oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
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/L*. However, in hypercalcaemia, just over half the circulating calcium is protein 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. It is only the ionised (unbound) calcium which is physiologically important, taking part in cellular activities such as neuromuscular contraction, coagulation and other cellular activities.
*The normal range is quoted for guidance only. Ranges may vary between laboratories or regions.
Correcting calcium levels
Add 0.1 mmol/L to calcium concentration for every 4 g/L that albumin is below 40 g/L 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/L because of the known inaccuracy of albumin measurement at low levels.
- Hypercalcaemia is an uncommon problem. Primary hyperparathyroidism is the most common cause. It affects mainly postmenopausal women. The incidence rate in the UK is 30 per 100,000.
- Hypercalcaemia is the most frequently encountered endocrine/electrolyte disorder in malignancy-associated hospitalised patients. Its incidence is 15 per 100,000 person-years. .
- The incidence in children is unknown but is thought to be even less common than in adults.
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.
Presentation of Hypercalcaemia
|At levels <2.8 mmol/L||At levels <3.5 mmol/L||At levels >3.5 mmol/L|
||All of the previous plus:
||All of the previous plus:
If the hypercalcaemia is long-standing, calcium may be deposited in soft tissues or may result in stone formation - eg, nephrocalcinosis, nephrolithiasis or chondrocalcinosis.
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.
Primary hyperparathyroidism is the most common cause of raised calcium levels, usually producing a mild hypercalcaemia.
- Malignancy - the most common cause of non-PTH-mediated hypercalcaemia.
- Granulomatous conditions - eg, sarcoidosis and tuberculosis.
- Endocrine conditions - eg, thyrotoxicosis, phaeochromocytoma and primary adrenal insufficiency.
- Drugs - eg, thiazide diuretics, vitamin D and vitamin A supplements.
- Familial - eg, familial hypocalciuric hypercalcaemia.
- Other - eg, prolonged immobilisation, calcium-alkali syndrome, AIDS.
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/L) and a longer duration of hypercalcaemia (more than six months).
- 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), calcium-alkali syndrome (formerly 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 Laboratory Values in Hypercalcaemia
|Condition||Serum Phosphate||Serum Alkaline Phosphatase||Urine Calcium||Urine Phosphate||PTH|
|Hyperparathyroidism||Low||Normal-high||High (in 67% of patients)||High||High|
|Vitamin D excess||Normal-high||Low||High||High||Low|
|Malignancy||Often low||High (except in haematological malignancy, when normal)||Variable||High||Variable|
|Calcium alkali syndrome||Normal-high||Normal||Normal||Normal||Low|
|Familial hypocalciuric hypercalcemia||Normal or low||Normal||Low (<200 mg/day)||Normal||High|
Interpreting PTH levels
- Raised PTH levels are suggestive of primary, secondary or tertiary hyperparathyroidism, or familial hypocalciuric hypercalcaemia.
- Low PTH levels are seen in granulomatous disease, iatrogenic causes (eg, renal dialysis), adrenal insufficiency, thyrotoxicosis,and vitamin D intoxication.
- The levels in malignancy may be low, normal or high.
- 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.
This can be considered under the headings of the immediate management of acute hypercalcaemia and the longer-term management of the underlying condition. National Institute for Health and Care Excellence Clinical Knowledge Summaries (NICE CKS) recommend that GPs should refer all patients with non-acute hypercalcaemia to the appropriate specialist, depending on the suspected cause (or to an endocrinologist if no cause can be found).
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.
- A loop diuretic such as furosemide. This is occasionally used where there is fluid overload but it does not reduce serum calcium .
- After rehydration, bisphosphonates (which act by reducing bone turnover) should be administered intravenously. Pamidronate and zolendronic acid are commonly used. Salmon calcitonin may also be given. It has fewer side-effects than bisphosphonates but is less effective in reducing hypercalcaemia.
- Glucocorticoids are useful for hypercalcaemia due to vitamin D toxicity, sarcoidosis and lymphoma.
- Gallium was identified as a useful drug when it was found that patients with malignancy having gallium scans did not develop hypercalcaemia. It may be given intravenously to patients with malignant hypercalcaemia who do not respond to bisphosphonates.
