkar

escape degradation in proteosomes / by macrophages

deposition in extracellular sites

IL-1 & IL-6 produced by inflammatory cells

SAA (Serum Amyloid associated protein)

Notes on Amyloidosis By Dr. Ashish Jawarkar

2 Endocrine system related

3 Isolated atrial amyloidosis

Notes on Amyloidosis By Dr. Ashish Jawarkar

* EACH TYPE IN DETAIL

Associated with plasma cell dyscrasias

Due to small molecular size bence jones protein is found in urine

Notes on Amyloidosis By Dr. Ashish Jawarkar

(ii) SECONDARY AMYLOIDOSIS (AA TYPE)

AA-amyloidosis of the splenic vessels in rheumatoid arthritis

Notes on Amyloidosis By Dr. Ashish Jawarkar

(iii) HEMODIALYSIS ASSOCIATED AMYLOIDOSIS (a 2 MICROGLOBULIN)

Also this protein is not filtered through the dialysis membranes

It gets deposited in synovium / tendons / joints

May lead to carpal tunnel syndrome

Notes on Amyloidosis By Dr. Ashish Jawarkar

(iv) FAMILIAL MEDITERRANEAN FEVER (AA PROTEIN)

Notes on Amyloidosis By Dr. Ashish Jawarkar

(v) FAMILIAL AMYLOIDOTIC POLYNEUROPATHY (mutant aTTR)

Familial amyloid neuropathy. Amyloid deposition in nerve. Sirius red stain

Notes on Amyloidosis By Dr. Ashish Jawarkar

(vi) SENILE SYSTEMIC AMYLOIDOSIS/SENILE CARDIAC AMYLOIDOSIS)

Present with restrictive cardiomyopathy and arrythmias

CARDIAC (HEART) AMYLOIDOSIS]. . Amyloidosis is an insoluble extracellular deposition of abnormal fibrillar

Notes on Amyloidosis By Dr. Ashish Jawarkar

(vii) DEPOSITION OF AMYLOID IN ENDOCRINE DISORDERS / TUMORS

Amyloid deposition in medullary ca thyroid

The amyloid is deposited in the Islets of Langhans, the endocrine pancreas

Notes on Amyloidosis By Dr. Ashish Jawarkar

(viii) ISOLATED ATRIAL AMYLOIDOSIS (a ANF) (atrial natriuretic factor)

(ix) SENILE CEREBRAL AMYLOIDOSIS (a protein)

Notes on Amyloidosis By Dr. Ashish Jawarkar

* ORGAN WISE MORPHOLOGY

Section of myocardium stained with iodine

Notes on Amyloidosis By Dr. Ashish Jawarkar

Deposition in walls of sinuses

Later fusion of both areas gives the