Hypercalcemia is a common problem encountered in the outpatient clinic and in hospitalized patients. Although the differential diagnosis is broad, making a correct diagnosis is generally straightforward. Identifying the mediator of hypercalcemia narrows the possible diagnoses and facilitates a diagnosis. Outpatients with asymptomatic hypercalcemia detected on routine testing are most likely to have primary hyperparathyroidism. Most patients hospitalized for symptomatic hypercalcemia have an underlying malignancy. For asymptomatic outpatients with hypercalcemia, evaluating in a stepwise manner, starting with PTH, is reasonable, only testing for other mediators when PTH is suppressed. The other mediators, PTHrP, 25(OH)D, 1,25(OH)2D, serum and urine protein immunoelectrophoresis, should be done when PTH is suppressed in outpatients and on admission in patients hospitalized for symptomatic hypercalcemia. Since PTH controls 1,25(OH)2D production, when PTH is suppressed and 1,25(OH)2D is "inappropriately normal," 1,25(OH)2D is the mediator of the hypercalcemia. The most recently discovered cause of hypercalcemia, loss-of-function mutations in CYP24A1, should be considered when 25(OH)D and/or 1,25(OH)2D are elevated in a patient with no evidence of malignancy or granulomatous disease. With a pathophysiological approach to diagnosis, the cause of hypercalcemia can be easily identified in most patients.
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