Board Review

A 59-year-old man is evaluated for hypercalcemia. He was recently diagnosed with multiple myeloma. He does not have anorexia, nausea, constipation, polydipsia, polyuria, or confusion. Medical history is otherwise unremarkable, and he takes no medications.

On physical examination, temperature is 36.4 °C (97.5 °F), blood pressure is 134/80 mm Hg, pulse rate is 80/min, and respiration rate is 12/min. BMI is 30. The remainder of his physical examination is normal, and no weakness is noted on neurologic examination.

Serum calcium level is 10.8 mg/dL (2.7 mmol/L).

Which of the following is the most appropriate next laboratory test for evaluating this patient's hypercalcemia?

A) 1,25-Dihydroxyvitamin D level

B) Ionized calcium level

C) Parathyroid hormone level

D) Parathyroid hormone–related protein level

Answer: B - Ionized calcium level

Objective: Diagnose pseudohypercalcemia.

Key Point

In patients with conditions in which increased protein binding of calcium may occur, such as hyperalbuminemia or paraproteinemia, an artificially elevated total serum calcium level must be excluded.

This patient's ionized calcium level should be checked. His total calcium level is elevated, but he is without clear symptoms associated with hypercalcemia. Approximately 40% to 45% of the calcium in serum is bound to protein, principally albumin, although the physiologically active form of calcium is in an ionized (or free) state. In most patients with relatively normal serum albumin levels, the total calcium usually accurately reflects the ionized calcium fraction. However, in clinical settings where increased protein binding of calcium may occur, the serum total calcium level may be elevated without a rise in the actual serum ionized calcium concentration. This may occur in patients with hyperalbuminuria (as may occur in those who are severely dehydrated), and in patients with a paraprotein capable of binding calcium (such as occasionally occurs in some patients with multiple myeloma). This phenomenon is sometimes termed pseudohypercalcemia (or factitious hypercalcemia). If present, a normal ionized calcium level may indicate that the elevated total calcium levels are due to excessive protein binding and potentially eliminate the need for further evaluation for hypercalcemia.

Measuring the 1,25-dihydroxyvitamin D level is useful in further assessing patients with non–parathyroid hormone (PTH)-mediated hypercalcemia to assess for excess vitamin D production. PTH testing is indicated in patients with hypercalcemia to differentiate between PTH-mediated and non–PTH-mediated hypercalcemia.

The hypercalcemia associated with multiple myeloma is caused primarily by tumor-induced, osteoclast-mediated bone resorption due to cytokines released by myeloma cells and is not PTH-mediated or due to excessive vitamin D levels. Measurement of PTH level and 1,25-dihydroxyvitamin levels may be indicated as part of this patient's evaluation only after true hypercalcemia has been established.

Parathyroid hormone–related protein (PTHrP) level measurement is useful in evaluating patients with non–PTH-mediated hypercalcemia but would not be indicated as a next study in this patient in whom pseudohypercalcemia has not been excluded.

Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):339-46. Link Out