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AMYLOIDOSIS.ppt AMYLOIDOSIS.ppt Presentation Transcript

  • AMYLOIDOSIS Senior Talk Collins Okolie PGY3
    • 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.
    • 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.
    • 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 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.
    • 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.
    • 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.
    • 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.