Amyloidosis

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AMYLOIDOSIS
Notes on Amyloidosis… By Dr. Ashish Jawarkar
Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics

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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


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* 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


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Chemical properties
Protein
(95%)

Types of protein
component
AL

AA

β amyloid protein

Transthyretin (TTR)

β 2 microglobulin
(A β 2 m)
Prions

Glycoprotein (P protein)
5%

Made up of complete immunoglobulin light chains (λ 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 Alzheimer’s
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
It’s a component of MHC class I
A β 2 m is deposited in patients on
Misfolded proteins accumulate in CNS in prion disease


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* 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


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Amylod depositon in glomerulus – congo red – polarizing microscopy

THIOFLAVIN:

Amyloid deposited in wall of cerebral blood vessel in alzheimer’s –
Thioflavin S stain


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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)


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METHYL VIOLET/
CRYSTAL VIOLET:

Metachromatic rose-pink staining amyloid in glomerulus
SIRIUS RED STAIN

Amyloid deposition in nerve fibre


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X RAY CRYSTALLOGRAPHY
Cross beta pleated sheet configuration

INFRARED SPECTROSCOPY

Infrared spectra of amyloids from isotope-labeled amyloid-β proteins


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ELECTRON MICROSOCOPY


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* 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


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* 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


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* EACH TYPE IN DETAIL
(i) PRIMARY AMYLOIDOSIS (AL TYPE) (IMMUNOCYTE DYSCRASIAS)
Most common form

Associated with plasma cell dyscrasias

Monoclonal plasma cells synthesize either λ or κ chains, that gives a M spike on electrophoresis

Due to small molecular size – bence jone’s 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.


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(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, Crohn’s and ulcerative colitis
3. skin popping in heroin abusers
4. non immunocyte derived tumors like renal cell carcinomas and Hodgkin’s

AA-amyloidosis of the splenic vessels in rheumatoid arthritis


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(iii) HEMODIALYSIS ASSOCIATED AMYLOIDOSIS (aβ 2 MICROGLOBULIN)
In patients with renal disease, β 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.


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(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.


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(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


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(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).


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(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


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

(ix) SENILE CEREBRAL AMYLOIDOSIS (a β 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,


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* 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


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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


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Sago spleen

Lardaceous spleen


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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


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HEART –
1. Subendocardial deposits
2. in between myocardial fibres
GIT –
Initially around blood vessels

Amyloidosis of esophagus

TONGUE –
MACROGLOSSIA

Macroglossia

amorphous eosinophilic hyaline deposits


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* SUMMARY CHART


Amyloidosis

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