Outline of Lecture
AMYLOIDOSIS
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.
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.
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
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.
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
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.
