Hypercalcaemia

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 is 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 guide only. Ranges may vary between laboratories or regions.

Correcting Calcium Levels

Add 0.1mmol/litre to calcium concentration for every 4g/litre that albumin is below 40g/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

• 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
• Hypercalcemia 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.
• The incidence in children is unknown but is thought to be even less common than in adults.³

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.

Causes of hypercalcaemia may be grouped into those secondary to raised parathyroid hormone (PTH) levels, and those mediated by other factors.

PTH mediated hypercalcaemia

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

Non-PTH mediated hypercalcaemia

• Malignancy - the most common cause of 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 D 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

Corrected calcium level - this will by definition be high.
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 levels³

• Raised PTH levels are suggestive of primary or secondary hyperparathyroidism, or familial hypocalciuric hypercalcemia.
• 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-imaging³

• Plain X-rays may show features indicative of bone abnormalities such as demineralisation, bone cysts, pathological fractures or bony metastases.
• Ultrasound scan, CT scan or 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.

Acute hypercalcaemia³

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

• Increasing the circulating volume with 0.9% saline helps to increase the urinary output of calcium.
• Addition of a loop diuretic e.g. furosemide enhances this effect by inhibiting the tubular reabsorption of calcium.
• In severe cases, agents to reduce bone turnover such as biphosphonates (e.g.pamidronate and zoledronic acid) or salmon calcitonin.⁵
• Plicamycin is occasionally used. It acts by inhibiting 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.⁶
• Gallium nitrate is sometimes indicated in patients with malignancy.⁷
• Haemodialysis or peritoneal dialysis may be relevant in patients with severe hypercalcaemia secondary to renal failure.

Non-PTH mediated hypercalcaemia

Treatment depends on the underlying condition.

PTH-mediated hypercalcaemia

• Asymptomatic patients may be treated conservatively with regular monitoring of bone density, renal function and serum and urinary calcium levels.⁴
• Dietary calcium should be reduced - e.g minimise the intake of dairy products, 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:⁴
  • A serum calcium raised 0.25mmol/litre above normal.
  • A urine calcium >400mg /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.