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Pathobiology > Amyloidosis > Flashcards

Amyloidosis Flashcards

1
Q

What is amyloidosis?

A

A group of disorders characterized by a diverse group of proteins accumulating extracellularly, forming amyloid protein fibrils which share similar physical properties

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2
Q

What does amyloid look like on H&E?

A

Smooth, glassy, eosinophilic extracellular material

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3
Q

What stain is used to visualize amyloid, and what two types of microscopy? How does the stain work?

A

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)

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4
Q

What is the structure and conformation of amyloid proteins and how was this confirmed?

A

Structure - thin, straight, criss-crossing fibrils (haystack appearance by TEM)

Conformation - Crossed beta-pleated sheets by X-ray crystallography

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5
Q

How does amyloidosis occur?

A

A protein is overproduced or misproduced so it cannot fold normally. If there is insufficient degradation it will accumulate as these insoluble fibrils

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6
Q

What component is conserved in all amyloid proteins?

A

Serum amyloid P component -> stabilizes the protein

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7
Q

What are the three major biochemical types of amyloid?

A

AL - amyloid light chain

AA - amyloid-associated

Abeta - Beta-amyloid

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8
Q

What are the 4 minor biochemical types of amyloid?

A

ATTR - transthyretin amyloid

Abeta2m - Beta-2 microglobulin amyloid

AE - endocrine amyloid

PrP amyloid - prion protein amyloid

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9
Q

How is AL amyloid formed?

A

Composed of complete or partial Ig light chains, typically lamda (rather than kappa) light chain

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10
Q

How is AA amyloid formed?

A

Derived from serum amyloid-associated protein, a positive acute phase protein made from hepatocytes

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11
Q

How is Abeta amyloid formed?

A

Formed if the Beta-secretase cleaves APP on the surface of neurons before alpha-secretase can (both always have gamma-secretase follow)

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12
Q

How is ATTR formed?

A

Transthyretin amyloid

Formed by a serum protein accumulating which transports T4 or retinol (vitamin A)

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13
Q

How is Ab2m formed?

A

Comprised of Beta-2 microglobulin, a protein component of the MHC class 1 molecule

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14
Q

How is AE formed?

A

Endocrine amyloid -> formed from proteins like calcitonin, islet amyloid polypeptide, and atrial natriuretic factor (ANF)

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15
Q

What are the four types of systemic amyloidosis? Which is most common?

A
  1. Primary amyloidosis - most common
  2. Secondary or reactive amyloidosis
  3. Hemodialysis-associated amyloidosis
  4. Senile amyloidosis
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16
Q

How does primary amyloidosis occur and what type of amyloid accumulates?

A

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

17
Q

How does secondary or reactive amyloidosis occur and what type of amyloid accumulates?

A

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

18
Q

How does hemodialysis-associated amyloidosis occur and what type of amyloid accumulates? Where does it tend to accumulate?

A

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

19
Q

How does senile systemic amyloidosis occur and what type of amyloid accumulates? Where does it tend to accumulate?

A

Transthyretin accumulates in elderly individuals

Usually normal, rarely genetic mutation. Affects elderly people

-> usually accumulates in the heart (senile cardiac amyloidosis)

20
Q

What are the two main types of localized amyloidosis?

A
  1. Cerebral amyloidosis

2. Endocrine amyloidosis

21
Q

What type of amyloid accrues in cerebral amyloidosis?

A

A-beta amyloid -> common in Alzheimer’s and cerebral amyloid angiopathy

22
Q

What are the three disorders in which you get endocrine amyloidosis (AE amyloid) and where does amyloid accumulate?

A
  1. Medullary thyroid carcinoma - cancer of parafollicular cells (C cells) which make calcitonin -> in thyroid
  2. Type 2 diabetes -> islet amyloid polypeptide accumulates in islets of Langerhaans, a biproduct of increased insulin output (pre-beta-cell failure)
  3. Isolated atrial amyloidosis -> amyloid deposits derived from atrial natriuretic factor (i.e. heart failure)
23
Q

Are there other localized places where amyloid proteins can deposit?

A

yes - it can end up just about anywhere, even the tongue

24
Q

What are the two types of hereditary / familial amyloidosis?

A
  1. Familial Mediterranean fever

2. Familial amyloidotic neuropathies

25
Q

What causes Familial Mediterranean fever?

A

Autosomal recessive mutation in pyrin, a regulator of pro-inflammatory cytokines. Leads to recurring fever and joint pains with overproduction of IL-1 -> systemic accumulation of AA amyloid

26
Q

What causes familial amyloidotic neuropathies? What does it affect?

A

Autosomal dominant disorder of transthyretin -> mutant ATTR accumulates in peripheral / autonomic nerves

27
Q

How do organs with amyloid appear grossly?

A

Enlarged, firm and pale

28
Q

What happens to blood vessels in interstitial and intravascular amyloid accumulation?

A

They become brittle and prone to hemorrhage

29
Q

What is the most common site of amyloid accumulation if you have systemic amyloidoses, and what will happen if this occurs?

A

Kidney

  • > accumulates within glomeruli, arteries, and interstitium
  • > proteinuria and eventual renal failure
30
Q

Where will amyloid accumulate in the liver and what happens if this occurs?

A

In the space of Disse (between the sinusoids and hepatocytes)

The hepatocytes around the accumulation will undergo pressure atrophy, but liver will not fail until late because there are a great excess of hepatocytes

31
Q

Why is amyloidosis in the spleen so diagnostic?

A

You will have splenomegaly but no thrombocytopenia (typical of splenomegaly)
-> amyloid protein will accumulate and not leave a place for platelets to stay

32
Q

What are sago spleen vs lardaceous spleen?

A

Sago spleen - accumulation of amyloid in white pulp

Lardaceous spleen - accumulation of amyloid in red pulp

33
Q

What happens when amyloid accumulates in the tongue?

A

Causes skeletal muscle atrophy and macroglossia -> speech / swallowing impairment since the tongue is so big.

34
Q

Where does amyloid tend to accumulate in the skin?

A

Under the eyelids

Pathobiology (20 decks)

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