Immunoglobulins and Monogammopathy Flashcards
Globulin measurement
Calculated parameter (total protein - albumin)
Ig usually migrate to gamma region on electrophoresis
Hypogammaglobulinaemia
Congenital
- immunodeficiency (lead to severe, recurrent bacterial infections)
Acquired immunosuppression
- multiple myeloma
- primary amyloidosis
- chronic lymphocytic leukaemia
- lymphoma
- nephrotic syndrome
Hypergammoglobulinaemia
Polyclonal (reactive; benign)
- chronic inflammation / infection
- autoimmune diseases
Monoclonal (plasma cell dycrasias)
- MGUS, MM, WM
Monoclonal Gammopathy: definition, associated conditions, characteristics, classes of paraproteins
Single clone of plasma cells producing structurally and immunologically homogenous Ig (i.e. paraproteins)
- Ig may be intact (most common), free light chains only or heavy chains only (rare)
Associated conditions
- monoclonal gammopathy of undetermined significance (MC)
- multiple myeloma
- waldenstrom’s macroglobulinaemia
- light chain amyloidosis
- POEMS
Characteristics
- hyperproteinaemia with normal or decreased albumin
- REVERSED A:G RATIO as first abnormal biochemical finding
Classes of paraproteins
- majority IgG (patients more susceptible to infection as other plasma cell clones suppressed)
- IgA (25%) - tend to hyperCa and amyloidosis
- free light chain only - renal failure, bone lesions, amyloidosis
Multiple Myeloma: definition, manifestations, diagnosis, smouldering MM
Neoplastic proliferation of a single clone of plasma cells producing monoclonal Ig
(non-secretory MM in 3-4% = paraproteins not detected by serum and urine electrophoresis)
Manifestations
- non-specific: weight loss, nausea, loss of appetite
- end organ damage: bone pain, height reduction, weakness, fatigue (anaemia), renal impairment
- haematological effects: recurrent infections (s. pneumoniae, h. influenzae and other gram-ve) due to suppression of normal plasma cells or chemotherapy; bleeding (BM failure), hyperviscosity (rare)
- amyloidosis
Diagnosis
- clonal bone marrow plasma cells >10% (>60% = definitive) and/or >30g/L monoclonal protein in serum or biopsy proven plasmacytoma
AND
- >1 of CRAB:
– hyperCa >2.75 mmol/L
– renal insufficiency - Cr >177 micromol/L or CrCl <40 ml/min
– anaemia - Hb<10
– bone lesions - osteolytic lesion (pathological fracture) on skeletal XR +/- MRI
Smouldering MM
- monoclonal protein >30g/L and/or clonal bone marrow plasma cells 10-60%
- absence of myeloma defining events (CRAB) or amyloidosis
Monoclonal Gammopathy of Undetermined Significance (MGUS): definition, presentations, risk factors for progression
Most common type of plasma cell dyscrasia found in 1-2% of adults population
- higher in >70
- 1-1.5% progress to MM each year (need follow up)
Lab:
- monoclonal protein <30g/L (stable over time)
- BM plasma cells <10%
- absence of Bence Jones proteins in urine
- no evidence of other B cell proliferative disorders
Presentations
- no CRAB
Risk factors for progression to MM
- high monoclonal protein concentration
- non-IgG
- abnormal free light chain ratio
- detectable light chain proteinuria
- immunoparesis
Investigations: Serum Ig Pattern
Quantification of IgG, IgA, IgM
Elevation can be due to polyclonal or monoclonal Ig production –> serum protein electrophoresis needed to interpret
Investigations: Serum Protein Electrophoresis
Done once elevated serum Ig detected
(or can directly do if suspect MM clinically)
- relies on net charge and size of protein to detect migration in electric field (agarose gel, pH 8-9)
- most proteins are negatively charged at high pH and migrate to anode
==> paraproteins are clones so MIGRATE AT SAME SPEED, creating SHARP SPIKES, usually within beta to gamma region
==> densitometric paraprotein quantitation + Serum Ig pattern to quantify– band size CORRELATES WITH MALIGNANT CELL POPULATION SIZE in BM
Uses
- detect, monitor and quantify paraproteins e.g. MGUS, MM, amyloidosis
- investigate symptoms associated with MM
Investigations: Serum Immunofixation electrophoresis
Type all new paraprotein bands and confirm monoclonality
- done automatically if SPE abnormal
Identify heavy and light chains
- antibodies against paraproteins applied to gel –> precipitate and stained
More sensitive than SPE –> part of SCREENING and for confirmation of complete RESPONSE to therapy
Investigations: Urine protein electrophoresis
Excess monoclonal Ig light chains (FLC) can be filtered and found in urine – BENCE JONES PROTEINS
First void morning urine for screening (convenient, concentrated)
24 hr urine for staging and monitoring
– >1g /day = diagnostic of MM or plasma cell dyscrasias
(doesn’t specific kappa or lambda)
Investigations: Serum Free Light Chain (FLC)
Heavy and light chains of Ig are synthesised separately
–> excess light chain produced is secreted into blood with intact Ig
==> serum FLC reflects plasma cell activity
Uses:
- AID diagnosis (+ SPE = simple and efficient tool)
- disease monitoring of monoclonal gammopathies (t1/2 = 2-6 hrs –> can see response over days)
- highest sensitivity –> early detection and identification of 70% non-secretory myeloma
- better treatment of AL amyloidosis
Interpretation:
- K:L FLC ratio most useful –> detect elevation of one specific subtype
- > 1.65 = kappa expansion
- <0.26 = lambda expansion
- other causes of abnormal FLC (cause both subtypes to change –> ratio relatively normal)
- -> increase in renal impairment, immune stimulation (autoimmune, infection), monoclonal plasma cell proliferation
- -> decrease in immune suppression
not applicable to rare types e.g. heavy chain disease, biclonal disease
Current standard for Ix of monoclonal gammopathy
SPE + FLC (94.3% sensitivity)
SPE + UPE traditionally (or if serum FLC n/a)
Usually in HK, just use SPE but can order FLC if high suspicion
Complication of Multiple Myeloma
AL Light Chain Amyloidosis
- nephrotic syndrome
- restrictive cardiomyopathy
- peripheral neuropathy
- hepatomegaly
Recall pathophysiology
Treatment (of MM)
- corticosteroid, cytotoxic therapy, proteasome inhibitors e.g. bortezomib, immunomodulatory drug e.g. lenalidomide
