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    AMYLOIDOSIS.ppt AMYLOIDOSIS.ppt Presentation Transcript

    • AMYLOIDOSIS Senior Talk Collins Okolie PGY3
    • OBJECTIVES
      • Definition
      • Mechanism of formation
      • Characteristics common to all amyloid subtypes
      • Classification
      • Clinical Importance/Symptoms
      • Diagnosis and Treatment
      • Take home message
    • Definition
      • A medical condition resulting from aggregation of extracellularly deposited abnormal proteins called amyloid fibrils that cause damage to organs and tissues.
      • These fibrils are insoluble, linear, rigid and measures approximately 7.5 to 10mm in width
    • Mechanism of formation
      • Amyloid fibrils arise from misfolded proteins. Alpha helix to beta pleated sheet
      • Proteins are deposited extracellularly
      • Proteins aggregate and form fibrils called amyloid fibrils.
      • Misfolded proteins may result from point mutations.
      • Deposited as localized vs systemic
      • -localized; close to cells producing it.
      • -Systemic; distant sites from these cells producing these abnormal proteins.
      • In 1854 Rudolph Virchow named it amyloid based on color after staining these proteins with iodine and sulfuric acid. Meaning cellulose or starch
    • Characteristics common to all amyloid subtypes
      • Hematoxylin and Eosin (HE) staining results in amorphous eosinophilic appearance when viewed on light microscopy.
      • Amorphous eosinophilic interstitial amyloid observed on renal biopsy
      • Picture was adapted from Bruce A Baethge. Amyloidosis Overview. www.emedicine.medscape.com
      • Congo red staining results in bright green fluorescence/birefringe apple green color when viewed under polarized light.
      • Congo red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light
      • Picture was adapted from Bruce A Baethge. Amyloidosis Overview. www.emedicine.medscape.com
      • Electron microscopy shows regular fibrillar structure
      • X-ray diffraction shows beta pleated sheet structure
    • Classification: Historical vs Modern
      • Historical (Clinical): Primary, Secondary, multiple myeloma associated, Familial.
      • Modern (Biochemical): Since 1960’s based on ability to solubilize fibrils and immunostain for protein subtypes.
      • 23 different human subtypes named based on A for amyloid followed the precursor protein e.g AL, AH.
    • Table was adapted from Harrison's principles of internal medicine 16 th edition vol II, chapter 310-Amyloidosis
    • Further Clinical Manifestations
      • CNS/Neuro: Neuropathy both autonomic and peripheral, dementia. Corneal deposits also.
      • Cardiac:
      • -Cardiomyopathy typically restrictive
      • -Heart failure predominantly right sided
      • -Angina
      • -Sudden death
      • -Syncope/pre-syncope
      • -ECG Abnormalities and Conduction disease
      • -Arrhythmia
      • -Cardiac tamponade occasionally, though uncommon.
      • -Hypotension
    • CARDIAC AMYLOID Adapted from K. Shah et al, Archives of internal medicine 2006.
      • Pulmonary:
      • -P leural effusions
      • -Parenchymal nodules
      • -Tracheal and bronchial infiltration causing hoarseness, airway obstruction and dysphagia.
      • Renal: P roteinuria, nephrotic syndrome, renal failure leading to kidney transplant or dialysis.
      • Heme: Bleeding abnormalities
      • Musc: Hypertrophy of muscles, macroglossia
      • Skin: Nodules, plaques, easy bruising
      • GI: Organomegaly ( Hepatomegaly, splenomegaly), gastroparesis, abnormal bowel movement usually constipation, malabsorption
    • Liver amyloid Adapted from www.google.com/liver amyloid images
    • Diagnosis
      • Unexplained medical disorder and you suspect amyloidosis: e.g heart failure, proteinuria, hepatic dysfunction
      • Check ECG, TTE, BNP, UPEP, SPEP
      • Ultimately, you need Tissue biopsy: Abd fat pad, rectal, salivary gland, endomyocardium.
      • Bone marrow biopsy
    • Treatment
      • Treatment of this medical disorder is limited and research is still in progress.
      • Treatment differs depending on subtype.
      • AL and AH
      • -High dose mephalan plus dexamethasone/prednisone
      • -In selected candidates autologous stem cell transplant is an option.
      • - The goal with treatment is to get rid of clonal plasma cells that lead to immunoglobulin protein
      • AA: Treat the infection or chronic inflammatory condition causing apo serum A protein elevation.
      • Familial Mediterranean fever: Colchicine
      • Other conditions are treated conservatively or require organ transplant
      • Prognosis is poor with this medical disorder.
    • TAKE HOME MESSAGE
      • Can affect any organ system
      • Hematoxylin and Eosin (HE) and Congo stain only tells you these are amyloid fibrils
      • Need to immunostain to determine subtype
      • Different subtypes are treated differently.
      • A lot still have to be known about the therapy as prognosis is poor for this disease.
    • References
      • Rajkumar, S. V. and M. A. Gertz. “Advances in the Treatment of Amyloidosis.” NEJM. 2007. 356: 2413-2415
      • Merlini G and V Bellotti. Molecular Mechanisms of Amyloidosis. New England Journal of Medicine 2003, August: 349:583
      • Baethge B. Amyloidosis Overview. www.emedicine.medscape.com
      • Bogov B, Lubomirova M and Kiperova B. Biopsy of subcutaneous fatty tissue for diagnosis of systemic amyloidosis. Hippokratia. 2008 Oct;12(4):236-9.
      • Dember LM. Modern Treatment of Amyloidosis: Unresolved questions. J Am Soc Nephrol. 2008 Dec 10.
      • Gorevic, Shah, K. B., et al. Amyloidosis and the Heart. Archives of Internal Medicine . 2006. 166: 1805-1813.
      • P. D. An overview of amyloidosis. UpToDate.com
      • J D Sipe and Alan Cohen. Amyloidosis . Harrison’s Principles of Internal Medicine. Chapter 30, page 2024
      • Images and tables were obtained from Harrison’s, Archives of internal medicine, emedicine and google as sited on each image.