Paraproteinemia

Paraprotein

A paraprotein is a monoclonal immunoglobulin or light chain present in the blood or urine; it is produced by a clonal population of mature B cells, most commonly plasma cells.¹

What is paraproteinaemia?

Paraproteinaemia represents a group of related diseases characterised by an unbalanced or disproportionate proliferation of immunoglobulin-producing cells, usually from a single clone. These cells frequently secrete a structurally homogeneous immunoglobulin (M-component) and/or an abnormal immunoglobulin. Plasma cell disorders can be considered as a spectrum of conditions ranging from monoclonal gammopathy of undetermined significance (MGUS), through asymptomatic, to symptomatic myeloma.¹

How common is paraproteinaemia? (Epidemiology)

The incidence of a paraprotein is 3.2% in people aged over 50 years.¹

Causes of paraproteinaemia (aetiology)

• Artefacts: heparinised blood sample.

• MGUS:^{2 3}

  • MGUS is defined by a low level of paraprotein <30 g/L, bone marrow plasma cells <10% and the absence of myeloma-related organ or tissue damage (predominantly renal, skeletal or bone marrow impairment).

  • Patients are often elderly and in good health.

  • MGUS requires no therapy and the overall risk of progression to myeloma is 1% per year.¹

  • Follow-up must be continued indefinitely because multiple myeloma, amyloidosis, macroglobulinaemia or related disorders may occur.

• Linfoma não-Hodgkin.

Malignant neoplastic conditions:

• Mieloma múltiplo. Effective treatments for myeloma have been developed over the last 15 years. Myeloma remains incurable but there have been improvements in overall survival and quality of life. Treatments include bortezomib, thalidomide and stem cell transplantation.⁴

• Lymphoproliferative diseases including chronic lymphocytic leukaemia, linfoma não-Hodgkin e Waldenstrom's macroglobulinaemia.

• Plasmacytoma (a tumour consisting of abnormal plasma cells that grows within the soft tissue or skeleton).

• Heavy chain diseases: there are 3 variants - gamma, alpha and mu heavy chain disease.⁵ The alpha variant is most common, occurring particularly in people from the Mediterranean and Middle East and often presenting with weakness, fatigue and fever.

• Síndrome de POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes).

• Amiloidose.

• Non-malignant systemic disease:¹

  • Autoimmune disease: artrite reumatoide, esclerodermia, tireoidite de Hashimoto.

  • Cutaneous disease: pioderma gangrenoso, necrobiotic xanthogranulomatosis.

  • Liver disease: hepatitis, cirrose.

  • Infectious disease: tuberculose, bacterial endocarditis.

• Miscellaneous syndromes:

  • Schnitzler's syndrome (chronic, non-pruritic urticaria associated with recurrent fever, bone pain, arthralgia or arthritis, and a monoclonal IgM gammopathy).

Symptoms of paraproteinaemia (presentation)

• Paraproteinaemia may be asymptomatic and discovered incidentally.

• Often nonspecific presentation with fever, malaise, and bone pain.

• Clinical indications for screening for M-protein:^{1 6}

  • Malaise and fatigue.

  • Bone disease (persistent back pain, osteopenia or lytic lesions).

  • Impaired renal function.

  • Normochromic normocytic anaemia ± pancytopenia.

  • Hypercalcaemia (confusion, muscle weakness, constipation, thirst, polyuria).

  • Recurrent bacterial infections.

  • Hyperviscosity (headache, visual disturbance, cognitive impairment, mucosal bleeding, breathlessness).

  • Nephrotic syndrome, cardiac failure, malabsorption.

  • Peripheral neuropathies, carpal tunnel syndrome.

  • Incidental persistent elevated erythrocyte sedimentation rate (ESR) or plasma viscosity (PV) or serum protein or globulin.

Diagnosing paraproteinaemia (investigations)

The differentiation of benign paraproteinaemia from neoplastic states is based on the absence of bone marrow disease, a relatively low and constant concentration of serum paraprotein, the absence of urine light chain excretion and normal levels of other serum immunoglobulins. It is important to test both urine and blood for paraprotein. In 15% of myeloma cases the diagnosis would be missed if only serum electrophoresis was performed with testing urine for Bence Jones' proteins.

• Serum protein electrophoresis showing M-protein: total protein and protein electrophoresis with paraprotein quantification, paraprotein typing, immunoglobulins G, A, M; beta-2-microglobulin.⁷

• FBC, blood film, ESR: underlying cause - eg, hypercalcaemia, high total protein, and high ESR or PV in patients with myeloma.

• Urine protein: Bence Jones' proteins (usually indicate multiple myeloma, amyloidosis or Waldenström's macroglobulinaemia).

• Bone marrow aspiration and trephine biopsy.

Management of paraproteinaemia

Management will depend on the underlying cause.

Prognóstico

This will depend on the underlying cause. In 2020 the five-year year survival rate for multiple myeloma was 52%.⁶ Patients with MGUS have a 1% annual risk of progression to myeloma.⁸