Myeloma & Plasma Dyscrasia Flashcards
What are immunoglobulins?
Antibodies - proteins produced by B cells and plasma
Describe the structure of immunoglobulins
Two heavy and two light chains bound by a disulphide bond. Each have a specific antigen binding site
Describe the different shapes of antibody
Monomer - IgD, IgE, IgG
Dimer - IgA
Pentamer - IgM
Where are B cells produced?
Bone marrow
How does the variable element of B cells arise?
V-D-J recombination
What happens to B cells when they leave the bone marrow?
Immature B cells with Ig on surface leave and go onto meet their target antigen - IgM
Where does the B cell encounter the antigen?
Follicle germinal centre of lymph node
What happens to the B cell in the lymph node?
Identifies the antigen
Improve the fit by mutation or deletion
Class switching
After the lymph node interactions what can happen to the B cell?
Return to the marrow as a plasma cell
Remain in circulation as memory B cell
What is the function of plasma cells?
Produce antibodies
Describe the appearance of plasma cells
Eccentric clock face nucleus on H and E stain
Open chromatin (synthesising mRNA)
Blue cytoplasm with lots of protein
Pale perinuclear area due to golgi apparatus
What do plasma cells look like on bone marrow aspirate?
Fried Egg
What is meant by polyclonal?
Lots of clones encounters specific antigen and ready to produce antibodies
What does a polyclonal immunoglobulinopathy imply?
Reactive aetiology
Name the causes of polyclonal immunoglobulinopathy
Infection
Autoimmune
Malignancy
Liver disease
What do monoclonal immunoglobulinopathies produce?
Paraprotein
How can monoclonal immunoglobulinopathies be investigated?
Serum electrophoresis
Immunofixation
Quantified by graph calculation
Describe serum electrophoresis
Sample serum on gel and apply voltage different proteins move different distances
Ig found in gamma region and should be diffuse more distinct band will appear in the presence of paraprotein
What does immunofixation do?
Mix with anti-sera that binds to heavy or light chains to classify Ig
What protein can be identify by urine electrophoresis?
Bence Jones Protein
What is BJP?
Excess light chains leak into the urine and precipitate
Name the causes of paraproteinaemia
MGUS Myeloma Amyloidosis Waldenstroms Leukaemia/NHL
What is myeloma?
Cancer of plasma cells
Describe the progression to myeloma
Normal
MGUS
Asymptomatic
Overt myeloma
What are the direct tumour effects of myeloma?
Bone lesions, increased calcium, bone pain, marrow failure (pancytopenia)
How can bone lesions present?
Focal erosion of bone - pepper pot skull
Compression fractures in spine
What are the paraprotein mediated effects of myeloma?
Renal failure
Immune suppression
Hyperviscosity
Amyloid
What is the commonest myeloma?
IgG
How does myeloma cause bone lesions?
Malignant cells produces cytokines that activate osteoclasts and suppress osteoblasts
Osteoclasts produce cytokines which stimulate more myeloma cells
Describe hypercalcaemia
Stones Bones Groans Psych moans Thirst Dehydration Renal impairment
What is the effect of myeloma on the kidney?
Tubular damage by light chains Precipitate causing casts Risk of sepsis NSAIDs --> AKI Hyperuricaemia due to high cell turnover Amyloid
What are casts?
Solid aggregates - light chains bind to Tamm horsfall protein causing obstructive uropathy
How is obstructive uropathy due to casts treated?
Hydration, stop nephrotoxic drugs, switch off light chain production with steroids/chemo
What is the median age of myeloma diagnosis?
65 years old
How is myeloma treated?
Combination chemotherapy - corticosteroids - alkylating agents - novel agents - monoclonal antibodies Autologous stem cell transplant
How do you monitor response to myeloma treatment?
Measure paraprotein
Describe the symptom control of myeloma
Opiate analgesia
Local radiotherapy
Bisphosphonates
Vertebroplasty
What does MGUS stand for?
Monoclonal gammopathy of undetermined significance
How is MGUS different to myeloma?
Paraprotein <30g/l
Fewer faulty plasma cells <10% of bone marrow plasma
No end organ damage
Normal calcium, renal function, Hb, no lytic lesions, no increased infections
Describe the pathology of AL amyloidosis
Small plasma cell clone - faulty light chain has the potential to misfiled and aggregate to be insoluble - beta pleated sheets become amyloid fibril
What happens as fibrils accumulate>
Build up in tissues and cause organ damage
How is AL amyloidosis treated?
Chemotherapy
For each organ describe the damage AL amyloid causes
Kidney - nephrotic syndrome Heart - cardiomyopathy Liver - organomegaly, LFT abnormality Neuropathy - autonomic/peripheral GI - malabsorption
How is AL amyloid diagnosed?
Biopsy - bone marrow, fat, renal - congo red stain which apple green birefringence on microscopy
Name the indirect scans for AL amyloid
SAP scan
Echo/MRI
Nephrotic range proteinuria
What is Waldenstrom’s Macroglobulinaemia?
Lymphoplasmactyoid neoplasm - clonal disorder of cells between lymphocyte and plasma
What are the tumour effects of Waldenstrom’s Macroglobulinaemia?
Lymphadenopathy
Splenomegaly
Marrow failure
What paraprotein is in Waldenstrom’s Macroglobulinaemia?
IgM
Describe the paraprotein effects of Waldenstrom’s Macroglobulinaemia
Hyperviscosity
Neuropathy
How does hyperviscosity present?
High levels of IgM
- fatigue
- visual disturbance
- confusion
- bleeding
- cardiac failure
- coma
- B symptoms
How is Waldenstrom’s Macroglobulinaemia treated?
Chemotherapy
Plasmaphoresis - removes paraprotein and replaces with donor FFP
