Normal Levels of Ionized Calcium Despite Persistent Increase in Total Calcium in a Patient With IgA Paraproteinemia

Approximately half of the calcium in the blood circulates in the ionized, free form; which is critical for cellular function. As a result, its levels are tightly regulated by homeostatic mechanisms dependent on hormones such as PTH, vitamin D, and fibroblast growth factor-23. The other half of the total calcium is in a complex with anions, predominantly albumin. Clinically, the levels of albumin are known to influence the relationship of total calcium to free calcium. However, the relevance of changes in other serum proteins on calcium homeostasis is less appreciated. We present the case of a 70-year-old woman who was followed over 5 years with persistently elevated total calcium levels but with normal ionized calcium levels. Her evaluation was notable for IgA paraprotein, which paralleled her history of elevated total serum calcium. Extensive clinical investigations did not reveal hyperparathyroidism or cancer-mediated hypercalcemia. Additional in vitro analyses comparing the plasma containing the IgA paraprotein against a healthy control revealed that a high-molecular-weight IgA paraprotein in the patient has increased capacity to reduce the amount of free calcium in solution, thus providing a direct mechanistic explanation for the clinical findings.