Amyloidosis Flashcards
What is amyloidosis?
A group of disorders characterized by a diverse group of proteins accumulating extracellularly, forming amyloid protein fibrils which share similar physical properties
What does amyloid look like on H&E?
Smooth, glassy, eosinophilic extracellular material
What stain is used to visualize amyloid, and what two types of microscopy? How does the stain work?
Congo-red stain -> dye intercalates between the beta-pleated sheet structure of the amyloid fibrils, which are each composed of sets of beta pleated sheets forming filaments, which are crossed at 90 degrees
Light microscopy -> stain will appear red-orange
Polarization microscopy -> appears green or yellow (if you turn it perpendicularly 90 degrees it will change to the other color, since the beta sheets are crossed and 90 degrees offset)
What is the structure and conformation of amyloid proteins and how was this confirmed?
Structure - thin, straight, criss-crossing fibrils (haystack appearance by TEM)
Conformation - Crossed beta-pleated sheets by X-ray crystallography
How does amyloidosis occur?
A protein is overproduced or misproduced so it cannot fold normally. If there is insufficient degradation it will accumulate as these insoluble fibrils
What component is conserved in all amyloid proteins?
Serum amyloid P component -> stabilizes the protein
What are the three major biochemical types of amyloid?
AL - amyloid light chain
AA - amyloid-associated
Abeta - Beta-amyloid
What are the 4 minor biochemical types of amyloid?
ATTR - transthyretin amyloid
Abeta2m - Beta-2 microglobulin amyloid
AE - endocrine amyloid
PrP amyloid - prion protein amyloid
How is AL amyloid formed?
Composed of complete or partial Ig light chains, typically lamda (rather than kappa) light chain
How is AA amyloid formed?
Derived from serum amyloid-associated protein, a positive acute phase protein made from hepatocytes
How is Abeta amyloid formed?
Formed if the Beta-secretase cleaves APP on the surface of neurons before alpha-secretase can (both always have gamma-secretase follow)
How is ATTR formed?
Transthyretin amyloid
Formed by a serum protein accumulating which transports T4 or retinol (vitamin A)
How is Ab2m formed?
Comprised of Beta-2 microglobulin, a protein component of the MHC class 1 molecule
How is AE formed?
Endocrine amyloid -> formed from proteins like calcitonin, islet amyloid polypeptide, and atrial natriuretic factor (ANF)
What are the four types of systemic amyloidosis? Which is most common?
- Primary amyloidosis - most common
- Secondary or reactive amyloidosis
- Hemodialysis-associated amyloidosis
- Senile amyloidosis
How does primary amyloidosis occur and what type of amyloid accumulates?
AL amyloid accumulates
Occurs as a part of plasma cell dyscrasias like multiple myeloma or B-cell lymphoma (if mature B cells)
-> overproduction of free light changes
How does secondary or reactive amyloidosis occur and what type of amyloid accumulates?
AA amyloid accumulates
Occurs in chronic inflammatory diseases with elevated acute phase proteins (rheumatoid arthritis, chronic IBD, even TB / osteomyelitis)
-> accumulation of serum amyloid-association protein from hepatocytes
How does hemodialysis-associated amyloidosis occur and what type of amyloid accumulates? Where does it tend to accumulate?
Beta-2 microglobulin
Occurs in long-term hemodialysis although less frequent now due to membrane pores being made large enough
Amyloid accumulates around joints / tendon sheaths, frequently causing carpal tunnel syndrome
How does senile systemic amyloidosis occur and what type of amyloid accumulates? Where does it tend to accumulate?
Transthyretin accumulates in elderly individuals
Usually normal, rarely genetic mutation. Affects elderly people
-> usually accumulates in the heart (senile cardiac amyloidosis)
What are the two main types of localized amyloidosis?
- Cerebral amyloidosis
2. Endocrine amyloidosis
What type of amyloid accrues in cerebral amyloidosis?
A-beta amyloid -> common in Alzheimer’s and cerebral amyloid angiopathy
What are the three disorders in which you get endocrine amyloidosis (AE amyloid) and where does amyloid accumulate?
- Medullary thyroid carcinoma - cancer of parafollicular cells (C cells) which make calcitonin -> in thyroid
- Type 2 diabetes -> islet amyloid polypeptide accumulates in islets of Langerhaans, a biproduct of increased insulin output (pre-beta-cell failure)
- Isolated atrial amyloidosis -> amyloid deposits derived from atrial natriuretic factor (i.e. heart failure)
Are there other localized places where amyloid proteins can deposit?
yes - it can end up just about anywhere, even the tongue
What are the two types of hereditary / familial amyloidosis?
- Familial Mediterranean fever
2. Familial amyloidotic neuropathies
