Calcium has a vital role to play in the effective working of the majority of cells in the body and it is therefore important that the optimal level be maintained by the body. The normal range for serum calcium is 2.25-2.5 mmol/litre^*. However, in hypercalcaemia, just over half the circulating calcium is protein bound (as opposed to hypocalcaemia in which 40% is bound) and therefore the level of circulating protein, principally albumin, must also be taken into consideration in making this measurement. The level for serum calcium is frequently given by laboratories as both an uncorrected level and a corrected level which has allowed for changes in albumin levels.

*The normal range is quoted for guidance only. Ranges may vary between laboratories or regions.

Correcting calcium levels

Add 0.1 mmol/litre to calcium concentration for every 4 g/litre that albumin is below 40 g/litre and a similar subtraction for raised albumin.

The "correction" is only approximate and does not replace measurement of ionised calcium concentration. Take special care where the measured albumin is less than about 20 g/litre because of the known inaccuracy of albumin measurement at low levels.¹

Epidemiology

• Hypercalcaemia is an uncommon problem. Primary hyperparathyroidism is the commonest cause, affecting approximately 4 per 100,000 population per annum and has a peak age of incidence of 50-60. It affects females more than males with a ratio of 3:1.²
• Hypercalcaemia is the most frequently encountered endocrine/electrolyte disorder in primary malignancy and one US study found an incidence of 5% of all malignancies, or in 15 per 100,000 total patients.³
• The incidence in children is unknown but is thought to be even less common than in adults.⁴

Presentation

As effective calcium regulation is required for the healthy working of most cells in the body, a rise in the level can produce a diverse collection of symptoms.

If the hypercalcaemia is long-standing, calcium may be deposited in soft tissues or may result in stone formation, e.g. nephrocalcinosis, nephrolithiasis or chondrocalcinosis.

Causes

Causes of hypercalcaemia may be grouped into those secondary to raised parathyroid hormone (PTH) levels and those mediated by other factors. Primary hyperparathyroidism and malignancy are responsible for greater than 90% of all cases.⁵

Parathyroid hormone-mediated hypercalcaemia

Primary hyperparathyroidism is the most common cause of raised calcium levels, usually producing a mild hypercalcaemia.

Non-parathyroid hormone-mediated hypercalcaemia

• Malignancy - the most common cause of non-parathyroid hormone-mediated (non-PTH-mediated) hypercalcaemia
• Granulomatous conditions, e.g. sarcoidosis and tuberculosis
• Endocrine conditions, e.g. thyrotoxicosis, phaeochromocytoma and primary adrenal insufficiency
• Drugs, e.g. thiazide diuretics, vitamin D⁶ and vitamin A supplements
• Familial, e.g. familial hypocalciuric hypercalcaemia
• Tertiary hyperparathyroidism - post-kidney transplant or chronic dialysis
• Other, e.g. prolonged immobilisation, milk-alkali syndrome, AIDS

Investigations^4,7

Corrected calcium level - this will by definition be raised. Compared with the hypercalcaemia of malignancy, hyperparathyroidism tends to be associated with lower serum calcium levels (<3 mmol/litre) and a longer duration of hypercalcaemia (more than 6 months).⁵

In the presence of a raised corrected calcium:

• A raised albumin level in the presence of a raised urea indicates dehydration.
• A raised albumin level in the presence of a normal urea suggests a cuffed specimen.
• A normal alkaline phosphatase is indicative of myeloma (raised plasma protein), milk-alkali syndrome, thyrotoxicosis or sarcoidosis.
• A raised alkaline phosphatase suggests bony metastases, sarcoidosis or thyrotoxicosis.
• A raised calcitonin level is suggestive of B-cell lymphoma.

The following table may be helpful in interpreting laboratory results:

Interpreting parathyroid hormone levels⁴

• Raised PTH levels are suggestive of primary or secondary hyperparathyroidism, or familial hypocalciuric hypercalcaemia.
• Low PTH levels are seen in granulomatous disease, iatrogenic causes (e.g. renal dialysis), adrenal insufficiency, thyrotoxicosis,and vitamin D intoxication.
• The levels in malignancy may be low, normal or high.

Radio-imaging⁴

• Plain X-rays may show features indicative of bone abnormalities, such as demineralisation, bone cysts, pathological fractures or bony metastases.
• Ultrasound scan, computerised tomography (CT) scan or intravenous pyelogram (IVP) may be required to detect abnormalities of the urogenital tract, such as calcification or stones.
• Ultrasound or technetium scan of the parathyroid glands may be indicated if hypertrophy or adenoma is suspected.

Management

This can be considered under the headings of the immediate management of acute hypercalcaemia and the longer-term management of the underlying condition.

