29th December 2024

Malignant hypercalcaemia

Overview of malignant hypercalcaemia

Malignant hypercalcaemia occurs in approximately 1 in 5 cancer patients and of all inpatients admitted with hypercalcaemia, cancer represents the most common cause.

Hypercalcaemia can be life threatening, resulting in progressive hypovolaemia, renal impairment, cognitive impairment and arrhythmia. It is, therefore, essential to detect and treat hypercalcaemia early, especially if free/adjusted Ca ≥ 3.0 mmol/L.

Note – a proportion of serum calcium is bound to albumin, and low serum albumin levels may result in a falsely low total calcium reading. Adjusted calcium (based on albumin) must be calculated to estimate free calcium levels.

Causes of malignant hypercalcaemia

Parathyroid hormone-related protein (PTHrP)

PTHrP production by cancer cells accounts for 80% of malignant hypercalcaemia. This is most commonly associated with squamous cell cancers (e.g. squamous cell lung cancer), renal, bladder, breast and ovarian cancers. The PTHrP stimulates osteoblasts to produce RANK-ligand, which then activates osteoclasts to resorb bone, resulting in hypercalcaemia. Of note, this ectopic production means that malignant hypercalcaemia may be present even in the absence of bony metastases.

Osteolytic bone metastases

Osteolytic bone metastases, commonly found in myeloma and breast cancer, account for 20% of malignant hypercalcaemia.

Other – calcitriol and PTH

Other causes of malignant hypercalcaemia make up less than 1% of cancer-related calcium release.

Ectopic 1,25-dihydroxyvitamin D (calcitriol) can be produced in ovarian and germ cell tumours that release 1-alpha hydroxylase or in lymphoma cells. Excess calcitriol release in either case will stimulate bone resorption.

PTH (parathyroid hormone) itself may be produced by tumours, in the case of parathyroid carcinoma, or through ectopic release by small cell lung cancers, lung adenocarcinomas and renal cell cancer.

Signs and symptoms of hypercalcaemia

Hypercalcaemia may present acutely, subacutely or may be asymptomatic and an incidental finding. High calcium levels can impact many organ systems and, if left untreated, can be fatal.

Investigations in malignant hypercalcaemia

A number of investigations should be carried out when investigating malignant hypercalcaemia:

• Routine blood tests for serum calcium, albumin, adjusted calcium, renal function
• Bone profile including PO4, PTH, 25-hydroxyvitamin D, calcitriol
  • If PTH is normal or low in case of known malignancy, PTHrP. In PTHrP-producing tumours, PTHrP will be high, PTH suppressed, and PO4 low due to hyperphosphaturia
  • In calcitriol-mediated hypercalcaemia, calcitriol will be elevated
  • In cases of ectopic PTH production, PTH will be high
• ECG – may show shortened QT interval, J waves, or other abnormalities
• Bone scan or skeletal survey in patients with known or suspected osteolytic metastases, e.g. myeloma, known bone metastases, leukaemia
• Chest X-ray to look for lung cancer or other causes of hypercalcaemia including sarcoidosis or TB

Management of malignant hypercalcaemia

Emergency management is required if calcium ≥3.0 mmol/L (Table 2).

If appropriate, the underlying malignancy should be treated. In many cases, hypercalcaemia is related to already advanced cancer. In haematological malignancies including myeloma, steroids may be of benefit.

Bisphosphonates are used if calcium remains high despite adequate IV rehydration. An important side effect of bisphosphonates is rebound hypocalcaemia, and it is therefore important to monitor calcium levels after administration and monitor for any clinical features of hypocalcaemia. Signs and symptoms include paraesthesia, muscle spasms or cramps, tetany and seizures. Eponymous signs include Trousseau’s sign – when inflating a blood pressure cuff to greater than systolic blood pressure, there is an involuntary carpopedal spasm of the ipsilateral wrist and hand and the Chvostek sign – when tapping in front of the ear overlying the course of the facial nerve, ipsilateral facial muscles will twitch.

References

• Cassidy J, Bissett D, Spence RAJ, Payne M, Morris-Stiff GJ. Oxford Handbook of Oncology. 4th ed. Oxford: Oxford University Press; 2015
• Shieh A, Martinez D. Hypercalcaemia of malignancy [Internet]. BMJ Best Practice. 2021 [cited 2022 Apr 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/1204
• Mirrakhimov AE. Hypercalcemia of malignancy: An update on pathogenesis and management. North American Journal of Medical Sciences. 2015;7(11):483
• Shane E, Berenson JR. Treatment of hypercalcemia [Internet]. Rosen CJ, Mulder, MD JE, editors. UpToDate. 2022 [cited 2022 Apr 17]. Available from: https://www.uptodate.com/contents/treatment-of-hypercalcemia