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Anatomic And Molecular Pathology > Amyloidosis > Flashcards

Amyloidosis Flashcards

1
Q

What is amyloidosis❓

What is the general pathophysiology behind it’s generation❓

A
  1. Amyloidosis is deposition of fibrillar proteins in the ECF which causes tissue damage
2. 
Inherited disorder/inflammation 
⬇️
Abnormal misfolding of proteins
⬇️
🚫degradation by proteasomes/macrophages 
⬇️
Aggregation of insoluble abnormal fibrils 
⬇️
Fibrillar deposits bind to proteoglycans, glycosaminoglycans (heparan and dermatan sulfate) and plasma proteins
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2
Q

How would you identify an amyloid❓

A 
1.
Light microscopy (H and E stain):
Amorphous
Eosinophilia 
Hyaline, extracellular substance

2.
Congo Red stain:
Pink/red tissue deposits

  1. Polarizing microscopy:
    Green birefringence
  2. Waxy, firm enlarged organ
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3
Q

Describe the:

  1. Physical
  2. Chemical structure

of an amyloid

A
  1. Election microscopy:
    Presence of continuous, non-branching fibrils

Diameter- 7.5-10nm

X-ray crystallography/Infrared Spectoscopy:
Cross-b-pleated sheet conformation

  1. Fibril proteins (95%)
    P component and glycoproteins (5%)
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4
Q

What are the forms of an amyloid fibril❓

A

1.
AL (Amyloid light chain) protein:
•made of complete immunoglobulin light chains or a.a terminal fragments
•produced by monoclonal population of plasma cells
•deposition is associated w plasma cell tumors

2.
AA (Amyloid Associated Type):
•derived from non-Ig protein made by liver SAA (serum amyloid associated) protein 
•circulates bound to HDLs
•produced in inflammatory states 
•associated w chronic inflammation 
•secondary amyloidosis

3.
Beta-amyloid protein:
•constitutes the core of cerebral plaques in Alzheimer’s dx
•deposited in walls of cerebral blood vessels

  1. TTR, Transthyretin:
    •serum protein that binds and transports thyroxine and retinol
    •mutant forms are deposited in some disorders (familial amyloid polyneuropathies)
    •and in the heart of the aged (senile systemic amyloidosis)
  2. Beta-microglobulin:
    •component of MHC class I, Normal serum protein
    •found in amyloidosis in pt with long-term hemodialysis
  3. Prion
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5
Q

The amyloid protein, TTR, Transthyretin, is seen in which conditions❓

A

Familial amyloid polyneuropathies

Senile systemic amyloidosis

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6
Q

The amyloid protein, b-microglobin, is seen in which condition❓

A

long-term hemodialysis

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7
Q

The amyloid protein, Beta-amyloid protein, is seen in which condition❓

A

Alzheimer’s dx

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8
Q

What other minor components are present in amyloids❓

A

Serum amyloid P component

Proteoglycans

Sulfate glucosaminoglycans

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9
Q

Primary amyloidosis…

  1. Caused by❓
  2. Systemic/local in distribution❓
  3. Is of which type❓
  4. Associates with which dx❓
A
  1. Clonal proliferation of plasma cells that synthesize an Ig
  2. Systemic in distribution
  3. AL-type and most common
  4. Multiple myeloma
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10
Q

Reactive Systemic amyloidosis…

  1. Caused by❓
  2. Systemic/local in distribution❓
  3. Is of which type❓
  4. Associates with which dx❓
A
  1. Secondary to chronic inflammation
  2. Systemic
  3. AA protein
4. 
Rheumatoid arthritis (3%)
IV heroin abusers 
Renal cell and Hodgkin lymphoma 
Ankylosing spondylitis 
Crohn dx
Ulcerative colitis
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11
Q

What is the mechanism of amyloid formation in reactive systemic amyloidosis❓

A 
Chronic inflammation
⬇️
IL-6 and IL-1 stimulate sustained SAA synthesis by hepatocytes 
⬇️
🚫breakdown of SAA
⬇️
Insoluble AA molecules
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12
Q

Heredofamilial amyloidosis…

  1. Caused by❓
  2. Systemic/local in distribution❓
  3. Is of which type❓
  4. Associates with which dx❓
A 
In Familial Mediterranean Fever:
⬇️
Encoding of pyrin protein
⬇️
Generation of pro-inflammatory cytokines
⬇️
Inflammation
⬇️
Excessive production of IL-1

OR

Familial amyloidotic polyneuropathies
⬇️
Alteration of structure of TTRs
⬇️
Misfolding and aggregation of mutant TTRs
⬇️
🚫proteolysis
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13
Q
  1. a. What is the mode of inheritance of Familial Mediterranean Fever❓

b. What is it characterized by❓
2. What is the mode of inheritance of Familial amyloidotic polyneuropathies❓

A

1.
a. Autosomal recessive

b. Bouts of fever
Inflammation of serosal surfaces

2.
Autosomal dominant

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14
Q

Endocrine amyloids can be found in which endocrine disorders❓

A

Medullary carcinoma of the thyroid

Islet tumors of the pancreas

Pheochromocytomas

Undifferentiated carcinomas of the stomach

Type 2 DM

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15
Q

Amyloid of aging…

  1. Systemic/local in distribution❓
  2. Associates with which dx❓
  3. Is of which type❓
A
  1. Systemic
  2. Restrictive cardiomyopathy
    Arrhythmias
  3. Normal TTR
    Mutant TTR
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16
Q

What morphological changes are observed in a kidney with amyloids❓

A

Grossly:
Normal/Shrunken (advances cases)

Histologically:
•Mainly glomerular deposition 
•Widened basement membrane of glomerular capillaries 
•Capillary narrowing (obliteration)
•Distortion of glomerular vascular tuft 
•Thickened mesengial matrix
17
Q

What morphological changes are observed in a spleen with amyloids❓

A

Gross:
Splenomegaly (800g)
Tapioca-like granules/sago spleen (deposits in splenic follicles)

OR

Deposition in walls of splenic sinuses and connective tissue framework of red pulp
Fusion give rise to large, maplike areas (lardaceous spleen)

18
Q

What morphological changes are observed in a liver with amyloids❓

A

Moderate to marked hepatomegaly

First appears in space of Disse

Encroaches on parenchymal cells and sinusoid

Disappearance of hepatocytes and total replacement

Normal function is preserved

19
Q

What morphological changes are observed in a heart with amyloids❓

A

Most occurs in systemic amyloidosis

Main organ involved in senile systemic amyloidosis

No significance changes OR
Enlarged, firm

20
Q

What is the main organ involved in senile systemic amyloidosis❓

A

The heart

21
Q

What other organs can be involved amyloidosis❓

A

Tongue (Macroglossia)

Joint deposition

Brain deposition (Alzheimer’s)

Respiratory tract (larynx to bronchioles)

Amyloidosis of peripheral and autonomic nerves

22
Q

What are the clinical features associated w amyloidosis❓

A

Asymptomatic

Non specific weakness, weight loss, syncope

Nephrotic/Renal failure/Uraemia

Congestive heart failure/Restrictive cardiomyopathy

Macroglossia/Malabsorption/Diarrhea

Bleeding

23
Q

How would you make a confirmatory diagnosis of amyloidosis❓

What is the prognosis❓

A

1.
Biopsy (mostly kidney)

Bone marrow aspirates (plasma cell neoplasm)

2.
Poor in generalized amyloidosis

Anatomic And Molecular Pathology (14 decks)

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