![Amyloidosis - kidney
Most common and
potentially most serious
form of organ
involvement
Gross – normal or
shrunken [due to ischemia
(vascular narrowing) in
advanced stage]
Microscopy – glomerular
deposit, interstitial,
peritubular, arterial wall
deposit](https://image.slidesharecdn.com/amyloidosis-191122174858/85/AMYLOIDOSIS-23-320.jpg)
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AMYLOIDOSIS
- 1. AMYLOIDOSIS DR. PAMELA NAYAK (PATHOLOGYDEPT, MMCH)
- 2. TOPICS OF DISCUSSION Definition Pathogenesis Properties of Amyloid - Physical - Chemical Classification Morphology Clinical presentation Diagnosis
- 3. Amyloidosis - Introduction Disorder characterized by extracellular deposition of amyloid (fibrillar proteinaceous substance) Amyloid fibril – made of misfolded protein Amyloid = amylose (starch) like They have staining characteristic similar to starch but they are unrelated to starch. Associated with a number of inherited and inflammatory disorder
- 4. Amyloidosis - Definition Amyloidosisis a disorder characterized by the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils leads to tissue damage and functional compromise.
- 5. Amyloidosis - Pathogenesis Intracellularlyin proteasomes Extracellularly by macrophages Normally degraded Misfolded proteins Amyloidosis – this normal control mechanism fails Misfolded protein accumulates outside cells.
- 6. Amyloidosis - Pathogenesis Twocategories of proteins that form Amyloid Amyloidosis: 1. Localized: involves single organ 2. Systemic: involves multiple organs or tissues Effect: tissue damage and compromised function Normal proteins that have inherent tendency to misfold (excessive production) Mutant proteins that are prone to misfolding
- 7. Amyloid – chemicalnature >20 chemically distinct amyloid exist Most common forms: AL (Amyloid light chain) AA (Amyloid associated) (Aβ) β-amyloid proteins • Complete Ig light chain or • Amino terminal fragments of light chain or both • (λ >> κ) • Non Ig protein • Synthesized by liver • Precursor protein SAA • Increased synthesis in inflammatory state • Found in Alzheimer disease • Derived from Amyloid precursor protein
- 8. Amyloid - chemicalnature Rare chemical forms: 1. Transthyretin (TTR) - mutant & normal 2. β2-microglobulin (Aβ2m) – long term hemodialysis 3. Misfolded prion proteins 4. Serum amyloid P component – contribute to amyloid deposition by stabilizing the fibrils and decreasing their clearance
- 9. Amyloid – physicalnature Electron microscopy: Continuous non- branching fibril Diameter – 7.5 – 10 nm X-ray crystallography & Infrared spectroscopy Cross β-pleated sheet conformation Common to all amyloid protein Responsible for their distinctive Congo red staining and birefringence
- 10. Pathogenesis : Major formsof Amyloid fibrils
- 11. Amyloidosis – classification 1.Primary amyloidosis 2. Reactive systemic amyloidosis 3. Heredofamilial amyloidosis 4. Hemodialysis associated amyloidosis 5. Localized amyloidosis 6. Endocrine amyloidosis 7. Amyloid of aging
- 12. Amyloidosis – classification 1.Primary amyloidosis: - Plasma cell disorder associated - AL type amyloid protein - Ig secreted by clonal plasma cell prone to form Amyloid (due to its intrinsic physio-chemical properties) 5 - 15% multiple myeloma cases develop amyloidosis (not all) - Amyloidogenic potential of particular chain depends upon its specific amino acid sequence.
- 13. Amyloidosis – classification Contd… Mostof AL amyloid do not have overt multiple myeloma or clonal B cell neoplasm - But they are classified as primary amyloidosis (their presentation is due to amyloid deposition without any associated disease) - Modest increase in plasma cell noted in marrow without any tumor effect (monoclonal gummopathy)
- 14. Amyloidosis – classification 2.Reactive systemic amyloidosis: (also k/a secondary amyloidosis) - Associated with inflammatory condition - AA type amyloid protein - Common association Rheumatoid arthritis (MC) – 3%, half of them clinically significant Ankylosing spondylitis Inflammatory bowel disease (previously common association – TB, bronchiectasis, chronic osteomyelitis) Other cause – Heroine abuse, solid tumors (RCC, HL)
- 15. Amyloidosis – classification Reactivesystemic amyloidosis: Inflammation IL6 & IL1 Liver SAA synthesis ( ) normally degrade Soluble end products Monocyte derived enzyme SAA Genetically derived mutant SAA - Resistant to degradation Insoluble AA molecule
- 16. Amyloidosis – classification 3.Heredofamilial Amyloidosis: Rare & occur in limited geographic area Familial Mediterranean fever (AR inheritence) – MC - AA type amyloid protein, - Related to the recurrent bouts of inflammation. Familial amyloidotic polyneuropathy –mTTR 4. Hemodialysis associated amyloidosis: - Patients on long-term hemodialysis - deposition of β2-microglobulin - cannot be filtered through dialysis membranes
- 17. 5. Localized Amyloidosis: -Involves single organ - Macroscopically normal or nodular deposits - Lung, larynx skin, urinary bladder, tongue - In some cases surrounded by lymphocytes and plasma cell & AL type amyloid.
