Week 2- Myeloma and other plasma disorders Flashcards
What are the roles of b cells?
Antigen presentation
Antibody production.
What are immunoglobulins?
Antibodies produced by B cells and plasma cells. They are proteins made up of five heavy and 2 light chains. Each antibody recognises a specific antigen.
Describe the basic structure of immunoglobulins?
The heavy chain makes up the backbone and the light chains are smaller and stuck onto the back. The end of the ‘Y’ shape has the antigen binding sites.
What shape is IgM?
Pentamer- with 5 antigen binding sites.
What shape is IgA?
Dimer- with two antigen binding sites.
What shape is IgG, IgE and IgD?
They are all monomers with one antigen binding site.
Describe the development of B cells? In their immature state what are they made up of?
They are initially produced in the bone marrow.
In their immature state they are just made up of Ig. This is made from the V-D-J region. They then exit the bone marrow to reach their target (and change the Ig to an IgE, or IgG etc).
Once B cells leave the bone marrow, what class do they have on them?
Initially they are IgM. However they can undergo class switches and switch to IgG, IgE or IgA.
NOTE- as part of the maturation process, the B cells at some point have to visit the lymph nodes. What occurs here?
What happens after they leave the lymph nodes?
They are then exposed to antigens. The ones that bind to the antigen survive and the ones that bind the antigen badly will undergo apoptosis.
They will then either return to the bone marrow as plasma cells or circulate as memory cells.
What is a plasma cell?
These are essentially antibody producing factories. They produce a lot of protein and therefore have plentiful RNA, and therefore their cytoplasm is blue. They have a pale perinuclear area- which is the golgi apparatus.
In healthy individuals, do they have a polyclonal or monoclonal antibody reportoire? How does this differ in malignancy?
In health you should have polyclonal antibodies. In malignancy you tend to have monoclonal antibodies and are therefore susceptible to infection etc etc.
In what situations do you get a polyclonal increase in antibody production?
Reactive changes e.g. infection, autoimmune, malignancy (reaction of the host to the malignant clone), liver disease.
In what situations do you get a monoclonal rise in antibodies?
All derived from clonal expansion of a single B cell (therefore you only get that one B cells antibody produced).
What is the other term for a monoclonal immunoglobulin (antibody)?
A paraprotein.
What are paraproteins a marker of?
Underlying clonal B cell disorder.
What investigations allow you to detect immunoglobulins?
Serum electrophoresis. The seperated serum proteins appear as distinct bands or zones. The gamma area is where the immunoglobulins are present.
What do you use serum immunofixation for?
It is used to classify the abnormal protein bands in the gamma area.
What are Bence Jones proteins?
They are light chains found on urine electrophoresis.
Why are Bence Jones proteins clinically relevant?
When immunoglobulins are generated, more light chains than heavy chains are produced, therefore excess light chain production is normally about 0.5g/day. However if this increases they can be found in the urine as Bence Jones proteins.
What type of free light chains are there? How do they differ on serum electrophoresis?
Kappa and lamda.
Kappa ones are found on their own whereas lamda ones are generally found as a dimer.
If you get a polyclonal increase in light chains, what may this be due too?
Infection
(There are other causes but I’m not sure what).
If you get a monoclonal increase in light chains, what can this be due too?
Monoclonal means there is only an increase in the one type of light chain e.g. kappa or lamda.
This could be due to disease processes such as muiltiple myeloma.
What are some causes of paraproteinaemia?
Myeloma
Amyloidosis
Lymphoma
Asymptomatic myeloma
Solitary or extramedullary plasmacytoma
Chronic lymphocytic leukaemia
Waldenstroms macroglobulinaemia
What is myeloma?
A plasma cell malignancy.
How does myeloma affect the body?
The clonal plasma cells have direct tumour affects and also the effects of the paraprotein.
How does myeloma affect the body (in terms of direct tumour cell affects)?
