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CMOD/PCM- Block 2 > Path: Amyloidosis > Flashcards

Path: Amyloidosis Flashcards

1
Q

What is amyloidosis?

A

a condition associated with a number of inherited immune and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional comprosmise

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2
Q

What makes the abnormal fibrils seen in amyloidosis?

A

aggregations of misfolded proteins; in their normal configuration they would be soluble

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3
Q

The fibrillar deposits in amyloidosis bind a wide variety of what EC substance?

A

proteoglycans and glycosaminoglycans, as well as plasma proteins

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4
Q

What is serum amyloid P component (SAP)?

A

a plasma protein that fibrillar deposits bind in amyloidosis

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5
Q

The presence of abundant charged ____ groups in the amyloid deposits give staining characteristics thought to resemble ____.

A

sugar; starch

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6
Q

With progressive accumulation, amyloid encroaches on and produces ____ ____ of adjacent cells.

A

pressure atrophy

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7
Q

True or False: amyloid is a single protein.

A

False - there are more than 20 different proteins that can aggregate and deposit to form fibrils with the appearance of amyloid

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8
Q

Is amyloidosis considered one or many diseases?

A

It’s considered a group of diseases having in common the deposition of similar-appearing proteins

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9
Q

By EM, all types of amyloid consist of continuous, nonbranching fibrils with a diameter of approximately ____ to ____nm.

A

7.5-10nm

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10
Q

What conformation does amyloid have, seen on Xray crystallography and IR spectroscopy?

A

cross-beta-pleated sheet conformation

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11
Q

Approximately 95% of amyloid material consists of ____ ____, with the remaining 5% being ____ and other ____.

A

fibril proteins; P component and other glycoproteins

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12
Q

What are the 3 most common forms of amyloid?

A
  1. AL (amyloid light chain)
  2. AA (amyloid-associated)
  3. Abeta (beta-amyloid protein)
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13
Q

What are AL proteins made of?

A

complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both

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14
Q

Is the production of AL type amyloid fibril protein from free Ig light chains secreted by a monoclonal or polyclonal population of cells? Which cell type secretes it?

A

monoclonal, plasma cells

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15
Q

The AA type of amyloid fibril is derived from what type of protein?

A

unique non-Ig protein made by the liver: MW of 8500 and 76 aa residues; derived by proteolysis from SAA

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16
Q

What is SAA?

A

serum amyloid-associated (SAA) protein is a larger precursor in the serum that is synthesized by the liver and circulates bound to HDLs; it is cleaved and forms AA fibrils

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17
Q

When is SAA production increased?

A

in inflammatory states as part of the acute phase response; therefore it’s associated with chronic inflammation and often called secondary amyloidosis

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18
Q

What type of amyloid protein makes the core of the cerebral plaques found in Alzheimer’s disease?

A

beta-amyloid protein

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19
Q

Beta amyloid protein is derived by proteolysis from what larger protein?

A

a transmembrane glycoprotein called amyloid precursor protein

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20
Q

What is transthyretin (TTR)?

A

normal serum protein that binds and transports thyroxine and retinol

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21
Q

What protein is the important deposit is familial amyloid polyneuropathies?

A

TTR (and its fragments)

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22
Q

What protein is responsible for complication of the course of patients on long-term hemodialysis?

A

beta-microglobulin, a component of MHC class I molecules and normal serum protein

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23
Q

In a minority of ____ disease in the CNS, misfolded ____ proteins can aggregate in the EC space and acquire to structural and staining characteristics of amyloid protein.

A

prion; prion

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24
Q

How might serum amyloid P protein contribute to amyloid deposition?

A

it might stabilize the fibrils and decrease their clearance

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25
Q

What should normally happen to misfolded proteins?

A

they should be degraded intracellularly in proteosomes, or extracellularly in macrophages

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26
Q

Misfolded proteins generally fall into 2 categories. What are they?

A
  1. normal proteins that have a tendency to fold improperly, and do so when produced in increased amounts
  2. mutant proteins that are prone to misfolding and subsequent aggregation
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27
Q

In states of chronic inflammation, macrophages produce IL-1 and IL-6 which induce liver production of ____ protein, which undergoes limited proteolysis to ____ protein.

A

SAA; AA

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28
Q

True or False: Amyloid is usually localized to a single organ, such as the heart.

