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Pathology🦠 > L15: Amyloidosis > Flashcards

L15: Amyloidosis Flashcards

1
Q

Amyloidosis is the disorder of?

A

Protein misfolding

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2
Q

Amyloids can form from a variety of protein; the following characteristics are shared properties:

A
  1. Misfolded proteins take the form of beta pleated sheets (which are insoluble & the reason why amyloids resist degradation)
  2. The misfolded proteins are resistant to degradation (intracellularly by proteasomes or extracellularly by macrophages as in a normal situation)
  3. The fibrillar deposits (from b-pleated sheets) bind to glycoproteins (e.g serum amyloid P [SAP]) ➡️ makes them resemble starch (amylose) ➡️ hence its name Amyloid

[SUMMARY]
1. Form beta sheets
2. Resist degradation
3. Bind to glycoproteins

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3
Q

To diagnose Amyloidosis, we use…

A
  1. Amyloid ultrastructure:
    Amyloid substances are characterized by a fibrillar appearance on electron microscopy
  2. Congo red staining ➡️ amyloid gives a redish/pink color
  3. Polarized light ➡️ apple-green
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4
Q

How is the amyloid given a red appearance?

A

The congo red stain binds to sugar (5% of amyloid protein)

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5
Q

The proteins that form amyloid fall into 2 categories:

A

1- Normal proteins that are produced in increased amounts and have a tendency to fold improperly and form fibrils

2- Mutant proteins that are prone to misfolding and subsequent Insoluble aggregation

Basically ya3ni wa7ed mnhum normal bas wayed is produced, w il thanee mo normal bl asas

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6
Q

Summarize the pathophysiology of Amyloids

A

incomplete proteolytic degradation of the misfolded proteins➡️ misfolded proteins deposit in the extracellular space often on basement membranes and around blood vessels ➡️ Amyloid deposits cause tissue injury and impair normal function by causing pressure on cells and tissues.

summary:
No degradation ➡️ Pressure on cell ➡️ Prevent cell from having their functional space ➡️ Tissue injury

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7
Q

True or false:

Amyloids do not evoke an inflammatory response

A

True

Explanation:
-Usually, tissue injury evoke an inflammatory response

-however, Pressure of amyloid deposition compromises the functions of tissues/organs but doesn’t trigger inflammation

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8
Q

Amyloid can be classified according to?

A
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9
Q

On clinical grounds, the systemic pattern of amyloidosis is sub-classified into?

A
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10
Q

On clinical grounds of Amyloidosis , the____________ pattern is sub-classified into primary amyloidosis and secondary amyloidosis

A

systemic

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11
Q

1) What is the most common form of amyloidosis in the US?
&
2) Amyloidosis of what organ is the most common and most serious feature of the disease?

A

1) Primary Systematic Amyloidosis
&
2) Amyloidosis in the kidney

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12
Q

What causes Primary & secondary systemic amyloidosis?

A

Primary: It is caused by AL protein (Amyloid Light chain), a protein produced by plasma cells

Secondary: Caused by AA (amyloid-associated) protein. This is derived from serum precursor SAA (serum amyloid- associated) protein

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13
Q

Describe how primary systematic Amyloidosis occurs

A

Cell cancer called MULTIPLE MYELOMA (high production of plasma cells; AL type is associated with some form of monoclonal B cell proliferation)
⬇️
Plasma cells secrete high amounts of antibodies
⬇️
So we have a high amount of light chain proteins produced which are λ and k (kapa), which are also called Bence Jones proteins
⬇️
Bc these proteins are produced in high amounts, they are prone to misfolding and to become insoluble
⬇️
They accumulate in the bone marrow and travel to different organs e.g. kidney, heart (systematic)

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14
Q

True or false

All multiple myeloma patients have amyloidosis

A

False

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15
Q

Defective degradation is the basis for___________ in many organs

A

fibril deposition

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16
Q

Why are the amyloid fibrils deposited in many organs?

A

Bc of defective degradation

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17
Q

What is diagnostic for multiple myeloma?

A

Bence Jones protein in the urine

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18
Q

How and where is the SAA protein synthesize?

A

synthesized in the liver under the influence of cytokines such as IL-6 and IL-1 produced during inflammation (Acute phase reaction).

