Amyloidoses

Question 1

What are the intracellular and extracellular protein quality control systems that exists to prevent protein folding disorders from happening?

Answer 1

• intracellular: proteasomes

- extracellular: macrophages

Question 2

What is the etiology/pathogenesis of systemic amyloidoses?

Answer 2

• plasma cell dyscrasia (light chain-derived)
• underlying chronic inflammation (AA amyloidosis)
• genetic predisposition (mutation in amyloid protein)

Question 3

What are the 2 main plasma cell dyscrasias, and which is the most common?

Answer 3

multiple myeloma and MGUS; MGUS is the most common

Question 4

What is the difference between multiple myeloma and a more general plasma cell dyscrasia?

Answer 4

• multiple myeloma: a true plasma cell malignancy

- plasma cell dyscrasia: low plasma cell burden with a small but dangerous clone

Question 5

AA “reactive” amyloidosis is secondary to which conditions?

Answer 5

long-standing inflammatory conditions, like RA, IBD, and Crohn’s

Question 6

Familial AA is due to mutations in the ____ gene, which encodes _______.

Answer 6

MEFV; pyrin (regulator of innate immunity)

Question 7

What is the pathogenesis of hereditary amyloidosis?

Answer 7

TTR mutation causes instability of tetramer –> tetramer dissociates and circulations as monomers –> fibrillogenesis

Question 8

What are the most common clinical presentations of hereditary amyloidosis?

Answer 8

polyneuropathies; cardiac, GI, and renal symptoms

Question 9

Why does a mutation in TTR not always lead to hereditary amyloidosis?

Answer 9

due to variable penetrance

Question 10

Hereditary amyloidosis can mimic which condition?

Answer 10

AL

Question 11

How can wt TTR cause amyloidosis?

Answer 11

wt TTR is prone to fibrillogenesis at older age, as protein quality control systems are less effective. This may cause cardiac amyloid at older age and particularly affects men.

Question 12

Hemodialysis-associated amyloidosis is associated with which protein?

Answer 12

beta-2 microglobulin (which is not effectively removed by dialysis) - causes many joint problems

Question 13

Which endocrine disorder may lead to amyloidosis?

Answer 13

type 2 diabetes

Question 14

Localized amyloidosis can be found in:

Answer 14

lung, larynx, skin, urinary bladder (mostly light chain; form tumor-like deposits that mimic tumors)

Question 15

ALect2 affects which body systems and which patient population?

Answer 15

• mostly renal, can be systemic

- may affect Mexican Americans more worldwide

Question 16

How are amyloidoses diagnosed?

Answer 16

• detection (ALL are Congo-red positive)

- typing of amyloid protein

Question 17

Early amyloidosis may be indistinguishable from which conditions?

Answer 17

minimal change, FSGS, diabetes (nephrotic syndromes)

*this is why Congo red must be used to rule out amyloid!

Question 18

Which imaging technique allows you to see the fibrillogenesis associated with amyloidoses?

Answer 18

electron microscopy only

Question 19

Provide a differential for proteinuria/nephrotic syndrome in adults.

Answer 19

• FSGS
• Minimal change
• Membranous nephropathy
• Diabetes
• Amyloidosis!

Question 20

What are the advantages vs. limitations of proteomics?

Answer 20

• advantages: global identification of proteins, discovery of unsuspected proteins
• limitations: difficult to detect low abundance proteins, as signals may be buried among more abundant proteins

Question 21

What is the newer generation of drugs that may target AL?

Answer 21

proteasome inhibitors

Question 22

What is the biggest challenging of managing amyloidosis?

Answer 22

early diagnosis!

Question 23

Amyloid can be detected in which surrogate site?

Answer 23

subcutaneous fat (typically from periumbilical abdomen)

Question 24

What are the advantages vs. disadvantages of cytogenetics over FISH?

Answer 24

• advantages: global picture and potential for discovery of unsuspected abnormalities; do NOT need to know what to look for (thus, no probe necessary)
• disadvantages: need to prepare tissue, less sensitivity

Question 25

What is the modern treatment for AA amyloidosis?

Answer 25

DMARDs (disease modifying anti-rheumatic drugs) - work on specific targets instead of entire immune system

Question 26

What are the treatments for hereditary amyloidosis?

Answer 26

• targeting the SOURCE of the protein (liver transplantation)
• targeting the protein itself (TTR tetramer stabilizers)