- 18. Amyloidosis – classification 6.Endocrine amyloidosis: - Microscopic deposits of localized amyloid found in certain endocrine tumors, such as - medullary carcinoma of the thyroid gland, - islet tumors of the pancreas, - pheochromocytomas, and - undifferentiated carcinomas of the stomach, and - in the islets of Langerhans in individuals with type II diabetes mellitus. Amyloidogenic proteins seem to be derived either from - polypeptide hormones (e.g., medullary carcinoma) or - unique proteins (e.g., islet amyloid polypeptide).
- 19. Amyloidosis – classification 7.Amyloid of aging Senile systemic amyloidosis: - systemic deposition of amyloid - in elderly patients (usually in their 70s and 80s). - previously called senile cardiac amyloidosis. (Because of the dominant involvement and related dysfunction of the heart) - The amyloid in this form is composed of the normal TTR molecule.
- 20. Amyloidosis – Organ involvement Noconsistent or distinctive pattern of amyloid deposit Predominant organ involvement Primary amyloidosis Secondary amyloidosis Familial Mediterranean fever • Heart • G I Tract • Respiratory organs • Peripheral nerves • Skin • Tongue • Kidney • Liver • Spleen • Lymphnodes • Adrenals • Thyroid • Kidney • Blood vessels • Spleen • Respiratory tract • Liver (rarely)
- 21. Amyloidosis – morphology Macroscopically: Involvedorgans - Enlarged - Grey in appearance - Waxy, firm in consistency
- 22. Amyloidosis - Morphology Microscopic: -Extracellular deposit - Often adjacent to basement membrane - In advanced stage, encroach, surrounds and destroying the cell
- 23. Amyloidosis - kidney Mostcommon and potentially most serious form of organ involvement Gross – normal or shrunken [due to ischemia (vascular narrowing) in advanced stage] Microscopy – glomerular deposit, interstitial, peritubular, arterial wall deposit
- 24. Amyloidosis - spleen Oneof two patterns of deposition is seen. Sago spleen - deposits are largely limited to the splenic follicles, producing tapioca-like granules grossly. Lardaceous spleen – amyloid involves the walls of the splenic sinuses and connective tissue framework in the red pulp. Fusion of the early deposits gives rise to large, map like areas of amyloidosis.
- 25. Amyloidosis – Clinical manifestation Amyloidosismay be found as an unsuspected anatomic change, having produced no clinical manifestations, or it may cause death. The symptoms depend on the magnitude of the deposits and on the particular sites or organs affected.
- 26. Amyloidosis – Clinical manifestation Clinicalmanifestations at first are often entirely nonspecific, such as – Weakness, Weight loss, Lightheadedness, or Syncope Somewhat more specific findings appear later and most often relate to renal, cardiac, and gastrointestinal involvement.
- 27. Amyloidosis - Diagnosis Histologicdemonstration of amyloid deposits in tissues. The most common sites biopsied are - The kidney, (when renal manifestations are present), or - Rectal or gingival tissues (in patients suspected of having systemic amyloidosis) Abdominal fat aspirates can also be used for the diagnosis of systemic amyloidosis. (Congo red stain) (The test is quite specific, but its sensitivity is low) Scintigraphy with radiolabelled serum amyloid P (SAP) - Rapid and specific test - Also measures extent of amyloidosis
- 28. Amyloidosis - Diagnosis Congored stain - Light microscopy – pink or red color deposit - Polarized microscope – Apple- green birefringence EM - Confirmatory
- 29. Amyloidosis - prognosis The prognosis for individuals with generalized amyloidosis is poor. Immunocyte derived amyloidosis (not including multiple myeloma) - median survival of 2 years after diagnosis. Persons with myeloma-associated amyloidosis have a poorer prognosis. Reactive systemic amyloidosis - somewhat better and depends to some extent on the control of the underlying condition. New therapeutic strategies aimed at - Correcting protein misfolding and - Inhibiting fibrillogenesis are being developed.
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