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The remaining 10% of cases of nonparathyroid hypercalcemia are caused by many different conditions.

Causes related to vitamin D include the following:

– Vitamin D toxicity.

– Granulomatous disease (especially sarcoidosis) due to an inappropriate production of 1,25(OH)₂D₃ by the granulomas. Hypercalcemia occurs in approximately 10% of patients with active pulmonary sarcoidosis. These patients have high levels of serum 1,25(OH)₂D₃ and normal PTH. The hypercalcemia reverses with the eradication of granulomas (e.g., using glucocorticoid) and by intravenous hydration. In addition, the reduction of sun exposure, avoidance of excessive exogenous vitamin D intake, and control of dietary calcium intake are efficacious in the control of hypercalcemia and hypercalciuria [11].

Causes related to endocrine disorders include the following:

– Hyperthyroidism: hypercalcemia is reported in tirotoxicosis and acute thyroiditis, and the mechanism appears to be thyroid hormone-mediated increased osteoclastic bone resorption.

– Pheochromocytoma: hypercalcemia is due to catecholamine-induced volume concentration, epinephrine-induced PTH secretion, and, in some cases of malignant tumors, secretion of PTHrP.

– Adrenal insufficiency (Addison crisis): factors that induce hypercalcemia include volume depletion with hemoconcentration and a reduction in the glomerular filtration rate, GFR, which facilitates increased tubular resorption of calcium and increased skeletal release of calcium.

– Pancreatic islet cell tumors: hypercalcemia can occur as the results of severe different abnormalities. These tumors may be of multiple endocrine neoplasia type 1 (MEN1) syndrome and occur in association with PHPT. However, the occurrence of hypercalcemia is particularly high in patients with tumor-secreted vasoactive intestinal polypeptide (VIPomas) via an unknown mechanism.

Causes related to high bone turnover include the following:

– Hyperthyroidism (see above).

– Immobilization: suppresses osteoblastic activity and increases osteocalastic bone resorption, leading to complete uncoupling of these 2 normally coupled processes. The result is a massive loss of calcium from bone, hypercalcemia, and low bone mineral density (BMD). It is suggested that the process may be mediated by sclerostin that is high in serum of immobilized patients and inhibits bone formation [12]. The process is most effectively reversed by the restoration of normal weight bearing. Alternate options are bisphosphonates.

– Thiazide diuretic use: due to increased renal tubular reabsorption of calcium. The finding of more severe hypercalcemia is a sign of an underlying disorder of calcium metabolism (e.g., PHPT).

– Vitamin A intoxication: treatment with a high dose of vitamin A analogs (more than 50,000 IU/day) can result in hypercalcemia due to an increase of osteoclastic activity.

– Milk-alkali syndrome: due to the ingestion of large amounts of milk or calcium supplements and soluble alkali (antacid). Two types are described: (a) chronic milk-alkali syndrome (Burnett syndrome), associated with soft tissue calcification in the kidneys and nephrocalcinosis, in which progressive renal failure can occur, and (b) acute milk-alkali syndrome, involving hypercalcemia, hyperphosphoremia, mild azotemia, and metabolic alkalosis.

Causes related to drugs include the following:

– Thiazide diuretic use (see above).

– Vitamin A intoxication (see above).