Prevalence of paraprotein interference in three clinical chemistry analytes in a routine biochemistry laboratory

To the Editor,

Paraprotein interference in biochemical measurements is a known problem. While the issue has been reported in the literature, it is frequently presented as individual case reports making the prevalence of such interference in the routine biochemistry laboratory difficult to estimate. Paraprotein interference has been described in a range of assays on multiple automated clinical chemistry platforms, including creatinine, phosphate, bilirubin, total protein, and HDL. ¹ Interference is most likely to occur if the paraprotein is an IgM type, due to its large pentameric structure, although IgA interference has also been reported. ² We aimed to determine the prevalence and extent of paraprotein interference using three commonly measured analytes (bilirubin, creatinine, and phosphate) which have been previously reported to suffer from assay interference.

Between July 2019 and February 2020, serum samples from patients with known monoclonal gammopathy, confirmed by protein electrophoresis, were identified using the laboratory database at Glasgow Royal Infirmary. Samples were re-analysed for creatinine, phosphate, or total bilirubin, where these analytes were part of the original request. Reaction curves for the repeated analyses were then compared visually to curves from control material to identify abnormalities suggesting interference. Numerical results for each test were also compared to the original value to take into account the effects of analyte stability. Analyses were performed on an Abbott Architect c16000 analyser (Abbott Diagnostics), and creatinine was measured using the enzymatic method.

A total of 188 samples were identified from 148 patients; 28% of paraproteins were present as IgA (at concentrations from 2 to 38 g/L), 53% as IgG (at concentrations 2–38 g/L) and 19% as IgM (at concentrations from 2 to 40 g/L). Several patients had two paraproteins of the same type, and one patient had both an IgA and IgG paraprotein. Within this cohort, 178 creatinine, 167 phosphate, and 146 total bilirubin tests were performed. Patient reaction curves differed significantly from control material for 2 out of the 148 patients. One patient showed interference in the total bilirubin assay, and the other in the creatinine assay. The patient with interference in the bilirubin assay had two samples with an IgM lambda paraprotein at 23 and 15 g/L, respectively. Both samples showed similar abnormalities in the reaction curve. The original and repeat bilirubin results for the two samples were 7 and 6 µmol/L, and 3 and 4 µmol/L, respectively. The patient with interference in the creatinine assay had a single sample with an IgM kappa paraprotein of 13 g/L. Creatinine was undetectable (<9 µmol/L) originally and the repeat result was 39 µmol/L. The sample was re-analysed in another laboratory using the Jaffe method, which gave a result of 110 µmol/L. This interference did not appear to be directly related to IgM paraprotein concentration, as the mean IgM concentration in the patient cohort was 11 g/L, and no interference was noted in several other samples with IgM concentration >20 g/L (the highest being 40 g/L).

This is the first study attempting to assess the prevalence of paraprotein interference in chemistry analyses in a routine laboratory. Although the sample size is small, the data suggest that the prevalence of interference is low, and should not cause significant issues for the majority of testing. However, as shown in this dataset, falsely lower results can be produced in the presence of interference. Blood testing laboratories should be aware of the possibility of interference especially if IgM paraprotein is present, and that this could have a significant effect on individual patient results.