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haematology > paraproteins > Flashcards

paraproteins Flashcards

1
Q

B cells

A

derived in bone marrow from pluripotent haemopoietic stem cells

part of adaptive immune system

dual roles
- antibody production
- acting as antigen presenting cells

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2
Q

immunoglobin

A

antibodies produced by B cells + plasma cells
- each Ig recognises a specific antigen

can be expressed on B cell surface (as B cell receptor) or released into the blood stream as antibodies by plasma cells

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3
Q

structure of immunoglobin

A

made up of 2 heavy + 2 light chains

heavy chain determines the class of antibody produced
all antibodies will contain either kappa or lamda light chains

togther the type of heavy + light chains are called the ISOTYPE of the antibody

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4
Q

B cell development

A

initial production + development in the bone marrow under control/influence of microenvironemnt

Ig variable element generated from V-D-J region recombination early in development

self-reactive cells removed
immature B cells with Ig on their surface exit bone marrow ready to meet their target

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5
Q

B cells in the periphery

A

travel to follicle germinal centre of lymph node where they encounter antigen

identify the antigen + improve the fit by somatic mutation or are deleted

may return to the marrow as a plasma cell or circulate as a memory B cell

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6
Q

plasma cell

A

a factory cell - pumps out antibody
eccentric “clock face nucleus” on H&E - off to one side of cell

open chromatin - synthesising mRNA
plentiful blue cytoplasm - laden with protein
pale perinuclear area = golgi apparatus

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7
Q

polyclonal increase in immunoglobulins

A

produced by many different plasma cell clones
reactive
- infection, autoimmune
- malignancy - reaction of host to malignant clone
- liver disease

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8
Q

monoclonal rise in immunoglobulins

A

all derived from clonal expansion of a single B cell, identical antibody + structure + specificity - same size + charge

monoclonal immungolulin = paraprotein
-> marker of underlying B cell or plasma cell disorder

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9
Q

how to detect immunoglobulins

A

serum electrophoresis -> detects abnormal protein bands

proteins separated into bands DON’t reflect similarity between function between molecules - just MOBILITY

albumin is most negatively charged molecule - hence is closest to anode

alpha 1 band predominantly contains alpha 1 antitrypsin

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10
Q

causes of paraproteinaemia

A

MGUS 56%
myeloma 18%
amyloidosis 10%
lymphoma
CLL
Waldenstroms macroglobulinaemia 2%

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11
Q

stages of myeloma

A

normal plasma cells -> MGUS clone (benign/premalignant) -> asymmtomatic myeloma -> myeloma

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12
Q

myeloma

A

cancer of plasma cells - a type of B lymphocyte that produces antibodies
- cancer in a specific type of plasma cell, results in large quantities of a single type of antibody being produced - monoclonal antibodies

median age 65
multiple myeloma -> where myeloma affects multiple areas of the body

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13
Q

myeloma is classified by isotype of antibody produced - which antibody is produced most?

A

IgG 59%
IgA 21%
Bence-jones myeloma - free light chain - 15%

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14
Q

myeloma risk factors

A

older age
male
black african ethnicity
family history
obesity

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15
Q

myeloma pathophysio

A

plasma cells are B cells of the immune system that have become activated to produce a certain antibody

When you measure immunoglobulins in myeloma, one of IgA, G, M, D, E will be significantly abundant
o >50% of the time its IgG
o Monoclonal paraprotein

Bence jones protein can be found in the urine of many patient with myeloma
o = the light chains of the antibody

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16
Q

myeloma presentation

A

CRABI
Calcium (hypercalcaemia)
Renal
Anaemia (normocytic, normochromic)
Bone lesions/pain
Infecion - reduced production of normal Ig, increase susceptibility

17
Q

viscosity of plasma in myeloma

A

hyperviscosity
- more proteins in blood - Ig

can cause -
- easy bruising, easy bleeding
- purple discolouration of extremities
- heart failure

18
Q

myeloma bone disease

A

Increase osteoclast activity + supressed osteoblast activity
- Osteoclasts absorb bone + osteoblasts deposit bone
- More reabsorbed than constructed = lytic bone lesions
- Caused by cytokines released from plasma cells + stroma cells when they are in contact with plasma cells

-> Lots of calcium reabsorbed leads to HYPERCALCAEMIA !

o Common locations – skull, spine, long bones, ribs
o Pathological fractures – vertebral body, femur

19
Q

what can be given to treat hypercalcaemia in myeloma?