Bone lesions
Increased calcium
Bone pain
Replace normal bone leading to marrow failure.
How does myeloma affect the body (in terms of paraprotein mediated affects)?
Renal failure
Immune suppression
Hyperviscocity
Amyloid
NOTE- in myeloma there is an increase in osteoclast activity, and suppresion of osteoblast activity therefore you can get pathological fractures and bone lesions. You can get multiple, punched out lytic lesions in the skull and wedge fractures in the spine etc.
What are the symptoms of hypercalcaemia?
STONES-renal colic and hypercalcaemic stones
BONES-increased osteolysis and fractures
GROANS- abdominal groans- anorexia, NandV.
Psychic MOANS- depression, confusion, hallucinations and coma
Why do you get hypercalcaemia in muiltiple myeloma?
Breakdown of bone leads to increased calcium levels.
How can myeloma affect the kidneys?
30% of patients have renal impairment at diagnosis
You can get:
Tubular cell damage from the light chains
Light chain deposition- cast nephropathy
Sepsis
Hypercalcaemia and dehydration
Drugs- NSAIDs
Amyloid
Hyperuricaemia
NOTE-
light chains are filtered by the glomeruli and enter the renal nephron. They are toxic to renal cells and can cause acute tubular necrosis. They can also stick together if the concentration is high enough and cause a plug in the nephron- this can cause acute kidney failure.
What is cast nephropathy?
The casts (clumps of light chains) are excreted in the urine. Needs to be treated promptly with steroids, the hypercalcaemia needs to be treated and so does the dehydration.
What is the treatment for myeloma?
Use high dose steroids as these are toxic to plasma cells. E.g. dexamethasone or prednisolone.
Aklylating agents e.g. cyclophosphamide
Novel agents e.g. thalidomide
Can use high dose chemo or autologous stem cell transplant in fit patients.
How can you monitor response to treatment in myeloma?
Monitor paraprotein levels.
What additional treatment (symptomatic) can you give myeloma patients?
Opiate analgesia (avoid NSAIDs as poor renal function)
Local radiotherapy- good for pain releif or spinal cord compression
Bisphosphonates- corrects hypercalcaemia and bone pain
Vertebroplasty- injection of sterile cement into bone to stabilise fractures.
What is monoclonal gammopathy of uncertain significance?
Paraprotein of less than 30g/l
Bone marrow plasma cells <10%
No evidence of myeloma end organ damage- normal calcium, normal renal function, normal Hb, no lytic lesions, no increase in infections.
What is AL amyloidosis?
Its a rare disorder of plasma cell clones.
The light chains produced by the plasma cells have just the right structure to stick together and form beta pleated sheets. Instead of being a small soluble protein they become a large sheet of proteins capable of tissue damage.
What does accumalation of amyloids in tissues cause?
End organ damage that slowly progresses.
It is a multisystem disease.
In the kidney- causes nephrotic syndrome
In the heart- causes cardiomyopathy
In the liver- organomegaly and deranged LFTs
Autonomic and peripheral neuropathy
Malabsorption in the GI tract.
How do you diagnose Al amyloidosis?
Biopsy with staining. Stains congo red.
Rectal or fat biopsy may be done if high clinical suspicion.
Apple green birefringence under polarised light.
What is Waldonstroms macroglobulinaemia?
Clonal disorder of cells intermediate between lymphocyte and plasma cells. Have a characteristic IgM paraprotein.
What effects can Waldonstroms macroglobulinaemia cause?
Tumour effects- lymphadenopathy, splenomegaly, marrow failure
Paraprotein effects- hyperviscocity, neuropathy
What are the clinical features of Waldonstroms macroglobulinaemia?
Hyperviscocity syndrome- fatigue, visual disturbance, confusion, coma, bleeding, cardiac failure
B symptoms- night sweats, weight loss
Treatment- chemotherapy, plasmapheresis.