A

It depends on the clinical condition, but amyloid can be localized (to a single organ) or generalized/systemic involving several organs.

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29
Q

What is the difference between primary amyloidosis and secondary amyloidosis?

A

primary is associated with a plasma cell disorder, whereas secondary is a complication of an underlying chronic inflammatory or tissue-destructive process

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30
Q

Primary amyloidosis is usually ____ in distribution and of the ____ protein type.

A

systemic; AL protein

31
Q

What are Bence-Jones proteins?

A

free, unpaired kappa or lambda light chains secreted by malignant plasma cells; these are secreted in addition to whole Ig molecules

32
Q

Due to their small molecular size, Bence-Jones proteins are excreted and concentrated where?

A

in the urine

33
Q

What is the amyloidogenic potential of a light chain and what determines it?

A

it’s the likelihood that a light chain will produce amyloid; determined by amino acid sequence

34
Q

True or false: most people with AL amyloidosis have an overt B cell neoplasm that is responsible for the overproduction of proteins prone to misfolding.

A

False - most people with AL amyloidosis DON’T have an overt B cell neoplasm; most cases however have a modest increase in the number of plasma cells in the bone marrow

35
Q

What protein is responsible in reactive systemic amyloidosis and what are the amyloid deposition patterns?

A

AA protein; systemic

36
Q

What are important/common underlying diseases for reactive systemic amyloidosis?

A

RA, ankylosing spondylitis, inflammatory bowel disease (esp. Crohn disease and ulcerative colitis)

37
Q

Heroin abusers who inject the drug subcutaneously have a high occurrence rate of ____ ____ amyloidosis.

A

generalized AA

38
Q

Is increased SAA production sufficient for the deposition of amyloid? Why/why not?

A

No - either because there is defective monocyte-derived enzyme that would otherwise cleave it to a soluble state, or a structural abnormality in SAA may render it resistant to degradation by macrophages

39
Q

What is familial Mediterranean fever?

A

“autoinflammatory” syndrome associated with excessive production of the cytokine IL-1 in response to inflammatory stimuli; clinically: attacks of fever accompanied by serosal inflammation

40
Q

The gene for familial Mediterranean fever encode a protein called ____.

A

pyrin

41
Q

What does pyrin do?

A

it’s one of a complex of proteins that regulated inflammatory reactions via the production of proinflammatory cytokines

42
Q

What is the basis of the familial amyloidotic polyneuropathies?

A

fibrils made of TTRs deposited in peripheral and autonomic nerves; formed because of genetically determined alterations to TTR structure that cause misfolding, aggregation, and resistance to proteolysis

43
Q

Patients on long-term hemodialysis can develop amyloidosis as a result of what?

A

deposition of beta-2 microglobulin which is present in high concentrations in patients with renal disease and not filtered through dialysis membranes; however with newer dialysis filters this complication has decreased substantially

44
Q

Localized amyloid masses can be nodular deposits encountered most often in what locations?

A

lung, larynx, skin, urinary bladder, tongue, and periorbital region

45
Q

True or false: frequently there are infiltrates of lymphocytes and monocytes in the periphery of localized amyloid masses.

A

False - there are infiltrates of lymphocytes and plasma cells

46
Q

Certain endocrine tumors may contain microscopic deposits of localized amyloid. In this setting the amyloidogenic proteins seem to be derived from what?

A

either polypeptide hormones or unique proteins

47
Q

____ ____ amyloidosis refers to the systemic deposition of amyloid in elderly patients (usually in their 70s and 80s).

A

Senile systemic amyloidosis

48
Q

Cardiomyopathy and arrhythmias are symptoms of what type of amyloidosis?

A

Senile systemic amyloidosis, previously called Senile cardiac amyloidosis, where the amyloid is derived from normal TTR

49
Q

True or False: amyloid is always visible macroscopically.

A

False - amyloid may or may not be macroscopically apparent; when it accumulates in larger amounts the organ is often enlarged and appears gray with a waxy, firm consistency

50
Q

When is amyloid deposition seen within cells histologically?

A

never - histologically, the amyloid deposition is always extracellular and begins between cells, eventually encroaching on and destroying them.

51
Q

The histological diagnosis of amyloidosis is based almost entirely on _________.

