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Haematology and Oncology > Amyloid > Flashcards

Amyloid Flashcards

1
Q

In myeloma, what happens to the uninvolved immunoglobulins?

A

There is a “reciprocal depression” of uninvolved Igs.

So, if you see very high amounts of IgG, then low amounts of IgM and IgA (etc) will be seen

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2
Q

What is the typical proteins that make up an immunoglobulin?

why are they named like this?

A

On each monomer there are 4 “chains” - 2 heavy and 2 light

The type of Ig is named because of the type of heavy chain.

There are five types of heavy chain:

  1. Gamma - makes IgG (note the first letter corresponds to the Greek letter)
  2. Alpha - IgA
  3. Epsilon - IgE
  4. Mu (myu) - IgM
  5. Delta - IgD

The light chains can be either kappa or lambda

B cells possess either kappa OR lambda, but never both together.

In a reactive lymph node, we should see a mixture of kappa-positive and lambda-positive cells.

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3
Q

What does M-band mean when reading a SEPP?

A

It refers to the monoclonal band. NOT IgM

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4
Q

What are some of the associations of MGUS that we might see clinically?

A

Peripheral neuropathy in a patient with paraproteinaemia

Haematological disorders such as acquired vWD

skin disease

immunosuprression

the M-proteins can have an antibody function (cause thyrotoxicosis, for example)

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5
Q

what is the recommended follow up of MGUS?

A

SEPP/FBC and biochem every 6 months or annually.

There is a 1% chance of myeloma each year.

Prior to initiating follow up, it’s worthwhile excluding myeloma (lol)

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6
Q

what are the most common types of myeloma?

A

IgG makes up roughly 60%

IgA 21%

light chains only 18% (light chains might not be seen on SEPP, and so you need urinary B-J proteins for diagnosis)

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7
Q

what happens with chromosomes in MM?

Do the malignant cells have normal numbers?

Are there any that have normal cells and if so, what is their major molecular abnormality?

A

There are a hyperdiploid group, and they require the microenvironment support to thrive

There are a group with normal numbers of chromosome, but they have a high prevalence of IgH (heavy chain) translocations
- these usually involve the “cyclin” proteins, which are things that control the cell cycle. Clearly they go bad and cause drama

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8
Q

how do we diagnose myeloma?

A
  1. SEPP and urine EPP (24 hour)
    - 3% of myeloma will be non-secretory (they are, but it’s just not identified by our archaic methods)!
    - (that is serum and urine EPP will be normal!)
  2. Skeletal survey - bone scan unhelpful as lytic lesions
  3. quantitative Igs
  4. BMAT

there are a bunch of other tests that are helpful but not diagnostic

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9
Q

what are the most common causes of renal impairment by myeloma?

A

the top 3 are hypercalcaemia,
dehydration
myeloma kidney (intratubular casts)

proximal renal tubular dysfunction due to tissue deposition is less common

amyloid is a problem but later in disease

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10
Q

how do we differentiate between:

  1. MGUS
  2. asymptomatic myeloma
  3. symptomatic myeloma
A
  1. MGUS - this is low levels of protein 30 &/or BM plasma cells >10%

there must be NO CRAB

(observe asymptomatic MM)

  1. M protein, BM plasma cells or plasmacytoma

there must be CRAB

CRAB is a mnemonic for organ dysfunction

c- calcium elevation (>2.75)
r - renal dysfunction (Cr >173)
a - anaemia (Hb <10)
b - bone disease (lytic lesions or OP)

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11
Q

what is the prognostics that we use for MM?

A

The International Scoring System (ISS)

based entirely on B2M and albumin

(no cytogenetics and no correction for renal impairment)

Stage I - low B2M and normal albumin

Stage II - between 1 and 3

Stage III - B2M > 5.5

these are used to provide median survival information

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12
Q

What is the therapy of asymptomatic myeloma?

A

careful observation

but be aware that with this condition they may still have higher infection risks due to hypogammaglobulinaemia (reciprocal)

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13
Q

How does zoledronate work in MM?

what impact does it have on MM?

any side effects of this?

A

It acts on the osteoclasts to reduce their action.

