Calculated globulin (CG) as a screening test for antibody deficiency

Abstract

Calculated globulin (total protein - albumin) is usually tested as part of a liver function test profile in both primary and secondary care and determines the serum globulin concentration, of which immunoglobulins are a major component. The main use hitherto of calculated globulin is to detect paraproteins when the level is high. This study investigated the potential to use low levels of calculated globulin to detect antibody deficiency. Serum samples with calculated globulin cut-off < 18 g/l based on results of a pilot study were collected from nine hospitals in Wales over a 12-month period. Anonymized request information was obtained and the samples tested for immunoglobulin levels, serum electrophoresis and, if appropriate, immunofixation. A method comparison for albumin measurement using bromocresol green and bromocresol purple was undertaken. Eighty-nine per cent (737 of 826) samples had an immunoglobulin (Ig)G level of < 6 g/l using the bromocresol green methodology with a cut-off of < 18 g/l, and 56% (459) had an IgG of < 4 g/l. Patients with both secondary and primary antibody deficiency were discovered and serum electrophoresis and immunofixation showed that 1·2% (10) had previously undetected small paraproteins associated with immune-paresis. Using bromocresol purple, 74% of samples had an IgG of < 6 g/l using a cut-off of < 23 g/l. Screening using calculated globulin with defined cut-off values detects both primary and secondary antibody deficiency and new paraproteins associated with immune-paresis. It is cheap, widely available and under-utilized. Antibody-deficient patients have been discovered using information from calculated globulin values, shortening diagnostic delay and time to treatment with immunoglobulin replacement therapy.

Keywords: common variable immunodeficiency; immunoglobulin; myeloma; primary antibody deficiency; screening; secondary antibody deficiency.

Figure 1

Correlation of calculated globulin levels with immunoglobulin (Ig)G. Fifty samples obtained anonymously for each level of calculated globulin (CG) at 15, 16, 17, 18, 19, 20, 21 and 22 g/l were tested for immunoglobulin levels and the correlation with IgG is shown. An IgG of 6 g/l corresponded to a CG level of 18 g/l and this was selected as the cut-off value for the bromocresol green (BCG) method.

Figure 2

Numbers of samples at each level of immunoglobulin (Ig)G. The numbers of samples at each level of IgG are shown for samples with a calculated globulin (CG) of < 18 g/l with only 11% of samples recorded with an IgG level in the normal range (6–16 g/l); 56% of samples had an IgG of < 4 g/l, which is 4 standard deviations below the mean for adults [bromocresol green (BCG) method].

Figure 3

Source of samples with an immunoglobulin (Ig)G < 6 g/l. A wide range of specialities is represented with a high number from surgery due probably to the use of intravenous fluids and blood products which may temporarily alter a calculated globulin (CG) [intensive care unit (ITU), general practice (GP), outpatients department (OPD), Teenage Cancer Trust unit (TCTU), accident and emergency (A&E), medical assessment unit (MAU].

Figure 4

Haematology diagnoses with IgG < 4 g/l. The largest category of antibody-deficient patients from haematology is from requests labelled lymphoma [lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, renal lymphoma, Mantle cell lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma and central nervous system (CNS) lymphoma] and a range of other haematological diagnoses reflecting either secondary antibody deficiency due to the disorder or subsequent to its treatment.

Figure 5

Diagnoses with immunoglobulin (Ig)G < 4 g/l from primary care. Diagnoses from 32 request forms from patients in general practice with IgG levels less than 4 g/l are shown. There are a significant number where drug monitoring is taking place and a number with a range of more non-specific symptoms. Congestive cardiac failure (CCF), ischaemic heart disease (IHD), chronic lymphocytic leukaemia (CLL) and information not available (NA).