A

bisphosphonates (pamidronate)
- inhibit osteoclasts

20
Q

renal failure in myeloma

A

tubular cell damage by light chains
light chain deposition - cast nephropathy
hypercalcaemia + dehydration - damage
bisphosphonates harmful to kidneys

(switch off light chain production with steroid/chem)

21
Q

blood results in myeloma

A

FBC - low WBC, anaemia
calcium - raised
ESR/plasma viscosity - raised

signs of renal failure
blood film - rouleaux formation

22
Q

myeloma investigations

A

bloods

protein electrophoresis
- raised concs of monoclonal IgG/IgA proteins will be present in the serum
- in urine, known as Bence-Jones proteins

bone marrow aspiration = definitive diagnosis
- number of plasma cells significantly raised

23
Q

management of myeloma

A

combination novel agent chemo = mainstay
- bortexomib + lenlidomide

steroids - dexamethasone

monoclonal antibodies - daratumumab
alkylating agents - cyclophosphamide, melphalan

young fit - high dose chemo/autologous stem cell transplant

-> use paraprotein level to monitor response
(symptoms control)

24
Q

myeloma symptoms control

A

Opiate analgesia – avoid NSAIDs

Local radiotherapy – good for pain relief of spinal cord compression

Bisphosphonates – corrects hypercalcaemia + bone pain

Vertebroplasty – inject sterile cement into fractured bone to stabilise

25
Q

myeloma prognosis

A

survival now 5-10yrs for younger patients

unfortunately relapse is inevitable

26
Q

monoclonal gammopathy of undetermined significance (MGUS)

A

where there is excess of a single type of antibody or antibody components without other features of myeloma or cancer
- paraprotein <30g/L
- often incidental finding, no evidence of myeloma end organ damage

slight increase in myeloma risk + monitored routinely

Mx = none

27
Q

AL amyloidosis

A

rare, multisystem disease
small plasma cell clone
mutation in the light chain - altered structure
- light chains can precipitate in tissues as an insoluble beta pleated sheet

the abnormal plasma cells produce abnormal forms of light chain protin which enter bloodstream + form amyloid deposits
- accumulation in tissues causes organ damage

28
Q

diagnosis of AL amyloidosis

A

organ biopsy confirming AL amyloid deposition
- congo red stain
- apple green birefringence under polarised light
- rectal/fat biopsy may be done if high clinical suspicion (less invasive)

evidence of deposition in other organs
- SAP scan - PET scan vibes
- echo/cardiac MRI
nephrotic range proteinuria

29
Q

mangement of AL amyloidosis

A

similar to myeloma
chemo to switch off light chain supply

porr prognosis esp if cardiac amyloid

30
Q

smouldering myeloma

A

progression of MGUS with higher levels of antibodies or antivody componenets
- premalignant - more likely to progress to myeloma than MGUS

Waldenstrom’s macroglobulinaemia = type of smouldering myeloma, excessive IgM specifically

31
Q

waldenstrom’s macroglobulinaemia

A

lymphoplasmacytoid malignancy characterised y secretion of monoclonal IgM paraprotein
- seen in older men

clonal disorder of cells intermediate between a lymphocyte + plasma cell

(IgM is pentameric!! myeloma mostly IgG)

32
Q

waldenstrom’s macroglobulinaemia clinical features

A

tumour effects
- lymphadenopathy
- splenomegaly
- marrow failure

paraprotein effects
- hyperviscosity
- neuropathy

B symptoms - night sweats, weight loss
cryoglobulinaemia - raynauds

33
Q

hyperviscosity syndrome in waldenstroms’s macroglobulinaemia

A

pentameric configuration of IgM increases serum viscosity

fatigue, visual disturbance, confusion
bleeding
cardiac failure

34
Q

waldenstroms macroglobulinaemia investigations

A

monoclonal IgM paraproteinaemia

diagnostic = bone marrow biopsy - infiltration of bone marrow with lymphoplasmacytoid lymphoma cells

35
Q

waldenstroms macroglobulinaemia management

A

chemo - rituximab based combination

plasmapheresis - removes paraprotein from circulation
- (treatment of hyperviscosity)
- remove patient plasma rich IgM paraprotein
- replace with donor plasma
- viscosity reduced

haematology (21 decks)

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