Introduction

A patient with hypercalcaemia in malignancy (HCM) may present with mild symptoms such as fatigue, mental dullness, weakness, anorexia or constipation. More severe symptoms may be nausea, vomiting, confusion, drowsiness or even coma. Pain may be precipitated or exacerbated by hypercalcaemia. Dehydration or cardiovascular collapse may occur in severe cases.

Diagnosis is by biochemical investigation. Allowances should be made for hypoalbuminaemia commonly seen in these patients. For every 1g/L the plasma albumin concentration falls below the mean normal albumin for a given laboratory, add 0.02 to the total calcium concentration as measured in mmol/L.

GPs may well be at the forefront of diagnosing and managing HCM, particularly as they are often dealing with advanced cases of cancer. The following lecture notes from the NSW Society of Palliative Medicine education meeting in July, delivered by Dr Howard Gurney, staff specialist, Medical Oncology, Westmead Hospital, will update readers on the pathophysiology and management of HCM. These notes have been reproduced from the Society's October 1995 Newsletter with permission from the management committee and the author.

As will be seen, most HCM is nephrogenic, rather than due to bone destruction.

Three hormones are important in calcium metabolism: parathyroid hormone (PTH), vitamin D and calcitonin. PTH acts on the kidney and bone as well as activating vitamin D, which acts on the gut, kidney and bone, to increase calcium. Raised serum calcium normally switches off PTH and switches on calcitonin, stopping calcium release from bone, and reducing renal calcium resorption, increasing urinary calcium loss.

Dr Gurney pointed out that HCM is commoner now because asymptomatic, mild (<3%) cases are picked up on routine biochemistry profiles that were not done so often in the past. Some of these cases are due to coincidental primary hyperparathyroidism, unrelated to cancer, and a parathyroid hormone level should be checked in otherwise well patients with limited disease when HCM is not expected clinically.

A key point Dr Gurney made was that we now know that HCM is not principally due to bone destruction by metastases, but rather it is a paraneoplastic phenomenon and unrelated to the presence of bone secondaries. In most cases HCM is due to release of humoral factors by the tumour which activate osteoclasts and interfere with renal excretion.

The main tumour product involved is a parathyroid hormone related protein (PTHrP) which was isolated and cloned from lung cancer cells in Melbourne in 1987. It is usually responsible for HCM in carcinomas but not in myeloma or lymphomas. It is genetically more complex than PTH, and only some of its actions are via the PTH receptor. The biochemical effects of PTH and PTHrP are similar except that PTHrP decreases bone formation and causes hypokalaemic alkalosis. PTHrP may also be involved in the development of bone metastases, as well as being a normal cytokine with non-PTH effects including control of foetal calcium metabolism and the growth and differentiation of adult epithelium.

APD takes several days to work and has its maximal effect at 5-7 days, wearing off in two weeks. Calcitonin works rapidly (2 hours) but wears off in days, and there is tachyphylaxis with repeated use. The claimed dose response effect of APD is now disputed. In some centres (especially Europe) the standard dose now is 60 mg. Elsewhere the recommended dose is related to the calcium level (2.65 - 3.0 45 mg; 3.6 - 4.0 60 mg; > 4.0 90 mg).

The side effects of APD are transient hypocalcaemia, fever and lymphopaenia. APD can be given repeatedly for recurrent HCM.