Amyloidosis

Question 1

What is amyloidosis?

Answer 1

• 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.

Question 2

Amyloidosis is fundamentally a…..

Answer 2

disorder of rotein misfolding

Question 3

Amyloid:

Answer 3

• not a structurally homogenous protein

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

Question 4

All amyloid deposits are…..

Answer 4

• composed of nonbranching fibrils

- formed of β-sheet polypeptide chains

Question 5

Dye for amyloids

Answer 5

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

Question 6

What happens with the misfolded proteins in amyloidosis?

Answer 6

they are accumulated outside the cell

Question 7

Describe the misfolded proteins in amyloidosis?

Answer 7

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

Question 8

Where does the misfolded proteins in amyloidosis come from?

Answer 8

• 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

Question 9

Most common amyloid proteins:

Answer 9

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

Question 10

AL (amyloid light chain) protein:

Answer 10

• 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

Question 11

AA (amyloid-associated) fibril:

Answer 11

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

Question 12

Where is SAA (serum amyloid-associated) synthesized?

Answer 12

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

Question 13

SAA =

Answer 13

serum amyloid-associated

Question 14

What leads to elevated SAA levels in the serum?

Answer 14

inflammation. in most instances does not lead to amyloidosis

Question 15

Long-standing inflammation leads to……

Answer 15

• 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.

Question 16

Aβ amyloid:

Answer 16

• 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)

Question 17

Where is the Aβ protein derived from?

Answer 17

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

Question 18

Transthyretin (TTR):

Answer 18

• 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

Question 19

β2-microglobulin:

Answer 19

• 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

Question 20

Aβ2m fibers are structurally similar to

Answer 20

β2m protein

Question 21

β2m protein is present in high levels…….

Answer 21

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.

Question 22

Amyloidosis may be….

Answer 22

• systemic (generalized): involving several organs

- localized, when deposites are limited to one single organ

Question 23

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

Answer 23

• 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

Question 24

Give an example of a primary amyloidosis;

Answer 24

Immunocyte dyscrasias with amyloidosis

Question 25

Give an example of a secondary amyloidosis;

Answer 25

Reactive systemic amyloidosis

Question 26

Primary amyloidosis: Immunocyte dyscrasias with amyloidosis

Answer 26

- AL type - most common form of amyloidosis - readily identifiable monoclonal plasma cell proliferation

Question 27

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

Answer 27

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

Question 28

What is affected in amyloidosis secondary to chronic inflammatory disorder;

Answer 28

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

Question 29

What is affected in primary (AL) amyloidosis:

Answer 29

- heart - GI tract - respiratory tract - peripheral nerve - skin - tongue

Question 30

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

Answer 30

- heart - GI tract - respiratory tract - peripheral nerve - skin - tongue - kidneys - liver - spleen

Question 31

In familial Mediterranean fever:

Answer 31

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

Question 32

Amyloidosis of the kidney;

Answer 32

- 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

Question 33

Amyloidosis of the spleen;

Answer 33

- moderate or even marked enlargement - producing tapioca-like granules on gross examination ("sago spleen") in the splenic follicles - splenic pulp ("lardaceous spleen") - red color

Question 34

Amyloidosis of the liver;

Answer 34

- 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

Question 35

Amyloidosis of the heart;

Answer 35

- 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

Question 36

What may produce macroglossia?

Answer 36

nodular depositions in the tongue

Question 37

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

Answer 37

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

Question 38

Nonspecific complaints of patients with amyloidosis;

Answer 38

- weakness - fatigue - weight loss

Question 39

How does the amyloidosis manifest itself;

Answer 39

- 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

Question 40

What is an important cause of death in cardiac amyloidosis?

Answer 40

cardiac arrythmias