1

AMYLOIDOSIS
Notes on Amyloidosis… By Dr. Ashish Jawarkar
Contact: pathologybasics@gmail.com Website: pathologybasics.wi...
2

OVERVIEW
1. Definition
2. Properties
a. Physical
b. Chemical
3. Appearance
4. Pathogenesis
5. Classification
a. Localiz...
3

* DEFINITION
Deposition of a
1. pathologic
2. acellular proteinaceous substance
3. in extracellular space
in various ti...
4

Chemical properties
Protein
(95%)

Types of protein
component
AL

AA

β amyloid protein

Transthyretin (TTR)

β 2 micro...
5

* APPEARANCE
LIGHT MICROSCOPY
Stains

Appearance

H&E STAIN:

Amorphous
Eosinophilic
Hyaline
Homogenous
Extracellular
A...
6

Amylod depositon in glomerulus – congo red – polarizing microscopy

THIOFLAVIN:

Amyloid deposited in wall of cerebral ...
7

TOLUIDINE BLUE:

Perimyocytic amyloid deposition in semi-thin plastic-embedded
myocardium. This micrograph illustrates ...
8

METHYL VIOLET/
CRYSTAL VIOLET:

Metachromatic rose-pink staining amyloid in glomerulus
SIRIUS RED STAIN

Amyloid deposi...
9

X RAY CRYSTALLOGRAPHY
Cross beta pleated sheet configuration

INFRARED SPECTROSCOPY

Infrared spectra of amyloids from ...
10

ELECTRON MICROSOCOPY

Notes on Amyloidosis… By Dr. Ashish Jawarkar
Contact: pathologybasics@gmail.com Website: patholo...
11

* PATHOGENESIS
Abnormally folded proteins
1. Normal proteins prone that misfold due to systemic conditions
2. mutant p...
12

* CLASSIFICATION
Hereditary
1 Familial Mediterranean
fever

Non hereditary
Generalised
1 Systemic senile amyloidosis

...
13

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

Associated with plas...
14

(ii) SECONDARY AMYLOIDOSIS (AA TYPE)
1. Secondary to infective conditions like TB, bronchiectasis, chronic osteomyelit...
15

(iii) HEMODIALYSIS ASSOCIATED AMYLOIDOSIS (aβ 2 MICROGLOBULIN)
In patients with renal disease, β 2 microglobulin is pr...
16

(iv) FAMILIAL MEDITERRANEAN FEVER (AA PROTEIN)
FAMILIAL MEDITERRANEAN FEVER is a hereditary genetically restricted dis...
17

(v) FAMILIAL AMYLOIDOTIC POLYNEUROPATHY (mutant aTTR)
Familial amyloid neuropathies(FAP) are a group of familial syste...
18

(vi) SENILE SYSTEMIC AMYLOIDOSIS/SENILE CARDIAC AMYLOIDOSIS)
(NORMAL aTTR)
Elderly patients

Present with restrictive ...
19

(vii) DEPOSITION OF AMYLOID IN ENDOCRINE DISORDERS / TUMORS
PRODUCING HORMONES
a. MEDULLARY CARCINOMA OF THYROID (a CA...
20

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

(ix) S...
21

* ORGAN WISE MORPHOLOGY
Gross:
1. The affected organ is enlarged
2. painting with iodine imparts yellow color which tu...
22

Microscopy:
KIDNEY –
Early
1. subtle thickening of mesangial matrix
2. widening of
a. basement membrane
b. peritubular...
23

Sago spleen

Lardaceous spleen

Notes on Amyloidosis… By Dr. Ashish Jawarkar
Contact: pathologybasics@gmail.com Websit...
24

The amyloid material is diffusely spread throughout the splenic parenchyma.
LIVER –
Early – deposition in space of Dis...
25

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

Amyloidosis o...
26

* SUMMARY CHART

Notes on Amyloidosis… By Dr. Ashish Jawarkar
Contact: pathologybasics@gmail.com Website: pathologybas...
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Amyloidosis

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This is a series of notes on general pathology.. Amyloidosis is a very important topic from exam point of view both for under and post graduates..topic is presented here with enough colour illustrations

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Amyloidosis

  1. 1. 1 AMYLOIDOSIS Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  2. 2. 2 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  3. 3. 3 * 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  4. 4. 4 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  5. 5. 5 * 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  6. 6. 6 Amylod depositon in glomerulus – congo red – polarizing microscopy THIOFLAVIN: Amyloid deposited in wall of cerebral blood vessel in alzheimer’s – Thioflavin S stain Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  7. 7. 7 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) Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  8. 8. 8 METHYL VIOLET/ CRYSTAL VIOLET: Metachromatic rose-pink staining amyloid in glomerulus SIRIUS RED STAIN Amyloid deposition in nerve fibre Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  9. 9. 9 X RAY CRYSTALLOGRAPHY Cross beta pleated sheet configuration INFRARED SPECTROSCOPY Infrared spectra of amyloids from isotope-labeled amyloid-β proteins Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  10. 10. 10 ELECTRON MICROSOCOPY Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  11. 11. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  12. 12. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  13. 13. 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 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. Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  14. 14. 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, 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  15. 15. 15 (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. Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  16. 16. 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. Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  17. 17. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  18. 18. 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). Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  19. 19. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  20. 20. 20 (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, Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  21. 21. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  22. 22. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  23. 23. 23 Sago spleen Lardaceous spleen Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  24. 24. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  25. 25. 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 Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics
  26. 26. 26 * SUMMARY CHART Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics

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