This case was all about evaluating a patient with a paraprotien. A paraprotein is a specific immunoglobulin produced by a clone of plasma or lymphoid cells. The immunoglobulin is composed of heavy chain and a light chain (either kappa or lambda light chain). You can see from the immunofixation below that this person is producing an IgM kappa paraprotein:
The differential diagnosis of a paraprotein is includes:
- Asymptomatic myeloma
- Plasma cell myeloma AKA multiple myeloma or simply myeloma
- Non-Hodgkin lymphoma (e.g. Waldenström’s macroglobulinaemia)
- POEMS syndrome (polyneuropathy, organomeglay, endocrinopathy, M protein, skin)
- Bone or extramedullary plasmacytoma
- AL amyloidosis
In our case the patient had symptoms of signs of amyloid, including orthostatic hypotension, peripheral neuropathy, nose bleeds and heart failure. Amyloid is a a disorder of abnormal protein folding, which aggregate to form beta pleated sheets which wind together forming insoluble fibrils. Amyloid occurs when there is sustained high concentration of normal proteins (e.g. inflammatory states, dialysis), normal concentration of highly amyloidogenic protein over long period of time (e.g. Alzheimer’s disease) or abnormal protein production (i.e. monoclonal light chains). All monoclonal light chains are structurally different and thus they are only occasionally amyloidogenic. Lambda light chains cause AL amyloidosis more so than kappa light chains.
Amyloid can be difficult to diagnose as the symptoms are often non-specific. Symptoms of amyloid include:
- Nephrotic syndrome with or without renal failure
- Cardiac failure
- Sensorimotor and/or autonomic peripheral neuropathy
- Raccoon eyes
- Abnormal bleeding (factor X deficiency, vascular fragility)
- GI symptoms including diarrhoea and malabsorption
- Hoarse voice
Amyloid may be diagnosed by finding a monoclonal protein or abnormal serum free light chain ratio and then linking symptomatology with the disorder. Alternatively it may be diagnosed following biopsy of a target organ. It is important to differentiate between amyloidosis due to monoclonal light chains (AL amyloidosis) from other causes e.g. AA amyloidosis due to chronic inflammation, B2MG amyloidosis (renal failure) or inherited transthyretin amyloidosis. There are numerous types, but the most common being AL amyloid. When amyloid is suspected it is important to confirm the presence of amyloid histologically – usually by the finding of apple green birefringence under polarised light microscopy using the congo red stain. This can be demonstrated on biospy of affected tissue e.g. kidney, bone marrow, liver. Fat pad and rectal biopsies are also occasionally used. Fat pad biopsies have a sensitivity of 50-80%.
The second step in the diagnosis is to confirm the type of amyloid. As paraproteins are commonplace, especially in elderly patients, this is not sufficient to diagnose AL amyloidosis. Immunohistochemistry, genetic testing and pattern of involvement can help differentiate.
The next step is to quantify organ damage. This includes testing for:
- Urinalysis – proteinuria/light chain on electrophoresis.
- FBC – anaemia – often mild, thrombocytopenia.
- U&Es – raised creatinine.
- LFTs – elevated ALP
- Clotting – there is abnormal clotting in 50% of cases – raised INR, factor X deficiency.
- Inflammatory markers – raised ESR, normal CRP.
- ECG – small complexes
- Echocardiography – ventricular thickening with reduced ventricle size.
- NTproBNP and cardiac troponins
- SAP scan to determine burden of amyloid load
The treatment of AL amyloid should ideally be delivered in the context of a clinical trial given its rarity. Anti-myeloma treatments are used in the management of myeloma. First line is generally the proteosome inhibitor bortezomib in combination with cyclophosphamide and steroid. Thalidomide also has activity in amyloid, along with other related agents e.g. lenalidomide and pomalidomide. In younger patients high dose melphalan chemotherapy should be considered followed by autologous stem cell transplantation.
Supportive treatment includes:
- Antibiotics when required
- Cardiac and renal transplantation in very specific cases
- Nutritional support
Summary of our case
Our case was an elderly patient with evidence of severe end organ damage including autonomic neuropathy and cardiac failure along with elevated NT-proBNP and cardiac troponins. Following discussion with the patient it was decided that palliative, best supportive care was the most appropriate option and she died two months later at home.
BCSH guidelines http://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/pdf
BCSH guidelines http://onlinelibrary.wiley.com/doi/10.1111/bjh.13156/pdf