Prevalence and Clinical Impact of Pseudohypercalcemia in Paraproteinemia: A Case and Cohort Study

<b>Background</b>: Hypercalcemia is a common and serious complication of malignancy, often contributing to morbidity and mortality. In patients with paraproteinemia, elevated total calcium with normal ionized calcium, termed pseudohypercalcemia, can complicate diagnosis and lead to inappropriate treatment. While this phenomenon has been described in case reports, its prevalence and clinical impact in routine practice remain poorly defined. <b>Methods</b>: We report a case of pseudohypercalcemia in a patient with IgG κ multiple myeloma and conducted a retrospective review of de-identified data to assess the prevalence and biochemical associations of pseudohypercalcemia in paraproteinemia. Available data included serum protein electrophoresis (SPEP), total calcium, albumin, total protein, creatinine, and parathyroid hormone (PTH). Associations between calcium status, paraprotein levels, and the gamma globulin gap were examined. <b>Results</b>: The index case demonstrated pseudohypercalcemia, with elevated total calcium (13.5 mg/dL) but normal ionized calcium (1.22 mmol/L), in the setting of IgG κ paraproteinemia (4.4 g/dL). In the retrospective cohort of 2537 samples, 986 (39%) had a single monoclonal paraprotein. Gamma globulin gap showed a moderate correlation with paraprotein concentration for IgG (r = 0.56, <i>p</i> < 0.0001) and IgA (r = 0.44, <i>p</i> < 0.0001), but a weaker relationship for IgM (r = 0.49, <i>p</i> < 0.0001). In contrast, total calcium showed no significant correlation with paraprotein concentration in the overall cohort. Among samples with elevated calcium (>10.5 mg/dL), the association between calcium and IgG paraprotein levels remained weak (r = 0.34, <i>p</i> = 0.23), and was similar for IgG κ (r = 0.61, <i>p</i> = 0.12) and IgG λ (r = 0.09, <i>p</i> = 0.87). Hypercalcemia was uncommon, occurring in only ~2% of IgG-positive samples, and rarely at paraprotein levels ≥ 1.5 g/dL. <b>Conclusions</b>: Pseudohypercalcemia in paraproteinemia is uncommon but clinically important, as total calcium may be artifactually elevated due to paraprotein-related assay interference, either from assay precipitation effects or calcium binding by paraproteins. Paraprotein burden correlates with gamma globulin gap but not with true calcium status. Reliance on total calcium alone may lead to diagnostic misclassification; ionized calcium should be measured in patients with monoclonal gammopathies to distinguish true hypercalcemia from analytical interference and avoid unnecessary treatment.