paraproteins

Question 1

B cells

Answer 1

derived in bone marrow from pluripotent haemopoietic stem cells

part of adaptive immune system

dual roles
- antibody production
- acting as antigen presenting cells

Question 2

immunoglobin

Answer 2

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

Question 3

structure of immunoglobin

Answer 3

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

Question 4

B cell development

Answer 4

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

Question 5

B cells in the periphery

Answer 5

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

Question 6

plasma cell

Answer 6

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

Question 7

polyclonal increase in immunoglobulins

Answer 7

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

Question 8

monoclonal rise in immunoglobulins

Answer 8

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

Question 9

how to detect immunoglobulins

Answer 9

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

Question 10

causes of paraproteinaemia

Answer 10

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

Question 11

stages of myeloma

Answer 11

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

Question 12

myeloma

Answer 12

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

Question 13

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

Answer 13

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

Question 14

myeloma risk factors

Answer 14

older age
male
black african ethnicity
family history
obesity

Question 15

myeloma pathophysio

Answer 15

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

Question 16

myeloma presentation

Answer 16

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

Question 17

viscosity of plasma in myeloma

Answer 17

hyperviscosity
- more proteins in blood - Ig

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

Question 18

myeloma bone disease

Answer 18

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

Question 19

what can be given to treat hypercalcaemia in myeloma?

Answer 19

bisphosphonates (pamidronate)
- inhibit osteoclasts

Question 20

renal failure in myeloma

Answer 20

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)

Question 21

blood results in myeloma

Answer 21

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

signs of renal failure
blood film - rouleaux formation

Question 22

myeloma investigations

Answer 22

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

Question 23

management of myeloma

Answer 23

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)

Question 24

myeloma symptoms control

Answer 24

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

Question 25

myeloma prognosis

Answer 25

survival now 5-10yrs for younger patients unfortunately relapse is inevitable

Question 26

monoclonal gammopathy of undetermined significance (MGUS)

Answer 26

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

Question 27

AL amyloidosis

Answer 27

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

Question 28

diagnosis of AL amyloidosis

Answer 28

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

Question 29

mangement of AL amyloidosis

Answer 29

similar to myeloma chemo to switch off light chain supply porr prognosis esp if cardiac amyloid

Question 30

smouldering myeloma

Answer 30

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

Question 31

waldenstrom's macroglobulinaemia

Answer 31

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)

Question 32

waldenstrom's macroglobulinaemia clinical features

Answer 32

tumour effects - lymphadenopathy - splenomegaly - marrow failure paraprotein effects - hyperviscosity - neuropathy B symptoms - night sweats, weight loss cryoglobulinaemia - raynauds

Question 33

hyperviscosity syndrome in waldenstroms's macroglobulinaemia

Answer 33

pentameric configuration of IgM increases serum viscosity fatigue, visual disturbance, confusion bleeding cardiac failure

Question 34

waldenstroms macroglobulinaemia investigations

Answer 34

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

Question 35

waldenstroms macroglobulinaemia management

Answer 35

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