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Letters to the Editor |
Departments of1
Pathology and Laboratory Medicine, and2
Hematology/Oncology, Emory University Hospital, Atlanta, GA
3 Grady Memorial Hospital, Atlanta, GA
4 Veterans Affairs Medical Center, Atlanta, GA
aAddress correspondence to this author at: Department of Pathology and Laboratory Medicine, Emory University Hospital, 1364 Clifton Road NE, Atlanta, GA 30322. E-mail csheppa{at}emory.edu.
To the Editor:
We read with interest the Technical Brief by Smogorzewska et al. (1) describing an artificially increased total bilirubin in a patient with a monoclonal IgM paraprotein. Monoclonal paraproteins have been shown to artifactually influence several automated assays of different methodologies, including nephelometry, turbidometry, and immunologic assays, by forming precipitates during the assay procedure (2)(3)(4)(5)(6)(7). The total bilirubin assay on the Hitachi 917 automatic chemistry analyzer (Roche Diagnostics) has been reported to yield falsely increased bilirubin values as a result of paraprotein interference (1)(8).
Smogorzewska et al. (1) and Pantanowitz et al. (8) described this artifact as rare, but we have identified 6 patients at 2 hospitals with documented paraproteins who had falsely increased serum total bilirubin. Notably, patients with artifactually high total serum bilirubin had direct bilirubin values within the reference interval. Smogorzewska et al. (1) and others have hypothesized that the Roche solubilizing agent is the cause of the error because this interference is absent in the direct bilirubin assay. This is yet to be confirmed, however, and there is no evidence from the literature addressing the nature of precipitate formation.
We manually performed the Roche assay on a serum sample from a patient with a documented paraprotein (100 g/L), reportedly increased total serum bilirubin (106 mg/L), and no clinical suspicion of liver disease or obstruction (Fig. 1
). We performed the assay in its entirety and found that precipitate began to form minutes after addition of Reagent 2. We also found that addition of Reagent 1 alone caused the formation of precipitate, but at a slower rate (90 min). No precipitate formed without the addition of Reagent 1. This finding supports the hypothesis by Smogorzewska et al. (1) and others that precipitation may be induced by the solubilizer in Reagent 1. Although the company released a bulletin in 2000 describing potential incorrect results in multiple myeloma patients, the problem has not been addressed to date. Unfortunately, the company provides no specifics regarding the surfactant used in Reagent 1 (7).
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Smogorzewska et al. (1) described a method by which they manually programmed the Hitachi 917 analyzer to trigger a flag when the difference between the absorbances at two different time points late in the reaction increased by >0.035. It is important to appreciate that none of the cases previously described by Pantanowitz et al. (8) or Smogorzewska et al.(1) were visibly icteric.
Of 191 patients with documented paraproteins in our 2 hospitals, we have identified a total of 6 patients with artifactually high bilirubin attributable to the presence of a known paraprotein and 2 other patients whom we highly suspect based on increased total bilirubin without an increase in direct bilirubin; all of these patients had anicteric specimens. Thus, the calculated frequency of this occurrence in our population is 
3%–4%, a significant number.
We therefore propose an equally effective and potentially easier way to identify patients with falsely increased total bilirubin values. The Hitachi 917 is equipped to determine serum indices, and we recommend that a software rule be set to hold any specimen for manual verification with an icteric index <2 and total bilirubin >20 mg/L. This approach effectively eliminates the release of artifactually high total bilirubin attributable to surfactant-induced turbidimetric changes in monoclonal paraproteins. Although use of the serum indices may decrease instrument throughput, their use ensures the quality of specimen results and may serve to highlight other unusual problems.
Footnotes
Editor’s note: The manufacturer has promised a reply, but none has been received at press time.
References
from a myeloma patient. Clin Chem 1997;43:2435-2437.The following articles in journals at HighWire Press have cited this article:
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  C. Monk, M. Wallage, J. Wassell, A. Whiteway, J. James, and R. Beetham A monoclonal protein identified by an anomalous lipaemia index Ann Clin Biochem, May 1, 2009; 46(3): 250 - 252. [Abstract] [Full Text] [PDF]
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 A. McLean-Tooke, C. Stroud, A. Sampson, and G. Spickett Falsely normal C4 in a case of acquired C1 esterase inhibitor deficiency J. Clin. Pathol., May 1, 2007; 60(5): 565 - 566. [Abstract] [Full Text] [PDF]
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