ACP American College of Physicians - Internal Medicine - Doctors for Adults

A 45-year-old man is evaluated for a 3-month history of fatigue, constipation, and polyuria. He also has a 5-year history of hypertension. Current medications are losartan and diltiazem.

Physical examination findings, including vital signs, are normal.

This patient's parathyroid hormone (PTH) level should be determined next. Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. The first step in the diagnosis of hypercalcemia is determination of the PTH level with an assay for intact PTH. If the PTH level is high or “inappropriately” normal, primary hyperparathyroidism is the diagnosis. If the PTH level is suppressed, a search for other entities that cause hypercalcemia must be conducted.

Calcitonin is secreted by thyroid parafollicular C cells. This serum level is elevated in patients with medullary thyroid cancer or C-cell hyperplasia. Calcitonin tends to lower the calcium level by enhancing cellular uptake, renal excretion, and bone formation. The effect of calcitonin on bone metabolism is weak and only relevant in pharmacologic amounts. Measurement of serum calcitonin is not indicated in a patient with hypercalcemia.

One of the ways in which PTH increases the serum calcium level is by up-regulation of the 1a-hydroxylase enzyme, which stimulates conversion of vitamin D to its most active form, 1,25-dihydroxy vitamin D. This form of vitamin D increases the percentage of dietary calcium absorbed by the intestine. Body stores of vitamin D are assessed by measuring the 25-hydroxy vitamin D level, which has a long half-life. Measurement of this patient's 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D levels may be appropriate if the parathyroid hormone level is suppressed. At this time, however, such measurement is not indicated.

Humoral hypercalcemia of malignancy results from the systemic effect of a circulating factor produced by neoplastic cells. The hormone most commonly responsible for this syndrome is parathyroid hormone–related protein (PTHrP). This peptide's N-terminal shares many homologic features with PTH and most, if not all, of the metabolic effects of PTH. Tumors that elaborate PTHrP are most commonly squamous cell carcinomas, such as those of the lung, esophagus, and head and neck. This patient has no evidence of cancer. The diagnosis of humoral hypercalcemia of malignancy can often be made in the absence of PTHrP measurements if a compatible malignancy, hypercalcemia, and suppressed PTH level are present.

Key Point

• The most common cause of hypercalcemia in the outpatient setting is hyperparathyroidism.