Calcium is stored in the body almost exclusively in the bone. Only about 1% is available in the extra-cellular fluid. Most laboratories measure total serum calcium although the biologically active fraction is the ionised calcium. This accounts for about half the calcium measured.

The main binding protein for calcium within the serum is albumin. Calcium levels can appear low or high if the serum albumin is low or high. Formulae have been used to adjust for this. One formula commonly used is to add 0.02 mmol/L of calcium to the total calcium for every 1g/L that the serum albumin is below 40 and to subtract in the same way for every 1g/L that the albumin is above 40. The result obtained gives an approximate estimate as to whether there is likely to be a normal amount of ionised calcium in the circulation. Ionised calcium is also affected by blood pH. Calcium disassociates from albumin in states of acidosis and binds in states of alkalosis. A mild tetany can be induced by hyperventilation.

Several hormones are involved in the regulation of calcium turnover of which the two most important are parathyroid hormone and 1, 25-dihydroxycholecalciferol.

Parathyroid Hormone

Parathyroid hormone is an 84 amino-acid polypetide secreted from the four parathyroid glands in response to the circulating calcium level mediated by a calcium receptor. The ultimate effect of parathyroid hormone within the bone is to stimulate osteoclast activity, bone breakdown and to release calcium into the circulation. In the kidneys it is a phosphaturic hormone and promotes calcium excretion. It stimulates the hydroxylation of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the kidneys.

Vitamin D

Vitamin D is a sterol which is synthesised in the skin as vitamin D3 (cholecalciferol). Vitamin D2 is used to fortify dairy products and is derived from a plant sterol. Vitamion D3 undergoes 25-hydroxylation to 25-hydroxycholecalicerol in the liver. It is converted in the kidneys to 1,25-dihydroxycholecalciferol, the active form, which promotes intestinal calcium absorption.

Hypercalcaemia

The two common causes of hypercalcaemia are primary hyperparathyroidism and malignancy. The relative frequency of each depends on the population surveyed. In community studies hyperparathyroidism is easily the most common cause. In hospital studies malignancy is more common.

Other causes of hypercalcaemia include thiazide diuretics, sarcoidosis, vitamin D intoxication, renal failure, milk alkali syndrome and familial hypocalciuric-hypercalaemia.

Symptoms Of Hypercalcaemiaa

In modern medical practice calcium is routinely measured as part of a biochemical profile. In consequence many more cases of hypercalcaemia come to light these days than in previous years. Most cases of hypercalcaemia are asymptomatic. More severe hypercalcaemia may cause tiredness, lethargy, thirst, polyuria, constipation and renal stones.

Hyperparathyroidism

Primary hyperparathyroidism affects women more commonly than men. It most commonly arises from an adenoma in one of the four parathyroid glands. In the minority of cases there may be hyperplasia of all four glands. In a few cases there is also an association with multiple endocrine neoplasia.

The hypercalcaemia may be mild to severe and there is hypophosphataemia. Although not routinely measured 1,25-dihydroxycholecalciferol levels are raised due to stimulation of the renal 1-hydroxylation process by PTH. The adenoma may be localised by ultrasound scanning or sestamibi scanning. In practice the best way to localise an adenoma if this is necessary is at operation when performed by an experienced parathyroid surgeon.

In most cases the hyperparathyroidism can be watched but surgery may be indicated in the following circumstances:

1. Serum calcium greater than 3 mmol/L.
2. Marked hypercalciuria (greater than 9 mmol/24 hours).
3. Renal stones, osteitis fibrosa cystica or neuromuscular disease.
4. Cortical bone mineral density greater than 2 SD below normal.
5. Reduced creatinine clearance in the absence of another cause.
6. Aged less than 50.

Secondary hyperparathyroidism does not cause hypercalcaemia but is as a result of the hypocalcaemia that can arise from chronic renal failure. In this case the serum phosphate levels are raised. Parathyroid gland can become autonomous as a result of prolonged stimulation in the face of chronic renal failure and tertiary hyperparathyroidism can arise. In this case hypercalcaemia does occur.