- Cinacalcet hydrochloride is a calcimimetic (= mimicking the action of calcium) agent that effectively reduces parathyroid levels in patients with secondary hyperparathyroidism.
- 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. Denosumab, a human monoclonal antibody that acts in this manner, is licensed for the prevention of osteoporotic fractures but is also useful for patients with persistent or relapsed hypercalcaemia of malignancy.
- Haemodialysis or peritoneal dialysis may be relevant in patients with severe hypercalcaemia secondary to renal failure.
Treatment depends on the underlying condition.
- Asymptomatic patients may be treated conservatively with regular monitoring of bone density, renal function and serum and urinary calcium levels.
- For symptomatic patients, dietary calcium should be reduced - eg, minimise the intake of dairy products and leafy vegetables. This approach has been questioned for asymptomatic patients, in whom 1000-1200 mg calcium daily has been recommended.
- Bed-bound patients should be mobilised if possible. Symptomatic patients will respond well to having the affected part of the parathyroid gland removed.
- There is no consensus on the operative treatment of asymptomatic patients. In general, it tends to be reserved for patients who have impaired renal function, hypercalciuria, low bone mineral density or severe hypercalcaemia.
Further reading & references
- Lunawat VK, Karale M; Hypercalcemia and PHPT presenting with mental health crisis - a case report. Psychiatr Danub. 2013 Dec;25(4):423-4.
- Dalemo S, Eggertsen R, Hjerpe P, et al; Long-term follow-up of patients with elevated serum calcium concentrations in Swedish primary care. Scand J Prim Health Care. 2013 Dec;31(4):248-54. doi: 10.3109/02813432.2013.861152.
- Lietman SA, Germain-Lee EL, Levine MA; Hypercalcemia in children and adolescents. Curr Opin Pediatr. 2010 Aug;22(4):508-15. doi: 10.1097/MOP.0b013e32833b7c23.
- Shane E et al; Hypercalcemia: Pathogenesis, Clinical Manifestations, Differential Diagnosis, and Management, American Bone and Mineral Research, 2006.
- Biochemical Calculations; Sydpath
- Fraser WD; Hyperparathyroidism. Lancet. 2009 Jul 11;374(9684):145-58.
- NHS Standard contract for specialised endocrinology services (Adult); NHS England, 2013/14
- Lumachi F, Brunello A, Roma A, et al; Medical treatment of malignancy-associated hypercalcemia. Curr Med Chem. 2008;15(4):415-21.
- Assadi F; Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2009 Apr;3(2):71-9.
- Carroll MF, Schade DS; A practical approach to hypercalcemia. Am Fam Physician. 2003 May 1;67(9):1959-66.
- Hypercalcaemia; NICE CKS, August 2010
- Patel AM, Adeseun GA, Goldfarb S; Calcium-alkali syndrome in the modern era. Nutrients. 2013 Nov 27;5(12):4880-93. doi: 10.3390/nu5124880.
- Cecchin D, Motta R, Zucchetta P, et al; Imaging studies in hypercalcemia. Curr Med Chem. 2011;18(23):3485-93.
- Acute hypercalcaemia; Society for Endocrinology, 2013
- Clines GA; Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):339-46. doi: 10.1097/MED.0b013e32834b4401.
- British National Formulary
- Leyland-Jones B; Treating cancer-related hypercalcemia with gallium nitrate. J Support Oncol. 2004 Nov-Dec;2(6):509-16.
- Miller RE, Branstetter D, Armstrong A, et al; Receptor activator of NF-kappa B ligand inhibition suppresses bone resorption and hypercalcemia but does not affect host immune responses to influenza infection. J Immunol. 2007 Jul 1;179(1):266-74.
- Hu MI, Glezerman I, Leboulleux S, et al; Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst. 2013 Sep 18;105(18):1417-20. doi: 10.1093/jnci/djt225. Epub 2013 Aug 29.
- Glendenning P; Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century, J Clin Endocrinol Metab 2002; 87: 5353-61.
- Langdahl BL, Ralston SH; Diagnosis and management of primary hyperparathyroidism in Europe. QJM. 2012 Jun;105(6):519-25. doi: 10.1093/qjmed/hcr225. Epub 2012 May 7.
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Laurence Knott
Dr Laurence Knott
Dr Adrian Bonsall