Beta-2 Microglobulin

Beta-2 microglobulin (B2M) is an 11.8 kDa protein, the light chain of the class I human leucocyte antigen (HLA) molecule. It is present on the surface of all nucleated cells and is shed at a steady rate, in proportion to the number and turnover of cells, mainly lymphocytes.

It is filtered freely at the glomerulus and almost completely reabsorbed and broken down in the proximal tubule. It is measured in serum, urine or cerebrospinal fluid by immunoassay or nephelometry, in mg/L.

Serum B2M reflects tumour burden and cell turnover in myeloma and lymphoma, and also glomerular filtration. Urinary B2M reflects tubular damage. The result is therefore read with the serum creatinine and the clinical setting.

Multiple myeloma has an incidence of about 5 to 7 per 100 000 people a year, and B2M is a core part of its staging. Chronic lymphocytic leukaemia, lymphoma and HIV infection also raise B2M. Dialysis related amyloidosis from B2M deposition affects most patients who have been on dialysis for over 10 to 15 years.

Indications. Staging and prognosis in multiple myeloma, prognosis in chronic lymphocytic leukaemia and lymphoma, assessment of proximal tubular dysfunction, evaluation of kidney function when cystatin C is not available, cerebrospinal fluid B2M in meningeal lymphoma or leukaemia, and dialysis patients with carpal tunnel syndrome or arthropathy.

Specimen. Serum (separated promptly), a random or timed urine, or cerebrospinal fluid. Urine for B2M must be buffered to a pH over 6, or collected into alkaline containers, because B2M is destroyed in acid urine (pH under 5.5) within hours. Serum is stable for days at 2 to 8 °C.

Serum. Adults under 60 years: 1.0 to 2.4 mg/L. Older adults: up to 3.0 mg/L. Values are assay specific.

Urine. Under 0.3 mg/L, or under 300 microg/g creatinine. Increase indicates tubular damage, provided serum B2M is normal.

Cerebrospinal fluid. Under 2.0 mg/L, with raised values in meningeal infiltration by lymphoma or leukaemia, and in meningitis, multiple sclerosis and AIDS.

Multiple myeloma. B2M with albumin is the basis of the International Staging System (ISS), and the revised ISS adds LDH and high risk chromosomal abnormalities.

• Stage I: B2M under 3.5 mg/L and albumin 35 g/L or more. Median survival over 5 years.
• Stage II: neither stage I nor III. Median survival about 4 years.
• Stage III: B2M 5.5 mg/L or more. Median survival about 2 years, longer with modern therapy.
• B2M reflects tumour burden and kidney function together, and in kidney failure the prognostic value is reduced.

Lymphoid malignancy. Raised in chronic lymphocytic leukaemia (over 3.5 to 4 mg/L predicts shorter time to treatment and survival), non-Hodgkin lymphoma (a component of prognostic indices) and Waldenström macroglobulinaemia (over 3 mg/L as a high risk feature).

Causes of raised serum B2M.

• Reduced glomerular filtration: acute and chronic kidney disease (values rise as GFR falls, and in dialysis patients reach 30 to 50 mg/L).
• Malignancy: myeloma, lymphoma, chronic lymphocytic leukaemia, and some solid tumours.
• Inflammation and immune activation: HIV infection, cytomegalovirus infection, systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, inflammatory bowel disease, sarcoidosis, hepatitis, and organ transplant rejection.
• Dialysis related amyloidosis, with joint pain, carpal tunnel syndrome, destructive arthropathy and bone cysts.

Causes of raised urinary B2M. Proximal tubular damage (Fanconi syndrome, cadmium and other heavy metals, aminoglycosides, tenofovir, cisplatin, Balkan nephropathy, tubulointerstitial nephritis), and overflow when serum B2M is very high (myeloma, lymphoma).

Critical values and findings needing immediate action.

• Serum B2M of 5.5 mg/L or more in a patient with myeloma, with kidney failure, hypercalcaemia or neurological signs.
• Rising B2M in a patient with lymphoma or leukaemia with new symptoms (fever, weight loss, night sweats).
• Raised cerebrospinal fluid B2M with neurological deficit in a patient with lymphoma or leukaemia.
• Rapid rise with falling urine output, since kidney function drives the level.

Interferences and pitfalls.

• B2M is not specific. Kidney impairment, infection and inflammation raise it without cancer.
• In kidney failure, B2M cannot be used to judge myeloma burden, and other markers (paraprotein, free light chains, marrow) are used.
• Urine in acidic conditions destroys B2M and gives false low results.
• Assays differ in range, and the same method is used for serial measurement. The ISS cut offs of 3.5 and 5.5 mg/L apply to specific assays.
• Hook effect is possible in very high concentrations.
• Heterophile antibodies can cause errors.
• B2M is a less accurate marker of GFR than creatinine or cystatin C in patients with inflammation or malignancy.
• Newer dialysis membranes (high flux) reduce B2M removal poorly, and levels remain high.

Special groups.

• Older adults: higher reference limits, and a small rise is expected.
• Dialysis patients: levels are chronically very high, and amyloid risk is related to duration.
• Children: reference limits are higher in infancy and fall to adult values, with use mainly in lymphoma and kidney disease.
• Pregnancy: no major change.
• Regions: HIV and tuberculosis raise B2M, and may confuse interpretation where lymphoma is suspected.

Follow up tests.

• Serum creatinine and eGFR, cystatin C
• Serum protein electrophoresis with immunofixation, serum free light chains
• 24-hour urine protein, calcium, albumin, LDH, full blood count
• Bone marrow examination, cytogenetics and FISH
• Whole body low dose CT or MRI, flow cytometry
• HIV testing
• Urine retinol binding protein or alpha-1 microglobulin for tubular damage
• Tissue biopsy with Congo red for amyloid