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19
Q

Describe how Secondary (reactive) systemic amyloidosis is caused

A

Acute inflammation
⬇️
Cytokines IL-6 & IL-1 produced during inflammation (acute phase reaction)
⬇️
They synthesize the precursor SAA protein
⬇️
Long-standing inflammation leads to elevated SAA levels and the deposition of AA amyloid
⬇️
AA amyloid deposits in many organs secondary to chronic inflammation and autoimmnune diseases.

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20
Q

Does elevation of SAA levels lead to amyloidosis

A

No,

  • Elevation of serum SAA levels is common to inflammatory states but in most instances does NOT lead to amyloidosis.
  • DEFECTIVE DEGRADATION by cellular enzymes or macrophages result in insoluble AA protein accumulation.
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21
Q

Other forms of systemic amyloidosis:

A

1- Familial amyloid polyneuropathies (inherited)👨‍👩‍👧‍👦
2- Senile systemic amyloidosis (very common in old people)👵🏼👴🏼
3 - Hemodialysis-associated amyloidosis

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22
Q

Familial amyloid polyneuropathies:

A

Transthyretin (TTR) is a normal serum protein that binds and transports thyroxine (Thyroid hormone: T4) and retinol.
⬇️
Mutations in the gene encoding TTR may alter its structure
⬇️
protein prone to misfolding and aggregation, and resistant to proteolysis.
⬇️
Amyloid deposition in these cases is predominantly in the peripheral and autonomic nerves. 🧠

23
Q

In Familial amyloid polyneuropathies, where are the amyloids deposited?

A

in the peripheral and autonomic nerves.

24
Q

Senile systemic amyloidosis:

A
  • systemic deposition of amyloid (TTR protein) in elderly people (usually in their 70s and 80s)
  • in such cases, the protein is structurally normal, but it accumulates at high concentrations.
25
Q

What is another name for senile systematic amyloidosis and why

A

Because of the dominant involvement of the heart (typically manifesting as a restrictive cardiomyopathy and arrhythmias), this form is also called senile cardiac amyloidosis.

26
Q

What protein is deposited in the organs in senile systematic amyloidosis

A

TTR protein

27
Q

What is Hemodialysis-associated amyloidosis caused by?

A

Caused by β2-Microglobulin (Aβ2m) ; a component of MHC class I molecules and a normal serum protein.

28
Q

Hemodialysis-associated amyloidosis :

A

β2-Microglobulin (Aβ2m) protein is present in high concentrations in the serum of patients with chronic renal disease
⬇️
This molecule is not cleared/filtered during hemodialysis (it cant pass the dialysis membranes)
⬇️
is retained in the circulation ➡️ accumulates and increases its tendency to misfold
⬇️
deposits in the synovium and joints.

∴ People with chronic renal failure undergo long-term hemodialysis & develop amyloid (Aβ2m) deposits in the synovium and joints.

29
Q

Localized senile cerebral amyloidosis is caused by?

A

Caused by Aβ amyloid.

30
Q

How is Localized senile cerebral amyloidosis caused?

A

large transmembrane glycoprotein called amyloid precursor protein (APP)
⬇️
Aβ peptide is derived from it
⬇️
this Amyloid deposits in cerebral blood vessels
⬇️
It is found in the cerebral lesions of Alzheimer disease (and causes ischemia in some conditions)

31
Q

Describe how endocrine amyloids deposit and where

A

So in this case we have normal protein, but due to cancer, high amounts are secreted leading to aggregation and amyloid deposition

32
Q

QUESTION

Which type of amyloid produces (AL)?

A. Immune derived
B. Reactive
C. Heredofamilial

A

ANSWER: A

why?
AL: amyloid light chain: primary systematic amyloidosis: immune derived

33
Q

What is the disease associated with senile cerebral localized amyloidosis?

A

Alzheimer’s disease

34
Q

Multiple myeloma and other monoclonal plasma cell proliferations are associated with which Amyloidosis Clinicopathologic category?

A

Primary systematic amyloidosis

35
Q

What is the major fibril protein in familial amyloidotic neuropathies and systematic senile amyloidosis?

A

ATTR

Amyloid transthyretin

36
Q

AA fibril amyloid protein is found in?

