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Beta2-Microglobulin 

  • Author: Mahasweta Gooptu, MBBS; Chief Editor: Eric B Staros, MD  more...
 
Updated: Sep 05, 2014
 

Reference Range

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]

The reference range of beta2 microglobulin in urine samples is 0-0.3 µg/mL. In serum or plasma samples, the reference range is 0-3 µg/mL.

It is recommended that each laboratory establish its own normal and pathological ranges of urine levels.[2, 3, 4]

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Interpretation

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.[5, 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.[5]

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.[6]

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Collection and Panels

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.[3]

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Background

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.[7]

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.[7]

Crystal structure of beta2 microglobulin. Crystal structure of beta2 microglobulin.
MHC macromolecular structure. MHC macromolecular structure.

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.[8]

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.[3]

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.[9] 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,[10] 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.[5] 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.[11]

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.[12, 13, 14, 15]

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.[16] 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.[6]

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.[17] 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.[18]

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Contributor Information and Disclosures
Author

Mahasweta Gooptu, MBBS Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Anthony P Scarpaci, MD Attending Physician, Medical Oncology/Hematology Associates, Albert Einstein Health Network

Disclosure: Nothing to disclose.

Chief Editor

Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital

Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology

Disclosure: Nothing to disclose.

References
  1. Bethea M, Forman DT. Beta 2-microglobulin: its significance and clinical usefulness. Ann Clin Lab Sci. 1990 May-Jun. 20(3):163-8. [Medline].

  2. Evrin PE, Wibell L. The Serum Levels and Urinary Excretion of beta2-Microglobulin in Apparently Healthy Subjects. Scandinavian Journal of Clinical & Laboratory Investigation. 1972. 29 (1):69-74.

  3. B2 microglobulin Assay [package insert]. Mainz, Germany: Orgentec. 2012. Available at [Full Text].

  4. Hibi Y, Uemura O, Nagai T, Yamakawa S, Yamasaki Y, Yamamoto M, et al. The ratios of urinary ß2-microglobulin and NAG to creatinine vary by age in children. Pediatr Int. 2014 Aug 20. [Medline].

  5. Durie BG, Stock-Novack D, Salmon SE, Finley P, Beckord J, Crowley J, et al. Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest Oncology Group Study. Blood. 1990 Feb 15. 75(4):823-30. [Medline].

  6. Adachi N. Beta-2-microglobulin levels in the cerebrospinal fluid: their value as a disease marker. A review of the recent literature. Eur Neurol. 1991. 31(4):181-5. [Medline].

  7. Nakamuro K, Tanigaki N, Pressman D. Multiple common properties of human beta2-microglobulin and the common portion fragment derived from HL-A antigen molecules. Proc Natl Acad Sci U S A. 1973 Oct. 70(10):2863-5. [Medline]. [Full Text].

  8. Floege J, Ketteler M. beta2-microglobulin-derived amyloidosis: an update. Kidney Int Suppl. 2001 Feb. 78:S164-71. [Medline].

  9. Henne V, Frei P, Bürgisser P. Beta-2-microglobulin--a rapid and automated determination for a broad range of clinical applications. Anticancer Res. 1997 Jul-Aug. 17(4B):2915-8. [Medline].

  10. Kyle RA, Treon SP, Alexanian R, Barlogie B, Björkholm M, Dhodapkar M, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003 Apr. 30(2):116-20. [Medline].

  11. Gatto S, Ball G, Onida F, Kantarjian HM, Estey EH, Beran M. Contribution of beta-2 microglobulin levels to the prognostic stratification of survival in patients with myelodysplastic syndrome (MDS). Blood. 2003 Sep 1. 102(5):1622-5. [Medline].

  12. Heegaard NH. beta(2)-microglobulin: from physiology to amyloidosis. Amyloid. 2009. 16(3):151-73. [Medline].

  13. Winchester JF, Salsberg JA, Levin NW. Beta-2 microglobulin in ESRD: an in-depth review. Adv Ren Replace Ther. 2003 Oct. 10(4):279-309. [Medline].

  14. Goodchild SC, Sheynis T, Thompson R, Tipping KW, Xue WF, Ranson NA, et al. Beta2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH. PLoS One. 2014. 9(8):e104492. [Medline]. [Full Text].

  15. Mangione PP, Esposito G, Relini A, Raimondi S, Porcari R, Giorgetti S, et al. Structure, folding dynamics, and amyloidogenesis of D76N ß2-microglobulin: roles of shear flow, hydrophobic surfaces, and a-crystallin. J Biol Chem. 2013 Oct 25. 288(43):30917-30. [Medline]. [Full Text].

  16. Hofmann B, Wang YX, Cumberland WG, Detels R, Bozorgmehri M, Fahey JL. Serum beta 2-microglobulin level increases in HIV infection: relation to seroconversion, CD4 T-cell fall and prognosis. AIDS. 1990 Mar. 4(3):207-14. [Medline].

  17. Uchanska-Ziegler B, Ziegler A. Ankylosing spondylitis: a beta2m-deposition disease?. Trends Immunol. 2003 Feb. 24(2):73-6. [Medline].

  18. Yang J, Qian J, Wezeman M, Wang S, Lin P, Wang M, et al. Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies. Cancer Cell. 2006 Oct. 10(4):295-307. [Medline].

 
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Crystal structure of beta2 microglobulin.
MHC macromolecular structure.
 
 
 
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