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PATHOMORPHOLOGY > Amyloidosis > Flashcards

Amyloidosis Flashcards

1
Q

What is amyloidosis?

A
  • it is a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of FIBRILLAR proteins are responsible for tissue damage and functional compromise.
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2
Q

Amyloidosis is fundamentally a…..

A

disorder of rotein misfolding

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3
Q

Amyloid:

A
  • not a structurally homogenous protein

- 23 different proteins can aggregate to form fibrils with the appearance of amyloid

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4
Q

All amyloid deposits are…..

A
  • composed of nonbranching fibrils

- formed of β-sheet polypeptide chains

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5
Q

Dye for amyloids

A
  • Congo red staining shows an apple-green birefringence under polarized light
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6
Q

What happens with the misfolded proteins in amyloidosis?

A

they are accumulated outside the cell

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7
Q

Describe the misfolded proteins in amyloidosis?

A
  • unstable
  • self-associate
  • leads to the formation of oligomers and fibrils that are deposited in the tissue
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8
Q

Where does the misfolded proteins in amyloidosis come from?

A
  • normal proteins that have an inherent tendency to fold improperly, associated to form fibirls, and do so when they are produced in increased amounts
  • mutant proteins that are prone to misfolding and subsequent aggregation
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9
Q

Most common amyloid proteins:

A
  • AL (amyloid light chain) protein
  • AA (amyloid-associated) fibril
  • Aβ amyloid
  • Transthyretin (TTR)
  • β2-microglobulin
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10
Q

AL (amyloid light chain) protein:

A
  • produced by plasma cells
  • made up of complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both
  • associated with some form monoclonal B cell proliferation
  • defective degradation has also been invoked as the basis of fibril formation, and perhaps particular light chains are resistant to complete proteolysis
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11
Q

AA (amyloid-associated) fibril:

A
  • a unique nonimmunoglobulin protein derived from a larger (12-kDa) serum precursor called SAA (serum amyloid-associated) protein that is synthesised in the liver
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12
Q

Where is SAA (serum amyloid-associated) synthesized?

A

liver, under the influence of cytokines such as IL-6 and IL-1 that are produced during inflammation

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13
Q

SAA =

A

serum amyloid-associated

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14
Q

What leads to elevated SAA levels in the serum?

A

inflammation. in most instances does not lead to amyloidosis

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15
Q

Long-standing inflammation leads to……

A
  • elevated SAA levels, and ultimately the AA form of amyloid deposits.
  • ppl who develop amyloidosis have an enzyme defect that result in incomplete breakdown of SAA, thus generating insoluble AA molecule.
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16
Q

Aβ amyloid:

A
  • found in cerebral lesions of Alzeheimer disease
  • Aβ is a 4-kDa peptide that constitutes the core of cerebral plaques and the amyloid deposits in cerebral blood vessles in this disease
  • Aβ protein is derived from a much larger glycoprotein called amyloid precursor protein (APP)
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17
Q

Where is the Aβ protein derived from?

A

Aβ protein is derived from a much larger glycoprotein called amyloid precursor protein (APP)

18
Q

Transthyretin (TTR):

A
  • normal serum protein
  • transports thyroxine and retinol
  • altered structure of this protein -> resistance to proteolysis
  • familial amyloid polyneuropathies; abnormal structure
  • senile systemic amyloidosis; the structure is normal but accumulated at hight concentrations
  • some cases of familial amyloidosis are associated with deposits of mutant lysozyme
19
Q

β2-microglobulin:

A
  • component of MHC class I molecule
  • normal serum protein
  • identified as amyloid fibril subunit (Aβ2m) in amyloidosis that complicated the course of patients on long-term hemodialysis
20
Q

Aβ2m fibers are structurally similar to

A

β2m protein

21
Q

β2m protein is present in high levels…….

A

in serum in patients with renal disease. 60-80% of patients on long-term dialysis developed amyloid deposits in the synovium, joints, and tendon sheaths.

