Calcium regulation and hypocalcaemia

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Calcium regulation and hypocalcaemia

Calcium homeostasis

The amount of calcium present in the extracellular fluid is very small in comparison to that stored in bone. Even in the adult, calcium in bone is not static; some bone is resorbed each day and the calcium returned to the ECF. To maintain calcium balance, an equal amount of bone formation must take place. Figure 35.1 shows how much calcium is exchanged between one compartment and another daily.

Fig 35.1 Normal calcium balance. Calcium is exchanged each day, in the amounts shown, between the extracellular fluid and the gut, bone and kidney.

Calcium homeostasis is modulated by hormones (Fig 35.2). Parathyroid hormone (PTH), which consists of 84 amino acids, is secreted from the parathyroid glands in response to a low unbound plasma calcium. PTH causes bone resorption and promotes calcium reabsorption in the renal tubules, preventing loss in the urine. 1,25-dihydroxycholecalciferol (1,25 DHCC) maintains intestinal calcium absorption. This sterol hormone is formed from vitamin D (cholecalciferol), following hydroxylation in the liver (at carbon-25) and kidney (at carbon-1). However, hydroxylation in the kidney is PTH dependent, and so even the absorption of calcium from the gut relies (albeit indirectly) on PTH.

Fig 35.2 The effects of PTH in restoring a low plasma calcium to normal.

Serum calcium

A healthy person has a total serum calcium of around 2.4 mmol/L. About half is bound to protein, mostly to albumin. Binding is pH dependent and is decreased in acidosis, because the amino acid side chains on albumin become more positively charged. Conversely, binding is increased if an alkalosis is present. Hence, the percentage of unbound calcium increases in acidosis and decreases if there is an alkalosis.

Unbound calcium is the biologically active fraction of the total calcium in plasma and maintenance of its concentration within tight limits is required for nerve function, membrane permeability, muscle contraction and glandular secretion. It is the unbound calcium concentration that is recognized by the parathyroid glands, and PTH acts to keep this concentration constant.

Laboratories routinely measure total calcium concentration (that is both the bound and unbound fractions) in a serum sample. However, this may give rise to problems in the interpretation of results because changes in serum albumin concentration cause changes in total calcium concentration. If albumin concentration falls, total serum calcium is low because the bound fraction is decreased (Fig 35.3). Remember that the homeostatic mechanisms for regulating plasma calcium respond to the unbound fraction, not to the total calcium. Patients with a low albumin have total serum calcium lower than the reference values, yet have normal unbound calcium. These patients should not be thought of as hypocalcaemic.

Fig 35.3 The binding of calcium to albumin.

In order to circumvent this problem and to ensure that patients with a low albumin are not mistakenly labelled as hypocalcaemic, clinical biochemists use the convention of the ‘adjusted calcium’. Most laboratories measure both total calcium and albumin, and, if the albumin is abnormal, calculate what the total calcium would have been if the albumin had been normal. One such calculation is:

Adjusted calcium (mmol/L) = Total measured calcium + 0.02(47– albumin)

Hypocalcaemia

The causes of hypocalcaemia include:

Vitamin D deficiency. This may be due to malabsorption, or an inadequate diet with little exposure to sunlight. It may lead to the bone disorders, osteomalacia in adults and rickets in children (see pp. 76–77).

Hypoparathyroidism.

Magnesium deficiency. This is a common cause in hospital patients.

Renal disease. The diseased kidneys fail to synthesize 1,25 DHCC (see pp. 28–29). Increased PTH secretion in response to the hypocalcaemia may lead to bone disease if untreated.

Hungry bone syndrome. There can be severe and potentially fatal hypocalcaemia with accompanying hypophosphataemia after parathyroidectomy, due to rapid remineralization of bone (after sudden decrease in PTH), especially after long-standing primary hyperparathyroidism with severe bone disease.

Pseudohypoparathyroidism. PTH is secreted but there is failure of target tissue receptors to respond to the hormone.

Rarer causes such as malignancy, acute rhabdomyolysis, acute pancreatitis, ethylene glycol poisoning or bone marrow transplantation.

Clinical features

The clinical features of hypocalcaemia include: neurological features such as tingling, tetany, and mental changes; cardiovascular signs such as an abnormal ECG; and cataracts.

A strategy for the investigation and differential diagnosis of hypocalcaemia is shown in Figure 35.4.

Fig 35.4 The investigation of hypocalcaemia.

Treatment

The management calls for the treatment of the cause of the hypocalcaemia, if this is possible. Oral calcium supplements are commonly prescribed in mild disorders. 1,25 DHCC, or the synthetic vitamin D metabolite 1α-hydroxycholecalciferol, can be given.

Clinical note

Trousseau’s sign is the most reliable indication of latent tetany. A sphygmomanometer cuff is inflated to above systolic pressure for at least 2 minutes while observing the hand. A positive response will be the appearance of typical carpal spasm, which relaxes some 5 seconds or so after the cuff is released.

Fig 35.5 Trousseau’s sign.

Case history 28

A 70-year-old woman attended her GP complaining of generalized bone pain. Biochemistry results on a serum specimen taken at the surgery showed the following:

• What further investigations would be appropriate?

Comment on page 167.

Calcium regulation and hypocalcaemia

‘Adjusted calcium’ should be used to avoid the problems of interpreting the total calcium concentration in patients who have abnormal serum albumin concentrations.

If a hypocalcaemic patient has low or undetectable PTH in serum, he/she is hypoparathyroid.

If PTH concentrations are appropriately elevated to the low calcium, then the reason for the hypocalcaemia is most likely to be vitamin D deficiency.

Patients with chronic renal failure often have hypocalcaemia due to the inability of renal cells to synthesize 1,25-dihydroxycholecalciferol. Secondary hyperparathyroidism and bone disease may result.

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