EVIDENCE-BASED ANSWER
First, establish that true hypercalcemia exists by repeating the serum calcium and measuring or calculating the physiologically active serum calcium when abnormalities in blood pH or albumin are found (SOR: C, expert opinion). Patients with unexplained asymptomatic true hypercalcemia should be screened for primary hyperparathyroidism (PHPT) and malignancy using an intact parathyroid hormone (PTH) level by immunoradioassay (SOR: C, expert opinion). Other recommended tests that can distinguish PHPT from malignancy and familial hypocalciuric hypercalcemia, as well as help manage patients with PHPT include urinary 24-hour calcium and creatinine levels, parathyroid hormone related peptide (PTHrP), alkaline phosphatase, calcitriol, and bone densitometry (SOR: C, expert opinion).
Clinical commentary
Choose tests carefully to reduce false positives
Jon O. Neher, MD
Valley Family Medicine, Renton, Wash
Including serum calcium measurements in the chemistry panels that physicians use to manage common conditions such as hypertension has resulted in an epidemic of incidental hypercalcemia. Tempting as it may be to ignore these unexpected numbers, they point to a significant underlying condition in some patients. This puts the family physician in a familiar clinical position—having to worry a patient just enough to convince him to consent to a careful, stepwise evaluation while somehow reassuring him that usually no problem is found. The best solution is to order each test for a reason, which would reduce the number of false positives that we spend so much time chasing.
Evidence summary
Make sure it’s true hypercalcemia
Measuring calcium levels in asymptomatic patients often leads to false-positive elevations caused by random error or changes in the level of physiologically active calcium because of alterations in blood pH or serum albumin. Serum calcium levels between 10.0 and 12.0 mg/dL indicate mild hypercalcemia; levels >14.0 mg/dL are severe. Because changes in pH and serum albumin levels alter levels of physiologically active calcium, authoritative sources recommend measuring or calculating physiologically active calcium if blood pH or albumin is abnormal.1,2 To determine the level, use the equation [4.0 – (plasma albumin)] × 0.8 + (serum calcium) or measure serum ionized calcium.2 Normal levels of serum ionized calcium for adults older than 19 years are 1.13 to 1.32 mmol/L, although the exact range can vary from laboratory to laboratory. Elevated physiologically active calcium indicates true hypercalcemia.
Assess for the most common causes, PHPT and malignancy
Evaluation of the patient with true hypercalcemia should include a detailed history, physical examination, and assessment of risk factors for all causes of hypercalcemia.1,2 PHPT and malignancy are the two most common causes of asymptomatic true hypercalcemia (TABLE).2
Laboratory evaluation targeting these causes, beginning with an intact PTH level, is a logical first step.1,2 Persistent hypercalcemia in the presence of elevated or inappropriately normal PTH concentrations confirms the diagnosis of PHPT.3 When serum calcium rises, PTH is normally suppressed. Normal intact PTH and low 24-hour urinary calcium excretion distinguishes patients with PHPT from those with less common familial hypocalciuric hypercalcemia.1,2