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
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%) Glycoprotein (P protein) 5%
Types of protein component AL
AA
amyloid protein
Transthyretin (TTR)
2 microglobulin (A 2 m) Prions
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 H&E STAIN: Appearance 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
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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 End products
If there is a defect in
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 2 Familial amyloidotic polyneuropathy Non hereditary Generalised 1 Systemic senile amyloidosis 1 Primary amyloidosis (immunocyte dyscrasias) 2 Secondary amyloidosis (reactive systemic amyloidosis) 3 Hemodialysis associated amyloidosis Localised 1 Senile cerebral amyloidosis 2 Endocrine system related a. Medullary Ca thyroid b. Islets of langerhans c. pheochromocytoma d. undifferentiated Ca stomach 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 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.
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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, 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
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(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.
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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 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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Amyloidosis

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Chemical properties Protein (95%) Glycoprotein (P protein) 5%

Types of protein component AL

Deposition of amyloid in splenic blood vessel wall

Deposition of amyloid in lymph node congo red LM

Amylod depositon in glomerulus congo red polarizing microscopy

Amyloid deposited in wall of cerebral blood vessel in alzheimers Thioflavin S stain

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 spectra of amyloids from isotope-labeled amyloid- proteins

deposition in extracellular sites

enzymes of proteosomes/ Macrophages

defective structure of SAA

Deposition of abnormal/ Non degraded SAA in Extracellular sites

Associated with plasma cell dyscrasias

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

AA-amyloidosis of the splenic vessels in rheumatoid arthritis

Also this protein is not filtered through the dialysis membranes

It gets deposited in synovium / tendons / joints

May lead to carpal tunnel syndrome

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

Present with restrictive cardiomyopathy and arrythmias

Amyloid deposition in medullary ca thyroid

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

Section of myocardium stained with iodine

SPLEEN Two patterns

Deposition in follicles (SAGO SPLEEN) (tapioca /sabudana )

amorphous eosinophilic hyaline deposits

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