AMYLOIDOSIS

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AMYLOIDOSIS

• Senior Talk
• Collins Okolie PGY3

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OBJECTIVES

• Definition
• Mechanism of formation
• Characteristics common to all amyloid subtypes
• Classification
• Clinical Importance/Symptoms
• Diagnosis and Treatment
• Take home message

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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

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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.

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• In 1854 Rudolph Virchow named it amyloid based on
  color after staining these proteins with iodine
  and sulfuric acid. Meaning cellulose or starch

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Characteristics common to all amyloid subtypes

• Hematoxylin and Eosin (HE) staining results in
  amorphous eosinophilic appearance when viewed on
  light microscopy.

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• Amorphous eosinophilic interstitial amyloid
  observed on renal biopsy
• Picture was adapted from Bruce A Baethge.
  Amyloidosis Overview. www.emedicine.medscape.com

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• Congo red staining results in bright green
  fluorescence/birefringe apple green color when
  viewed under polarized light.

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• 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

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• Electron microscopy shows regular fibrillar
  structure
• X-ray diffraction shows beta pleated sheet
  structure

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Classification Historical vs Modern

• Historical (Clinical) Primary, Secondary,
  multiple myeloma associated, Familial.
• Modern (Biochemical) Since 1960s 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.

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Table was adapted from Harrison's principles of
internal medicine 16th edition vol II, chapter
310-Amyloidosis
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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

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CARDIAC AMYLOID
Adapted from K. Shah et al, Archives of internal
medicine 2006.
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• Pulmonary
• -Pleural effusions
• -Parenchymal nodules
• -Tracheal and bronchial infiltration causing
  hoarseness, airway obstruction and dysphagia.
• Renal Proteinuria, nephrotic syndrome, renal
  failure leading to kidney transplant or dialysis.

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• Heme Bleeding abnormalities
• Musc Hypertrophy of muscles, macroglossia
• Skin Nodules, plaques, easy bruising
• GI Organomegaly (Hepatomegaly, splenomegaly),
  gastroparesis, abnormal bowel movement usually
  constipation, malabsorption

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Liver amyloid
Adapted from www.google.com/liver amyloid images
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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

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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

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• 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.

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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.

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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 349583
• 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
  Oct12(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. Harrisons
  Principles of Internal Medicine. Chapter 30, page
  2024
• Images and tables were obtained from Harrisons,
  Archives of internal medicine, emedicine and
  google as sited on each image.