Acute hypercalcaemia⁴

Treatment should be initiated in hospital on the advice of a specialist and should include:

• Increasing the circulating volume with 0.9% saline, helping to increase the urinary output of calcium.
• Addition of a loop diuretic, e.g. furosemide is thought to enhance this effect by inhibiting the tubular reabsorption of calcium. However, this is controversial. One review of the evidence recommended that furosemide should be superseded by biphosphonates in all hypercalcaemic patients.³ Another study recommended that intravenous crystalloid fluids, with or without loop diuretics, or other therapies (e.g.calcitonin, gallium nitrate or corticosteroids) should be used as second-line, should biphosphonates fail.⁸
• Agents which reduce bone turnover, e.g. biphosphonates such as .pamidronate and zoledronic acid or salmon calcitonin, should certainly be used as first-line in severe cases.^9,10
• Plicamycin is occasionally used. It acts by inhibiting ribonucleic acid (RNA) synthesis and killing osteoclasts.
• Cinacalcet hydrochloride is particularly useful for patients with chronic renal disease and secondary hyperparathyroidism. It acts by altering the configuration of the calcium-sensing receptor in cell membranes .
• Prednisolone may be appropriate in hypercalcaemia secondary to granulomatous disease and tuberculosis.¹¹
• Gallium nitrate is sometimes indicated in patients with malignancy.¹²
• A new experimental approach to malignancy-associated hypercalcaemia involves the blockade of receptor activator of nuclear factor kappa-B ligand, usually abbreviated as RANKL. RANKL is a key element in the differentiation, function and survival of osteoclasts, which plays an essential role in removing calcium ions from the bone in response to PTH stimulation.
• Haemodialysis or peritoneal dialysis may be relevant in patients with severe hypercalcaemia secondary to renal failure.

Non-parathyroid hormone-mediated hypercalcaemia

Treatment depends on the underlying condition.

Parathyroid hormone-mediated hypercalcaemia

• Asymptomatic patients may be treated conservatively with regular monitoring of bone density, renal function and serum and urinary calcium levels.⁷
• Dietary calcium should be reduced, e.g minimise the intake of dairy products and leafy vegetables.
• Bed-bound patients should be mobilised if possible. Symptomatic patients will respond well to having the affected part of the parathyroid gland removed.
• Surgery should also be considered in asymptomatic patients who have:⁷
  • A serum calcium raised 0.25 mmol/litre above normal.
  • A urine calcium >400 mg/day.
  • A bone density reduced at any site to a T score <-2.5.
  • A creatinine clearance reduced by 30% in patients age >50 years.

Document references

1. Biochemical Calculations; Sydpath 2008.
2. Kim L, Makdissi A; Hyperparathyroidism. eMedicine. Updated: Sep 24, 2009.
3. Lumachi F, Brunello A, Roma A, et al; Medical treatment of malignancy-associated hypercalcemia. Curr Med Chem. 2008;15(4):415-21. [abstract]
4. Claudius I Fattal O; Hypercalcaemia eMedicine.com 2006
5. Assadi F; Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2009 Apr;3(2):71-9. [abstract]
6. Joshi R; Hypercalcemia due to Hypervitaminosis D: Report of Seven Patients. J Trop Pediatr. 2009 Apr 1. [abstract]
7. NIH Consensus Development Program Consensus Development Conference Reports 1990; Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism
8. McMahan J, Linneman T; A Case of Resistant Hypercalcemia of Malignancy with a Proposed Treatment Algorithm (September). Ann Pharmacother. 2009 Jul 21. [abstract]
9. Body JJ; Current and future directions in medical therapy: hypercalcemia. Cancer. 2000 Jun 15;88(12 Suppl):3054-8.; Cancer. 2000 Jun 15;88(12 Suppl):3054-8. [abstract]
10. Auron A, Tal L, Srivastava T, et al; Reversal of hypercalcemic acute kidney injury by treatment with intravenous bisphosphonates. Pediatr Nephrol. 2009 Mar;24(3):613-7. Epub 2008 Oct 7. [abstract]
11. Sato T, Tsuru T, Hagiwara K, et al; Sarcoidosis with acute recurrent polyarthritis and hypercalcemia. Intern Med. 2006;45(6):363-8. Epub 2006 Apr 17.; Intern Med. 2006;45(6):363-8. Epub 2006 Apr 17. [abstract]
12. Pecherstorfer M, Brenner K, Zojer N; Current management strategies for hypercalcemia. Treat Endocrinol. 2003;2(4):273-92. [abstract]

Internet and further reading

• Joshi D, Center JR, Eisman JA; Investigation of incidental hypercalcaemia. BMJ. 2009 Nov 20;339:b4613. doi: 10.1136/bmj.b4613.
• Clines GA, Guise TA.; Endocr Relat Cancer. 2005 Sep;12(3):549-83. Review.

Acknowledgements