Amyloidosis

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Notes on Amyloidosis… By Dr. Ashish Jawarkar Contact: [email protected] Website: pathologybasics.wix.com/notes Facebook: facebook.com/pathologybasics

AMYLOIDOSIS

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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 Glycoprotein (P protein) (95%) 5%

Types of protein component

AL Made up of complete immunoglobulin light chains (λ chains) secreted by plasma cells. Found in plasma cell tumors

AA 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

β amyloid 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

Transthyretin (TTR) 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

β 2 microglobulin (A β 2 m)

It’s a component of MHC class I A β 2 m is deposited in patients on

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

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* CLASSIFICATION

Hereditary Non hereditary Generalised Localised

1 Systemic senile amyloidosis

1 Familial Mediterranean fever 2 Familial amyloidotic polyneuropathy

1 Primary amyloidosis (immunocyte dyscrasias) 2 Secondary amyloidosis (reactive systemic amyloidosis) 3 Hemodialysis associated amyloidosis

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 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 Deposition in walls of sinuses (SAGO SPLEEN) (tapioca /sabudana ) 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

Health & Medicine

Transcript of Amyloidosis