Beta2 Microglobulin

Serum and plasma beta₂ microglobulin values have emerged as markers for the activation of the cellular immune system, as well as a tumor marker in certain hematologic malignancies. Urine beta₂ microglobulin values indicate renal filtration disorders. Measurement of values in both serum and urine can help distinguish a problem of cellular activation from a renal disorder. ^[1]

Normal findings ^[2] :

• Blood: 0.70-1.80 mcg/mL
• Urine: ≤300 mcg/L
• Cerebrospinal fluid (CSF): 0-2.4 mg/L 

Interpretation depends on the specific clinical indication and context.

Low serum levels of beta₂ microglobulin essentially indicate decreased disease activity in conditions for which beta₂ microglobulin is used as a prognostic marker (multiple myeloma, lymphoma, leukemia) or the absence of such a disease process. However, low beta₂ microglobulin levels are never used to rule out a particular disease (eg, lymphoma) in the absence of other more definitive tests. ^{[3, 1]}

Increased serum beta₂ microglobulin levels reflect increased activity of the disease process in question and can be an exquisitely sensitive marker for this purpose in many hematologic disorders. The absolute value is less important than the historical values, except in certain situations such as multiple myeloma, in which a value of less than 4 µg/mL was found to correlate with increased survival. ^[3]

Increased urine beta₂ microglobulin levels reflect tubular disorders of the kidney. In such cases, serum beta₂ microglobulin levels are usually normal, since the dysfunction is in tubular reabsorption.

Increased CSF beta₂ microglobulin levels are seen in certain conditions such as multiple sclerosis, AIDS dementia complex, and meningeal spread of hematologic tumors. ^[4]

Beta₂ microglobulin can be determined in urine, serum, or plasma samples.

It is not necessary to draw the sample in a fasting state, and no special preparations are necessary.

Blood is collected by venipuncture in a red-top tube and centrifuged to separate serum from cells after clot formation.

Samples may be stored refrigerated at 2-8°C for 5 days. For longer storage (up to 6 months), samples should be stored frozen at -20°C. To avoid repeated thawing and freezing, the samples should be aliquoted.

Bilirubin and hemolysis do not significantly affect the procedure. However, gross lipemia can interfere with results.

Beta₂ microglobulin is a component of certain panels, such as chronic lymphocytic leukemia (CLL), lymphoma, or multiple myeloma prognostic/monitoring panels. ^[5]

Description

One of the important functions of the human immune system is distinguishing self from nonself molecules. Most nucleated cells in the human body carry class I antigens that help the immune system identify self molecules. These antigens have a heavy chain and an associated light chain. This light-protein chain, which can be shed into serum, is called beta₂ microglobulin. The molecule was discovered initially as a serum protein. ^[6]

Beta₂ microglobulin is an 11.8-kD protein (see first image below), which forms one of the chains of the major histocompatibility complex (MHC) class I molecule normally present on the surface of every nucleated cell in the human body. The other 3 include alpha₁, alpha₂, and alpha₃ (see second image below). This protein further functions to present antigens to cytotoxic T lymphocytes that are carrying out surveillance for infection. ^[6]

The synthesis rate of beta₂ microglobulin varies from 2-4 mg/kg/day, with a half-life of 2.5 hours. Plasma concentrations vary from 1-3 µg/mL. Ninety percent of beta₂ microglobulin is eliminated via glomerular filtration and almost completely reabsorbed by the proximal tubules. Thus, in individuals with chronic kidney disease, particularly end-stage renal disease, beta₂ microglobulin can accumulate in the blood. In vitro, the synthesis and release of beta₂ microglobulin can be induced by acidosis, endotoxin, or inflammatory cytokines. ^[7]

Serum beta₂ microglobulin has now been identified as an important prognostic marker in a large number of hematologic and nonhematologic disorders. Urine beta₂ microglobulin levels are high in renal tubular disorders despite normal plasma levels, reflecting a dysfunction in reabsorption by the proximal tubules. ^[5]