Malignancy

Malignancies can cause hypercalcaemia either due to bone destruction or the secretion of a parathyroid hormone related peptide. Assays are available for this peptide but tend to be reserved for research purposes. The peptide binds to the PTH receptor.

Tumours most prone to causing hypercalcaemia are squamous cell lung carcinomas, breast carcinomas that have metastasised to the bones, myeloma, HTLV1 associated lymphomas, renal cell carcinoma, tumours of the oesophagus, ovary and naso-pharynx. There may be signs of malignancy either due to the primary tumour or to spread on examination.

Thiazide Diuretics

Thiazides lead to increased renal resorption of calcium and can cause hypercalcaemia particularly when in combination with another cause of hypercalcaemia.

Sarcoidosis And Other Granulomatous Diseases

Mild hypercalcaemia may be seen in sarcoidosis and sometimes diseases such as leprosy and tuberculosis. It results from an increased conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. Unlike hyperparathyroidism and most malignancies this suppresses with steroids which may be of diagnostic value.

Familial Hypercalcaemia

Hypercalcaemia with hyperparathyroidism is seen in multiple endocrine neoplasia (MEN) Type I (parathyroid, pancreatic and pituitary tumours) and Type IIa (parathyroid adenoma, phaeochromocytoma and medullary carcinoma of the thyroid). A family history of hyperparathyroidism should alert the doctor to the possibility of other endocrine neoplasias.

A family history of hypercalcaemia should also alert the doctor to the possibility of familial hypocalciuric-hypercalcaemia. This is an autosomal dominant disorder affecting the calcium receptor. Reduced activity of the calcium receptor leads to a mildly raised serum calcium level and reduced urinary calcium excretion. The PTH levels are normal. It is important to consider this diagnosis because it does not respond to parathyroidectomy, unlike hyperparathyroidism.

Where either an MEN syndrome or hypocalciuric-hypercalcaemia is likely, family members should be screened.

Vitamin D Excess

Vitamin D is administered in the treatment of rickets and osteomalacia, osteoporosis and hypocalcaemia. It can also be bought in health food shops and may be added to foods. Overdose either due to prescribed vitamin D or from over the counter preparations can lead to hypercalcaemia.

The hypercalcaemia resolves when the vitamin D is reduced or withdrawn. Prescribed vitamin D may be a particular problem for patients on dialysis and calcium levels need careful watching.

Milk Alkali Syndrome

This uncommon condition can be seen in people who use antacids excessively. The antacid itself is not absorbed and this leads to a systemic alkalosis, hypercalcaemia and eventually, if untreated, renal impairment.

Treatment Of Hypercalcaemia

The need for treatment of hypercalcaemia depends on the degree of hypercalcaemia and whether symptoms are present. Many cases of hyperparathyroidism are left untreated and these days surgery would be uncommon with a calcium of less than 3 mmol/L. The indications for surgery are given above.

In cases of mild hypercalcaemia advice is given to drink plenty of fluids and in hyperparathyroidism the calcium is observed every six to twelve months. As yet there is no commercially available calcium receptor antagonist although one is undergoing trials. Drugs which may increase hypercalcaemia, such as thiazide diuretics, should be stopped if this is possible.

Severe Hypercalcaemia

The absolute level for severe hypercalcaemia is not defined and depends on symptoms.

In the presence of symptoms such as nausea, vomiting and polyuria intravenous rehydration should be started promptly. It is usual to give 3 or 4 litres of saline a day for a few days. Once adequate fluid resuscitation has been given, a loop diuretic may be added.

A bisphosphonate is given intravenously. Pamidronate or etidronate are the usual agents. Bisphosphonates act by binding to hydroxyapatite in bone and decreasing bone turnover. They do not work immediately and the calcium only starts to fall after two or three days and reaches a low point after about a week.

Prednisolone at 30 mgm to 60 mgm may be tried in conditions that respond to steroids (sarcoidosis and other granulomatous disease, vitamin D intoxication). Calcitonin can also be used as it works more quickly than the bisphosphonates but its effect is not maintained.