22
Q

Amyloidosis may be….

A
  • systemic (generalized): involving several organs

- localized, when deposites are limited to one single organ

23
Q

The systemic, or generalized, category of amyloidosis is subclassified into….

A
  • primary amyloidosis; when associated with a monoclonal plasma cell proliferation
  • secondary amyloidosis; when it occurs as a complication of an underlying chronic inflammatory or tissue destructive process
24
Q

Give an example of a primary amyloidosis;

A

Immunocyte dyscrasias with amyloidosis

25
Q

Give an example of a secondary amyloidosis;

A

Reactive systemic amyloidosis

26
Q

Primary amyloidosis: Immunocyte dyscrasias with amyloidosis

A
  • AL type
  • most common form of amyloidosis
  • readily identifiable monoclonal plasma cell proliferation
27
Q

Multiple myeloma (systemic amyloidosis in 5%-15% of patients);

A

a plasma cell tumor characterized by multiple osteolytic lesions throughout the skeletal system
- the malignant plasma cells characteristically synthesize abnormal amounts of a single specific immunoglobulin, producing an M (myeloma) protein spike on serum electrophoresis

28
Q

What is affected in amyloidosis secondary to chronic inflammatory disorder;

A

kidneys, liver, spleen, lymph nodes, adrenals, and thyroid, as well as many tissue.

29
Q

What is affected in primary (AL) amyloidosis:

A
  • heart
  • GI tract
  • respiratory tract
  • peripheral nerve
  • skin
  • tongue
30
Q

What is affected in reactive systemic amyloidosis (secondary amyloidosis):

A
  • heart
  • GI tract
  • respiratory tract
  • peripheral nerve
  • skin
  • tongue
  • kidneys
  • liver
  • spleen
31
Q

In familial Mediterranean fever:

A
  • widespread

- involving the kidneys, blood vessels, spleen, respiratory tract, and (rarely) liver

32
Q

Amyloidosis of the kidney;

A
  • the most common most common and most serious feature of the disease
  • abnormally large (200-800mg), pale, gray, and firm; in long-staning cases, the kidney may be redused in size
  • amyloid deposits are found principally n the glomeruli, but they are also present in the interstitial peritubular tissue as well as in the wall blood vessels
33
Q

Amyloidosis of the spleen;

A
  • moderate or even marked enlargement
  • producing tapioca-like granules on gross examination (“sago spleen”) in the splenic follicles
  • splenic pulp (“lardaceous spleen”)
  • red color
34
Q

Amyloidosis of the liver;

A
  • may cause massive enlargement (9000mg)
  • pale, grayish, and waxy on both the external surface and cut section
  • amyloid deposits first appear in the space of Disse
  • liver cells undergo compression ATROPHY and are eventually replaced by sheets of amyloid
  • normal liver function
35
Q

Amyloidosis of the heart;

A
  • may occur either as isolated organ involvement or as a part of a systemic distribution
  • systemic involvement -> usually AL form
  • isolated form (senile amyloidosis)
  • gray-pink, dewdrop-like subendocardial elevations, particulary evident in the atrial chambers
  • pressure atrophy
36
Q

What may produce macroglossia?

A

nodular depositions in the tongue

37
Q

Where does the β2-microglobulin amyloid in patients receiving long-term dialysis most commonly occur?

A

carpal ligaments of the wrist, resulting in compression of the median nerve (leading to carpal tunnel syndrome)

38
Q

Nonspecific complaints of patients with amyloidosis;

A
  • weakness
  • fatigue
  • weight loss
39
Q

How does the amyloidosis manifest itself;

A
  • hepatomegaly
  • splenomegaly
  • cardiac abnormalities (disturbances or restrictive cardiomyopathy)
  • renal involvement giving rise to severe proteinuria (nephrotic syndrome) often is the major cause of symptoms in systemic amyloidosis
40
Q

What is an important cause of death in cardiac amyloidosis?

A

cardiac arrythmias

PATHOMORPHOLOGY (6 decks)

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