Aetiology

Hypercalcaemia is caused by either primary hyperparathyroidism or cancer in over 90% of instances.[2][10] The remaining aetiologies are numerous and rare.[11] Primary hyperparathyroidism is a pathologic and unregulated excess of parathyroid hormone (PTH) leading to elevated calcium. Malignancy is the most common cause of hypercalcaemia that leads to inpatient care. Other less frequent aetiologies are bone diseases, granulomatous conditions, and diet.[2] In the case of malignancy or granulomatous disease, determining the aetiology may be more important than the electrolyte imbalance itself.

Primary hyperparathyroidism

The most common cause of hypercalcaemia is primary hyperparathyroidism, which has an estimated prevalence in the general population of 0.86% and is more common in women.[12] About 85% of cases are due to a single adenoma of one of the parathyroid glands while most of the other 15% is four-gland disease. Less than 1% of cases are caused by parathyroid cancer.[13] Primary hyperparathyroidism ranges in severity from very mild and asymptomatic, to severe disease complicated by the consequences of bone loss, including fractures and osteitis fibrosa cystica (von Recklinghausen disease).

Malignancy

Hypercalcaemia may be associated with malignancies through two mechanisms:[14][15]

  • Bony involvement by the tumour: may lead to massive osteoclastic activity (osteolytic lesions) when the calcium flux overwhelms homeostatic mechanisms

  • PTH-related protein (that acts on PTH receptors): secreted by a variety of tumours.

Between 25% and 30% of patients with cancer will develop hypercalcaemia at some point over the course of their disease.[15] Common malignancies that can lead to hypercalcaemia include multiple myeloma, leukaemia, lung cancer, and breast cancer. When malignancies cause hypercalcaemia, the tumour is typically very advanced.

Malignancies that produce hypercalcaemia may be associated with multiple endocrine neoplasia (MEN) type 1 (Wermer) and MEN type 2a (Sipple) or isolated familial hyperparathyroidism.[13] There is an association of primary hyperparathyroidism with neurofibromatosis and von Hippel-Lindau disease.

Less common aetiologies

Metabolic

  • Vitamin D is a fat-soluble vitamin that can become toxic when excessive amounts are taken in over time. Self-dosing is the usual cause. Overdosing with 1-alpha-hydroxylated vitamin D metabolites (alfacalcidol or calcitriol) can result in hypercalcaemia; chronic administration must be avoided or carefully monitored.

  • Hyperthyroidism can lead to hypercalcaemia and almost always hypercalciuria as a consequence of rapid bone turnover.

  • Calcium can be abnormally absorbed in milk-alkali syndrome with a massive intake of calcium. Milk-alkali syndrome is caused by excess dietary milk or alkali (e.g., because of dyspepsia) or excess calcium supplementation (e.g., in postmenopausal women).[16]

  • Excess calcium intake or exaggerated supplementation with over-the-counter products can readily and frequently lead to hypercalcaemia.

  • Vitamin D is elevated in granulomatous disease such as sarcoidosis. The mechanism is enhanced conversion of vitamin D by macrophages.

  • Immobilisation in adolescents and young people causes massive bone demineralisation and hypercalcaemia. The robust state of bone mineralisation in young people means there is a larger mobile calcium pool to create and sustain the hypercalcaemia than in older patients. Excess bone metabolism of any aetiology can lead to hypercalcaemia.

  • Paget's disease.

  • Excess bone turnover with hypercalcaemia and suppressed PTH can also be associated with excess vitamin A intake.

Iatrogenic

  • Lithium affects renal calcium reabsorption and stimulates PTH secretion.[2] Hypercalcaemia reverses when lithium is stopped.

  • Thiazide diuretics increase calcium reabsorption in the distal convoluted tubule of the kidney.[17] Hypercalcaemia reverses when thiazide diuretic is stopped.

Congenital

  • Familial hypocalciuric hypercalcaemia can be confused with hypercalcaemia due to hyperparathyroidism, as abnormal calcium sensing in the parathyroid glands and kidneys leads to mild elevation of PTH and reduced calcium excretion.

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