There is likely to be downstream effects of this

it has demonstrated an improved OS and PFS

the major thing to think about is osteonecrosis of the jaw which is more likely in patients on it for malignancy. Interestingly the risk is higher for those with MM than breast CA

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14
Q

what treatment do we use for MM?

A

If less than 65 years, melphalan and autoSCT with thal maintenance

if older, melphalan, pred and thalidomide.

melphalan has been used for a while. it makes up the most of conditioning around autoHST

thalidomide is used as maintenance

alloHST are still only investigational

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15
Q

how does thalidomide work?

what are the side effects?

A

we don’t really know. there are likely to be many mechanisms. could be directly toxic, could work on microenvironment, could work on cytokines.

the exact mech is not known

the side effects:
- it was initially used for anti-nausea effects in pregnant women. it’s side effects are based around this!

makes ppl tired, makes ppl constipated (think about the opposite of gut irritation)

causes a peripheral neuropathy in almost 100% if taken long enough

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16
Q

what is the standard treatment in MM when ppl can’t take an autoHST?

A

melphalan, pred and thalidomide

17
Q

how does Bortezomib work?

side

A

This medication is called Velcade and it is a proteosome inhibitor

it’s mechanism of action is a bit tricky. It blocks the 26S proteosome, but the way it stops MM is by stopping the degradation of I-kappa-B.

This works because “degraded I-kappa-B” allows NF-kappa-B to cause growth and replication of the MM cells.

Therefore, it blocks the proteosome, leads to less action of a downstream molecule and stops MM

18
Q

what is the treatment of relapse MM?

A

it can either be lenalidomide based or bortezomib based

19
Q

Typically patients with myeloma have osteolytic lesions.

Are there any MM-like conditions associated with osteosclerotic lesions?

A

there is an entity called osteosclerotic myeloma

It is associated with POEMS syndrome

Polyneuropathy
Organomegaly (LN and HSM)
Endocrinopathy (adrenal, thyroid, pit, gonads, PTH and pancreatic - variable issues)
M-protein
Skin changes - hyperpigment, white nails, haemangiomata

20
Q

where does amyloid deposit?

what does it look like on electron microscope?

A

interstitium. it is not about intracellular deposits

the electron microscope shows fibrils and beta pleated sheets

it looks pink in H&E stain

apple green under polarising light

21
Q

what are the causes of amyloidosis?

A

it could be due to normal protein in high concentration

  • SAA (serum amyloid A protein = secondary/reactive amyloid)
  • B2M - dialysis associated amyloid

normal protein with secondary factors
- “wild type” transthyretin in senile amyloid

unique protein with abnormal conformation

  • monoclonal light chains in AL amyloid
  • mutant transthyretin - hereditary cardiac amyloid
22
Q

what type of protein causes the disease on AL amyloid?

A

It is the Amyloid Light chain (AL)

this is because, as a normal process, the plasma cell makes extra light chain to each heavy chain.

The left over light chains are released and cause damage to the body

it can cause a wide range of problems

aside from macroglossia (look for indentation in the tongue from the teeth) and “raccoon eyes” - fragility bruising of the eyes after sneezing, it can be confused with anything

in the heart can cause a restrictive CMP - thick septum is the main thing.

If you seen thick septum without HTN or AS, consider amyloid

23
Q

why was the free light chain assay so important?

A

we haven’t been able to measure serum free light chains for a long time - because nearly all assays gave result for both free light chains AND those bound to heavy chains.

however, a crafty company came up with an assay to look at the part of the Ig that is normally hidden by the heavy chain

now we can detect free light chains that weren’t previously identifiable

24
Q

what is the treatment of amyloid?

A

try to treat the complications

then consider MM drugs to bring down the plasma cell activity

25
Q

why is the ALP typically normal in myeloma with bone disease?

A

ALP is released by osteoblastic activity.

In myeloma (an osteolytic process), the major effector cell is the osteoclast

26
Q

if you suspect someone has myeloma and SEPP and urinary EPP have been negative, what is the next investigation?

A

serum free light chains

then

BMAT

27
Q

which proteins are in EVERY amyloid deposit?

A

serum amyloid P (which mops up free DNA to prevent autoimmunity)

heparin aminoglycans are also universal

transthyretin, SAA, B2MG and immunoglobulin light chain are all associated with their disease, but not the others

Haematology and Oncology (11 decks)

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