The serum level of PTH distinguishes primary hyperparathyroidism from other disorders causing hypercalcemia, because it is the only hypercalcemic disorder resulting from excessive production of PTH. Serum phosphate levels are inversely proportional to PTH levels because PTH promotes the urinary excretion of phosphate. Although hypophosphatemia suggests hyperparathyroidism, it may also be present in patients with cancer, because certain tumors secrete phosphaturic factors. In addition, anorexia alone will lower serum phosphorus, thereby confounding its use as a diagnostic tool for parathyroid disease. High levels of 25-hydroxyvitamin D, or 25(OH)D (also known as calcidiol) suggest an excessive intake of vitamin D. A very high concentration of this usually inactive compound can result in hypercalcemia. A high concentration of 1,25-dihy-droxyvitamin D, or 1,25(OH)₂D (also known as calcitriol) occurs only in hyperparathyroidism, granulomatous diseases, and, rarely, malignant disease.

Primary hyperparathyroidism is the most common cause of hypercalcemia; often, the hypercalcemia is the only clinical manifestation (see Plates 3-2 and 3-3). In patients with mild-to-moderate hyperparathyroidism, radiographs usually do not reveal bone disease and the serum phosphate level is often normal. Also, serum 1,25(OH)₂D levels are elevated in less than 50% of patients. Therefore, the most specific and reliable tool in the diagnosis of hyperparathyroidism is the measurement of serum PTH level.

Malignancies cause hypercalcemia by increasing bone resorption either locally through skeletal metastases (e.g., breast cancer and multiple myeloma) or by secreting hormonal factors that stimulate resorption (e.g., lung and renal cell cancer). Hypercalcemia is usually a late manifestation of hypercalcemia due to a nonparathyroid mechanism and usually occurs only after the tumor is apparent. The presence of such a tumor is therefore an important clue to the etiology of hypercalcemia. Hypercalcemia is rarely the first manifestation of occult cancer but is more typically seen in patients with widespread end-stage disease.

Sarcoidosis and, rarely, other granulomatous diseases such as tuberculosis and histoplasmosis also lead to hypercalcemia, because of an increase in the synthesis of 1,25(OH)₂D. Hyperparathyroidism is the other disease in which the level of 1,25(OH)₂D is elevated, but the PTH level is also elevated. In sarcoidosis, by contrast, the PTH level is normal or reduced and the level of the angiotensin-converting enzyme (ACE) activity is often elevated. Although this finding is not specific to sarcoidosis, the absence of high ACE activity levels makes the diagnosis very unlikely. Certain malignancies such as lymphomas cause hypercalcemia also by increasing the synthesis of 1,25(OH)₂D. Fortunately these are rare events.

Hyperthyroidism, or thyrotoxicosis, rarely causes mild hypercalcemia. The diagnosis is based on clinical and laboratory evidence of hyperthyroidism and restoration of a normal serum calcium level with antithyroid therapy.

The milk-alkali syndrome is typically caused by excessive intake of both milk and absorbable alkalis such as sodium bicarbonate and calcium carbonate. Because absorbable alkalis are not often used as antacids, this syndrome is rare; however, ingestion of large amounts of calcium (usually more than 4 g/day) can produce the syndrome. The diagnosis is made by a careful history and by observing the patient’s response to withdrawal of calcium.

Immobilization due to fractures or paralysis increases calcium release from bone resulting in hypercalcemia and hypercalciuria is common. Hypercalcemia, although uncommon, may develop when the rate of bone turnover is high, as in childhood or adolescence, and in extensive Paget disease.