Indications/Applications

Serum and plasma beta₂ microglobulin values have emerged as markers for the activation of the cellular immune system, as well as a tumor marker in certain hematologic malignancies. Urine beta₂ microglobulin values indicate renal filtration disorders. Measurement of values in both serum and urine can help distinguish a problem of cellular activation from a renal disorder. ^[1]

Malignancies

Significantly elevated levels of beta₂ microglobulin can be found in lymphoproliferative disorders such as monoclonal gammopathies of immunoglobulin G (IgG) (multiple myeloma), malignant lymphomas, and chronic lymphocytic leukemia. ^[8] Values have been shown to correlate with prognosis. However, elevated beta₂ microglobulin levels are not a specific finding and cannot be used to establish a diagnosis.

In Waldenström macroglobulinemia, ^[9] beta₂ microglobulin levels, upon diagnosis, influenced timing of treatment and survival. In multiple myeloma, serum values of less than 4 µg/mL were associated with significant increase in survival. ^[3] Prospective analyses has now confirmed that, along with karyotype and second only to it, beta-2 microglobulin is a prognostic marker for survival in myelodysplastic syndromes. ^[10]

Renal diseases

Beta₂ microglobulin accumulates in the serum of individuals with renal failure. Although decreased clearance appears to be the primary reason for elevation of beta₂ microglobulin levels in persons with end-stage renal disease, it has been postulated that the uremic state may result in increased production of the molecule. In some such patients, it can deposit in joint spaces and cause synovitis. This phenomenon is termed dialysis-related amyloid (DRA), or AB-amyloid. Secondary modifications of the molecule, such as glycation, limited proteolysis, and conformational changes, contribute to this phenomenon, which can also affect uremic predialysis patients. ^{[11, 12, 13, 14]}

Interestingly, while this phenomenon is not seen in renal transplant recipients, rejection of the allograft has been associated with high serum beta₂ microglobulin levels.

HIV

In cases of HIV infection, increasing levels of beta₂ microglobulin exhibited an inverse correlation to the CD4+ T-lymphocyte count and indicated disease progression. ^[15] However, it is not currently being used clinically for this purpose.

Neurologic diseases

Elevated CSF beta₂ microglobulin levels have been shown to correlate with disease activity in multiple sclerosis, neuro-Behçet disease, sarcoidosis, AIDS dementia complex, and meningeal dissemination of malignant hematologic malignancies. ^[4]

Rheumatologic disease

Some authors believe that ankylosing spondylitis is partly caused by deposition of beta₂ microglobulin within the joints, in a similar mechanism as dialysis-related amyloid arthropathy. These authors note that this may in part explain the strong association between the HLA-B27 allele (with beta₂ microglobulin as its product) and this inflammatory arthritis. ^[16] However, beta₂ microglobulin levels are normal in this condition.

Considerations

Beta₂ microglobulin is shed from the surface of nucleated cells into serum; increased levels can be seen in a wide variety of disorders that involve increased cell turnover and/or activation of the immune system. Whereas this makes beta₂ microglobulin a marker for myriad diseases, it also makes it a relatively nonspecific marker. This has led to its use as a quantitative prognostic marker much more than as a diagnostic marker. Indeed, there are virtually no conditions in which beta₂ microglobulin can be used to make a diagnosis.

Despite this limitation, beta₂ microglobulin is often part of the initial panels for certain diseases (multiple myeloma, Waldenström macroglobulinemia, myelodysplastic syndromes) in which the baseline value of beta₂ microglobulin affects staging, prognosis, and treatment.

The value of increased beta₂ microglobulin levels in CSF and urine are less clearly defined than in serum. The value of following levels as a marker of disease progression still needs to be established in prospective trials.

Finally, the role of anti–beta₂ microglobulin monoclonal antibodies as potential immunotherapy for certain leukemias is actively being investigated, although such therapies are strictly experimental at this time. ^[17]