A
  1. Secondary (reactive) systematic amyloidosis
  2. Familial Mediterranean Fever
37
Q

List the hereditary Amyloidosis

A
  1. Familial Mediterranean fever
  2. familial amyloidotic neuropathies (several types)
  3. Systematic senile amyloidosis
38
Q

No question just a picture of amyloidosis pathogenesis:

A
39
Q

Amyloidosis of the kidney:

  1. What happens to the shape of the kidney?
  2. Where are the amyloid deposits found in the kidney?
A
  1. The kidney may be abnormally large (due to accumulation of protein) and firm or may be atrophied due to ischemia.
  2. The amyloid deposits are found in the glomeruli and the walls of the blood vessels causing marked vascular
    narrowing
40
Q

What happens when the amyloid deposits cause the blood vessels to narrow?

A

Glomeruli can’t reabsorb protein➡️Nephrotic syndrome➡️Edema

41
Q

Amyloidosis of the heart occurs…

(Don’t forget to name the form of amyloid involved)

A

1- As isolated organ involvement in older persons (senile cardiac amyloidosis).
-The amyloid in this form is mostly derived from normal TTR.

2- As part of a systemic distribution
(Systemic involvement is usually of the AL form).

42
Q

Amyloidosis of the heart:

  1. Where are the deposits found?
  2. What are the effect of these deposits on that area?
  3. The patient is clinically presented with what disease?
A
  1. Amyloid deposits are typically found in the myocardium
  2. They cause pressure atrophy of the myocardial fibers.
  3. Patients present with a restrictive cardiomyopathy and arrhythmias.

(For ur knowledge: Cardiomyopathy is a general term for diseases of the heart muscle, where the walls of the heart chambers have become stretched, thickened or stiff. This affects the heart’s ability to pump blood around the body.)

43
Q

Amyloidosis of the Liver:

  1. Where are the deposits found?
  2. What are the effect of these deposits on that area?
A

Amyloid deposits in hepatic parenchyma.
⬇️
The trapped liver cells undergo compression atrophy
⬇️
They are eventually replaced by sheets of amyloid.
⬇️
Amyloidosis of the liver may cause enlargement of the organ (hepatomegaly), bc of protein accumulation

44
Q

Most and least organ affected by Amyloidosis:

A

Most: kidney
Least: liver

45
Q

What is the Prognosis of Amyloidosis

A

The prognosis of systemic amyloidosis is poor, with the mean survival time after diagnosis ranging from 1 to 3 years.

Prognosis depends on the control of the underlying condition.

46
Q

TRUE OR FALSE

Resorption of amyloid after treatment is common.

A

False, it’s rare

47
Q

the clinical course of amyloidosis depends on?

A

the site or organ affected and the severity of the involvement.

48
Q

What are the nonspecific common manifestations of Amyloidosis and what are the later ones?

A

Nonspecific common: weakness, fatigue, and weight loss

Later manifestations (associated with affected organ):

1) kidney:
Renal involvement ➡️ severe proteinuria (nephrotic syndrome) ➡️ major cause of symptoms in 2° amyloidosis ➡️ renal failure

2) Cardiac amyloidosis:
Manifested as conduction disturbances & cardiac arrhythmias➡️ imp causes of death
(40% of the patients with AL amyloid died of cardiac disease.)

3) Liver:
Hepatosplenomegaly: Rare but significant clinical dysfunction.

49
Q

What is the most important tool in the diagnosis of Amyloidosis? Confirmation can be obtained by?

A

Biopsy and Staining (congo red)

Confirmation can be obtained by ELECTRON MICROSCOPY to see the thin fibrils.

50
Q

What are low risk methods for the diagnosis of systematic amyloidosis?

A

1) Rectal and gingival biopsy specimens,
2) abdominal fat aspirates
are low-risk methods for systemic types.

51
Q

When diagnosing Amyloidosis, biopsy is taken from ?

A

The organ involved

52
Q

Typing of the Amyloid: AA, AL, and ATTR types of amyloid can be distinguished from one another by?

A

specific immunohistochemical (Antibody specific for antigen) staining that target the specific precursor protein.

53
Q

In suspected cases of AL amyloidosis what kind of tests are done?

A

serum and urinary protein electrophoresis is done.

And to confirm the type of amyloidosis, Immunostaining is done to detect specifically the kappa/lambda light chain

54
Q

Summary of the diagnosis of Amyloidosis:

A

Pathology🦠 (2 decks)

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