Platform-dependent IgM paraprotein interference caused a 71.3% discrepancy in total calcium results between two analyzers using the same Arsenazo III method, with IgM-related precipitation and optical scattering identified as underlying mechanisms, ultimately leading to a diagnosis of Waldenström macroglobulinemia.
Key Findings
Background
Two analyzer platforms using the same Arsenazo III method produced markedly discordant total calcium results due to IgM paraprotein interference.
The Hitachi platform reported total calcium of 4.95 mmol/L ('hypercalcemic crisis'), while the Beckman Coulter AU platform reported 2.89 mmol/L (mildly elevated).
The discrepancy represented a 71.3% difference in total calcium between the two platforms.
Both platforms used the Arsenazo III colorimetric method, yet produced substantially different results from the same serum sample.
The case involved an 85-year-old man admitted for low back pain.
Background
The Hitachi platform reported severe hyponatremia while the Beckman Coulter AU platform reported only milder hyponatremia in the same patient sample.
Hitachi reported sodium of 125 mmol/L (severe hyponatremia), whereas Beckman Coulter AU reported 133 mmol/L (milder hyponatremia).
Direct ion-selective electrode (ISE) measurements excluded true hyponatremia.
The sodium discordance paralleled the calcium discordance, suggesting a common platform-specific interference mechanism.
Results
IgM-related precipitation and optical scattering were confirmed as the underlying mechanisms of analytical interference.
Dilution studies, polyethylene glycol (PEG) precipitation, reaction-curve inspection, and simulation experiments were performed to investigate the mechanism.
IgM paraprotein precipitation caused optical scattering that interfered with absorbance-based measurements.
Platform-specific mixing dynamics determined the magnitude of interference, explaining why two platforms using the same assay chemistry produced different results.
Direct ISE measurements excluded true hypercalcemia and true hyponatremia, confirming the results were analytical artifacts.
Results
Recognition of biochemical-clinical discordance and targeted method comparison led to a diagnosis of Waldenström macroglobulinemia.
The investigation was prompted by unexplained discrepancies between platforms and between laboratory results and the patient's clinical presentation.
The analytical investigation prompted hematological evaluation.
The final diagnosis was Waldenström macroglobulinemia, a condition characterized by IgM paraprotein production.
The authors note that failure to recognize analytical interference may delay recognition of underlying disease.
Results
Platform-specific mixing dynamics, rather than assay chemistry alone, determined the magnitude of IgM paraprotein interference.
Both platforms used the Arsenazo III method yet produced results differing by 71.3% for total calcium.
Simulation experiments were used to demonstrate how platform-specific mixing dynamics contributed to differential interference.
Reaction-curve inspection was used as one investigative tool to identify anomalous reaction kinetics attributable to IgM interference.
This finding indicates that method comparisons across platforms with the same stated chemistry may still yield clinically significant discrepancies when paraproteins are present.
Discussion
Unexplained inter-platform analytical discrepancies may delay recognition of underlying hematological disease if not appropriately investigated.
The authors highlight that IgM paraproteins, particularly from conditions such as Waldenström macroglobulinemia, can cause misleading analytical interference in electrolyte and calcium measurements.
The case demonstrates that biochemical-clinical discordance should trigger targeted laboratory investigation including dilution studies, PEG precipitation, and direct ISE measurement.
The authors emphasize that monoclonal immunoglobulins, particularly IgM, are an important source of platform-dependent analytical interference.
What This Means
This research describes a case where a blood test for calcium and sodium produced wildly different results depending on which laboratory analyzer was used — even though both machines used the same testing chemistry. In an 85-year-old man, one analyzer suggested a life-threatening calcium crisis and severe low sodium, while the other showed only mildly abnormal results. More accurate direct measurement methods confirmed neither condition was actually present. The discrepancy was caused by an abnormal protein (IgM paraprotein) in the patient's blood that physically interfered with how each machine detected and measured calcium and sodium, with the specific internal mixing mechanics of each analyzer determining how severely the results were distorted.
This research suggests that when laboratory results don't match what is expected based on a patient's symptoms, the discrepancy itself can be an important clue. Investigating the source of conflicting test results — through techniques like dilution testing, special precipitation methods, and cross-platform comparison — can reveal that the abnormal readings are being caused by an underlying disease. In this case, following up on the analytical interference led to the diagnosis of Waldenström macroglobulinemia, a type of blood cancer that produces large amounts of IgM protein.
The broader implication is that the same laboratory test run on different machines can give dramatically different answers when unusual proteins are present in the blood, and that laboratory professionals and clinicians need to be aware of this possibility. Relying on a single analyzer's result without considering platform-specific interference could lead to inappropriate treatment or, as highlighted here, delay in diagnosing a serious underlying condition.
Wang S, Duan X, Zou Y, Gui J. (2026). Analytical interference by IgM paraprotein causing platform-dependent electrolyte discrepancies: a case-based laboratory investigation.. Biochemia medica. https://doi.org/10.11613/BM.2026.030901