A

its staining characteristics

52
Q

Under what conditions will you see apple-green birefringence?

A

looking at Congo red stained amyloid under polarized light, you’ll see the apple-green birefringence which is caused by the crossed beta-pleated configuration of amyloid fibrils

53
Q

Why might the kidney appear shrunken in amyloidosis?

A

ischemic changes caused by the deposition of amyloid in the arterial and arteriolar walls

54
Q

Where in the kidney is amyloid primarily deposited?

A

glomeruli

55
Q

What is the process of glomerular amyloidosis?

A

first deposition in mesangial matrix and basement membranes of glomerular capillaries; then cause capillary narrowing and distortion of the glomerular vascular tuft; eventually the capillary lumens are obliterated and the glomerulus is flooded by masses of amyloid

56
Q

What are the two possible patterns of amyloid deposition in the spleen?

A
  1. deposits limited to splenic follicles - called sago spleen
  2. amyloid in walls of splenic sinuses and CT framework in the red pulp; fusion of early deposits gives rise to lardaceous spleen
57
Q

In what organ will there eventually be total replacement of parenchyma by amyloid?

A

liver

58
Q

Describe the amyloid deposition process and consequences in the liver.

A

appears first in space of Disse and progressively encroaches on hepatic cells and sinusoids; eventually pressure atrophy and deformity occurs, as well as deposits in vessels and Kupffer cells; however normal liver function can be preserved

59
Q

Talk to me about amyloidosis of the heart.

A

can occur in any form of amyloidosis, but is the major organ involved in senile systemic amyloidosis; may or may not have macroscopic changes; when the deposits are subendocardial the conduction system of the heart may be damaged, accounting for EEG abormalities noted in some patients

60
Q

Nodular depositions of amyloid in the tongue may cause ____.

A

macroglossia

61
Q

The respiratory tract may be involved in amyloidosis, focally or diffusely from ____ down to ______-?

A

larynx down to smallest bronchioles

62
Q

How does amyloidosis result in carpal tunnel, and which patients have this as a clinical feature?

A

deposition of amyloid in the wrist can compress the median nerve, resulting in carpal tunnel syndrome; happens most prominently in hemodialysis patients

63
Q

How do clinical manifestations of amyloid deposition initially present?

A

as non-specific symptoms, including weakness, weight loss, light-headedness, or syncope

64
Q

Renal involvement in amyloidosis gives rise to ____ that can be severe enough to cause nephrotic syndrome.

A

proteinuria

65
Q

How might cardiac amyloidosis present?

A

as insidious congestive heart failure, conduction disturbances, and arrhythmias; these may prove fatal

66
Q

How might amyloidosis of the GI tract present?

A

can be asymptomatic entirely, or present as difficulty swallowing, malabsorption, diarrhea, digestion disturbances

67
Q

What happens if AL amyloid bind factor X?

A

it will inactivate Factor X, a very important coagulation factor, leading to a life-threatening bleeding disorder

68
Q

What is the prognosis of generalized amyloidosis?

A

poor; AL amyloidosis has median 2yr survival rate

69
Q

What is the prognosis of systemic reactive amyloidosis?

A

even worse than AL amyloidosis

70
Q

Where are therapeutic strategies aimed for treating amyloidosis?

A

at correcting protein misfolding and inhibiting fibrillogenesis

71
Q

Hepatic amyloidosis is most likely to correlate with elevated serum levels of what and why?

A

ALP - this is released in states of liver injury, especially with biliary obstruction and space-occupying lesions, think - because the bile ducts are squeezed
*ALP NOT released with primary hepatocellular disease

72
Q

What are the initial and later symptoms of amyloidosis?

A

initial symptoms are non-specific and include weakness, weight loss; later symptoms include dyspnea, light-headedness, syncope (heart), edema/kidney failure, heart failure, dementia, and peripheral neuropathy

73
Q

Why do amyloid deposits in the heart lead to cardiac arrhythmias?

A

cardiac myocytes have to touch each other to conduct the rhythm, so protein deposition in between them would decreased conductance and would also lead to pressure atrophy of the heart cells

74
Q

Cardiac amyloidosis is most often due to ____ deposition, often in elderly black men.

A

transthyretin

CMOD/PCM- Block 2 (41 decks)

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