The albumin bound fraction of calcium accounts for approximately half plasma calcium and this proportion is physiologically inactive. Ideally, ionised calcium should be measured but techniques for this are not suitable for routine use. An adjustment for the effect of abnormal concentrations of albumin is therefore made to help interpret total plasma calcium estimations. The precise formula for calcium adjustment will depend on laboratory methods and should be derived locally.
The commonest cause of hypercalcaemia in the community is a parathyroid adenoma although in hospital practice it is now excess therapeutic vitamin D (or vitamin D derivatives) and malignancy. It is important to note that 10-15% of cases of hypercalcaemia due to malignancy have associated hyperparathyroidism. This subgroup should be identified as these individuals have considerably longer rates of survival than those with purely malignancy associated hypercalcaemia.
Effect of drug therapies
Many patients with hypercalcaemia will be dehydrated on presentation and should be adequately rehydrated. Samples for PTH etc MUST be taken before any other active therapies. This is essential as bisphosphonates cause a rapid increase in PTH as a consequence of the fall in calcium, even before the plasma calcium has fallen into the reference range.
The hypercalcaemia of vitamin D intoxication may last for many weeks after cessation of vitamin D intake since 25OH vitamin D has a long elimination half life (10-20 days).
Hypercalcaemia revealed by thiazide diuretics may be due to volume contraction with an increase in calcium binding proteins but is also due to increased renal tubular absorption of calcium. Thiazides may unmask patients with early hyperparathyroidism or vitamin D excess.
Familial hypocalciuric hypercalcaemia
FHH is an inherited condition in which the plasma calcium is "set" at a high value. Affected individuals do not suffer from any of the complications of hypercalcaemia and parathyroidectomy has no effect on the plasma calcium. The diagnosis can be made by measuring urine calcium excretion which is lower than would be expected in the hypercalcaemia of hyperparathyroidism. PTH is often marginally raised in FHH despite mild hypercalcaemia and it is important that FHH is considered in the differential diagnosis.
FHH is defined by the following biochemical criteria:
- 24h urine calcium < 6.25 mmol in presence of raised plasma calcium
- calcium : creatinine molar ratio < 0.17
- fasting calcium excretion rate < 22 µmol/ L glomerular filtration in presence of raised plasma calcium and detectable PTH
- Barth JH, Fiddy JB, Payne RB. Adjustment of serum total calcium for albumin concentration: effects of non-linearity and regression differences between laboratories. Ann Clin Biochem 1996;33:55-58.
- Gunn IR, Wallace JR. Urine calcium and serum ionized calcium, total calcium and parathyroid hormone concentrations in the diagnosis of primary hyperparathyroidism and familial benign hypercalcaemia. Ann Clin Biochem 1992;29:52-58.
- Hutchesson AC, Bundred NJ, Ratcliffe WA. Survival in hypercalcaemic patients with cancer and co-existing primary hyperparathyroidism. Postgrad Med J 1995;71:28-31.
- Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs RW Jr, Lasker RD. The hypocalciuric or benign variant of familial hypercalcaemia: clinical and biochemical features in fifteen kindreds. Medicine 1981;60:397-412.