In the case of malignancy treatment of the underlying malignancy should be considered if the tumour is still treatable by this stage. Hypercalcaemia is often a fairly late event in the course of malignancy and indicates a worsening of the prognosis.

Hypocalcaemia

Mild hypocalcaemia may be asymptomatic. The degree to which there are symptoms depends on the absolute level of the hypocalcaemia and the rate of fall of the calcium. Neuromuscular membranes become irritable and paraesthesiae around the face and at the extremities can be experienced. Tetany can follow. Clinically these can be demonstrated by the Chvostek's sign where the facial nerve is tapped over the parotid gland. A twitching is seen at the angle of the mouth.

Trousseau's sign is demonstrated when a sphygmomanometer cuff is inflated to above arterial pressure. It is left in this position for a couple of minutes and the hand adopts the main d'accoucheur position with flexion at the metacarpo-phalangeal joint bringing the 4th and 5th fingers into the palm but leaving the 2nd and 3rd fingers more extended. The thumb is flexed across the palm. Electrocardiographically a prolonged QT interval may be seen. Muscle cramps can occur, laryngospasm and even seizures.

Causes For Hypocalcaemia

There are many causes of hypocalcaemia only a few of which are particularly common.

Hypocalcaemia can be iatrogenic and may be transient or occasionally permanent following parathyroid or thyroid surgery. Radiation to the thyroid gland can also lead to hyperparathyroidism.

Hyperparathyroidism may be auto-immune and can be associated with vitiligo, type I diabetes and cutaneous yeast infection as part of the polyglandular syndrome.

Chronic renal failure can lead to hypocalcaemia. Here there is secondary hyperparathyroidism.

A nutritional deficiency of vitamin D or malabsorption of vitamin D can lead to rickets in childhood and osteomalacia in adult life. This leads to a secondary hyperparathyroidism but rarely to hypocalcaemia.

Malignancy can cause hypocalcaemia if excess osteoblastic activity leads to increased bone formation. Chemotherapy can cause the release of phosphates when there is a large amount of tumour cell destruction and this binds calcium leading to hypocalcaemia.

Resistant hypocalcaemia may be due to concomitant magnesium deficiency. Magnesium is necessary for the release of PTH secretion and magnesium deficiency should be corrected to allow correction for hypocalcaemia.

Hypocalcaemia can occur in acute pancreatitis. Lipases released in the pancreatitis cause fat breakdown in the body with binding to calcium in a process known as saponification.

Treatment Of Hypocalcaemia

As before, the need for treatment and the type of treatment depends on the degree of hypocalcaemia and whether symptoms are present. Acute hypocalcaemia with calcium levels of less than 1.9 mmol/l, signs of tetany or ECG changes require treatment with intravenous calcium gluconate 10 ml of 10% solution diluted. A further calcium infusion may be required with calcium and ECG monitoring. It is important to check the magnesium level. The blood pH affects the amount of ionised calcium in the circulation. In settings where hypocalcaemia occurs with acidosis correction of the acidosis will reduce the amount of ionised calcium and aggravate the hypocalcaemia. Care must be taken to ensure that sufficient doses of calcium are given as replacement.

Long term treatment of hypocalcaemia is with oral calcium supplements and vitamin D orally. There are a number of preparations of vitamin D available.

Vitamin D is used either to enhance the absorption of dietary calcium even though there is not a primary deficiency of vitamin D or as replacement where vitamin D is low or absent. There are a number of preparations available but 1,25-dihydroxycholecalciferol is rapidly acting and doses can be easily adjusted. The dose is titrated to the patient's requirement and is normally between 0.5 mcg and 1 mcg a day.

Where vitamin D deficiency is due to dietary problems low doses only are required. Where it is due to problems of malabsorption higher doses are required. Where the problem is with renal failure and therefore there is defective 1-hydroxylation then the 1,25 preparation should be used. Other preparations of vitamin D such as vitamin D2 are available but they have a longer duration of action and therefore dose adjustment can give problems.