Monitoring patients with monoclonal gammopathies

Diagnosis of monoclonal gammopathies, when used in conjunction

with immunofixation

Protein electrophoresis alone is not considered an adequate

screening for monoclonal gammopathies.

Serum proteins can be grouped into 5 fractions by protein electrophoresis

(PEL):

   - Albumin, which represents almost 2/3 of the total serum protein

   - Alpha-1, composed primarily of alpha-1-antitrypsin (A1AT), an

     alpha-1-acid glycoprotein

   - Alpha-2, composed primarily of alpha-2-macroglobulin and haptoglobin

   - Beta, composed primarily of transferrin and C3

   - Gamma, composed primarily of immunoglobulins (Ig)

The concentration of these fractions and the electrophoretic pattern may be

characteristic of diseases such as monoclonal gammopathies,

A1AT deficiency disease, nephrotic syndrome, and inflammatory

processes associated with infection, liver disease, and autoimmune diseases.

See "An Expanded Algorithm for the Laboratory Evaluation of

Suspected Multiple Myeloma" in Special Instructions. Also see

"Diagnosis and Monitoring of Multiple Myeloma" in Publications.

TOTAL PROTEIN

> or = 1 year:  6.3-7.9 g/dL

PROTEIN ELECTROPHORESIS

Albumin:  3.4-4.7 g/dL

Alpha-1-globulin:  0.1-0.3 g/dL

Alpha-2-globulin:  0.6-1.0 g/dL

Beta-globulin:  0.7-1.2 g/dL

Gamma-globulin:  0.6-1.6 g/dL

An interpretive comment is provided with the report.

Monoclonal gammopathies:  

-A characteristic monoclonal band (M-spike) is often found on PEL in the

 gamma-globulin region and more rarely in the beta or alpha-2 regions.

 The finding of a M-spike, restricted migration, or hypogammaglobulinemic

 PEL pattern is suggestive of a possible monoclonal protein and should

 be followed by #8823 "Monoclonal Protein Study, Urine," which

 includes immunofixation (IF), to identify the immunoglobulin heavy chain

 and/or light chain.

-A monoclonal IgG or IgA >3 g/dL is consistent with multiple

 Myeloma (MM).

-A monoclonal IgG or IgA < 3 g/dL may be consistent with

 monoclonal gammopathy of undetermined significance (MGUS),

 primary systemic amyloidosis, early or treated myeloma, as well

 as a number of other monoclonal gammopathies.  

-A monoclonal IgM > 3 g/dL is consistent with macroglobulinemia.  

-The initial identification of a serum M-spike >1.5 g/dL on PEL should

  be followed by #8823 "Monoclonal Protein Study, Urine."

- The initial identification of an IgM, IgA, or IgG M-spike >4, >5, and >6 g/dL

  respectively, should be followed by #8168 "Viscosity, Serum."

-After the initial identification of an M-spike, quantitation of the M-spike

 on follow-up PEL can be used to monitor the monoclonal gammopathy.

 However, if the monoclonal protein falls within the beta region (most

 commonly an IgA or an IgM), quantitative immunoglobulin levels may

 be more a useful tool to follow the monoclonal protein level than PEL.

 A decrease or increase of the M-spike that is greater than 0.5 g/dL

 is considered a significant change.

-Patients suspected of having a monoclonal gammopathy may have

 normal serum PEL patterns. Approximately 11% of patients with

 MM have a completely normal serum PEL, with the monoclonal

 protein only identified by IF. Approximately 8% of MM patients

 have hypogammaglobulinemia without a quantifiable M-spike

 on PEL but identified by IF. Accordingly, a normal serum PEL does

 not rule out the disease and should not be used to screen for the

 disorder. The #81756 "Monoclonal Protein Study, Serum," which includes

 IF, should be done to screen if the clinical suspicion is high.                                                         

Other abnormal PEL findings:

-A qualitatively normal but elevated gamma fraction (polyclonal

 hypergammaglobulinemia) is consistent with infection, liver disease,

 or autoimmune disease.  

-A depressed gamma fraction (hypogammaglobulinemia) is consistent

 with immune deficiency and can also be associated with primary

 amyloidosis or nephrotic syndrome.

-A decreased albumin (<2 g/dL), increased alpha-2 fraction (>1.1 g/dL),  

 and decreased gamma fraction (<1 g/dL) is consistent with nephrotic

 syndrome, and when seen in an adult >40 years, should be

 followed by #8823 "Monoclonal Protein Study, Urine."

-In the hereditary deficiency of a protein (eg, agammaglobulinemia,

 A1AT deficiency, hypoalbuminemia), the affected fraction is faint or

 absent.

-An absent alpha-1 fraction is consistent with A1AT deficiency disease

 and should be followed by a quantitative A1AT assay (#8161 "Alpha-1-

 Antitrypsin, Serum"). 

A normal serum PEL does not rule out disease. #81756 "Monoclonal

Protein Study, Serum," which includes immunofixation, should be done

to screen if the clinical suspicion is high.

Very large IgG M-spikes (>4 g/dL) may saturate the protein stain. In

these situations, quantitative IgG assays (#8160 "Immunoglobulin G

[IgG], Serum) should be performed to accurately determine M-spike

concentrations to monitor disease progression or response to therapy.

Fibrinogen will migrate as a distinct band in the beta-gamma fraction.

Serum specimen from new patients with a beta-gamma band are to

be treated with thrombin to ensure complete conversion of fibrinogen.

Hemolysis may augment the beta fraction.

Penicillin may split the albumin band.

Radiographic agents may produce an uninterpretable pattern.

Kyle RA, Katzmann JA, Lust JA, Dispenzieri A:

Clinical indications and applications of electrophoresis

and immunofixation. In Manual of Clinical Laboratory

Immunology. 6th edition. Edited by NR Rose, et al.

Washington DC,  ASM Press, 2002 pp 66-70