Calcium metabolism is regulated by parathyroid hormone (PTH) and vitamin D. Vitamin D increases intestinal absorption of calcium. PTH increases serum calcium by enhancing reabsorption by the renal tubule and mobilizing calcium stores from bone. It also stimulates conversion of vitamin D to its active metabolite. Low calcium levels cause a feedback increase in PTH secretion.

The most common causes of elevated serum calcium are primary hyperparathyroidism and malignancy-related bone resorption. It can also be seen in hypervitaminosis D that results from excess ingestion of vitamin D. Primary hyperparathyroidism refers to an elevated PTH due to increased endogenous production from the parathyroid glands. Some medications, including lithium, cause hypercalcemia by inducing primary hyperparathyroidism .

Lithium changes the receptor set point for calcium sensing in parathyroid cells leading to increased PTH secretion and hypercalcemia. Lithium also has some direct effects on bone metabolism. Elevated levels are seen in almost 80% people in the few weeks after lithium administration but most remain within the normal range and are not clinically significant. In about 10% patients, long-term treatment leads to elevation of serum calcium beyond the normal range [1]. This usually occurs after many years of lithium treatment. Lithium seems to cause hyperplastic parathyroid disease though in many cases, parathyroid adenomas have been found [2]. The latter may represent an unmasking of preexisting clinically insignificant parathyroid adenomas.

If lithium is stopped, serum calcium levels return to normal in most but not all cases. In these patients, surgery to remove the hyperplastic parathyroid tissue may be necessary.