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Hypercalcaemia


Hypercalcaemia
Hypercalcaemia occurs when serum calcium rises above 2.6 mmol/L. The most common causes are primary hyperparathyroidism and malignancy. The hallmark of hypercalcaemia of malignancy is a low PTH level, while primary hyper-parathyroidism is typically associated with a normal or high PTH (Figure 16.1).

Hypercalcaemia

Hypercalcaemia with suppressed PTH
Malignancy must be excluded in all cases of hypercalcaemia where PTH is suppressed. Malignant causes of hypercalcaemia are usually associated with squamous cell epithelial tumours resulting from the secretion of PTH-related peptide (Figure 16.1). Hypercalcaemia of malignancy occurs in large or advanced tumours, and bony metastases are not always present. Hypercalcaemia with a low PTH can also be seen in benign granulomatous disease such as TB or sarcoidosis (Figure 16.1).

Hypercalcaemia with non-suppressed PTH
When PTH is elevated or in the upper part of the normal range, malignancy is unlikely. The usual cause is primary hyperparathyroidism (Figure 16.1) which is usually caused by a single parathyroid adenoma. Parathyroid hyperplasia in more than one gland suggests a genetic cause (e.g. MEN; Chapter 14). A very high serum calcium (>3.5 mmol/L) with a large parathyroid tumour indicates parathyroid cancer but this is exceptionally rare. Parathyroid cancer may occur rarely in association with jaw tumours (hyperparathyroidism–jaw tumour syndrome).
Clinical features
Primary hyperparathyroidism is often asymptomatic and discovered incidentally during routine blood tests. Non-specific symptoms include tiredness, and generalised aches and pains. Specific symptoms include polyuria and polydipisa, due to nephrogenic diabetes insipidus. Other symptoms are abdominal pain and constipation. Frank psychiatric symptoms may be present in the elderly. Nephrocalcinosis and renal calculi occur in about 5% of patients. Long-standing disease can give rise to metabolic bone disease, which can have a classic cystic appearance on X-ray (brown tumours) due to osteoclastic activity, and should not be confused with primary bone neoplasms.
Investigation
The hallmark of primary hyperparathyroidism is hyper-calcaemia in the presence of high or non-suppressed PTH. PTH can be in the upper part of the normal range in mild disease. Low phosphate is usually present as a result of the phosphaturic effect of PTH. High alkaline phosphatase (ALP) reflects increased bone turnover and is common in patients with coexisting vitamin D deficiency. PTH may be very high due to both primary and secondary hyperparathyroidism in such patients. Bone density may be reduced, especially at the distal radius. Renal ultrasound may show nephrocalcinosis. Sub-periosteal erosion of the phalanges can be present in severe disease (Figure 16.2b).
Familial hypocalciuric hypercalcaemia
The main differential diagnosis of hypercalcaemia with non- suppressed PTH is familial hypocalciuric hypercalcaemia (FHH). This rare condition is caused by a genetic defect in the calcium sensing receptor. It is distinguished from primary hyperparathyroidism by demonstration of a low urine calcium: creatinine ratio. In FHH there is usually a family history of mild hypercalcaemia. It is important to exclude FHH before sending a patient for an unnecessary neck exploration.
Localisation of parathyroid adenoma
If parathyroid surgery is planned, the adenoma should be localised. This can be difficult if the lesion if small. In experienced hands, parathyroid ultrasound will detect an adenoma in 70–90% of cases, although this technique is highly operator-dependent. Sestamibi isotope scanning is often used alongside ultrasound, while other techniques in use in some centres include single-photon emission CT (SPECT), CT/MRI and 4-D CT.
Treatment of hyperparathyroidism
Management is guided by the degree of symptoms and the serum calcium level. Surgery should be considered if serum calcium is >2.85 mmol/L and/or if symptoms are debilitating. Inelderly patients with primary hyperparathyroidism, hypercalcaemia often worsens during intercurrent illness and simple rehydration can improve levels. Long-term complications of primary hyperparathyroidism include osteoporosis and nephrocalcinosis, hence these may be indications for surgery. Young patients and those with severe acute hypercalcaemia are also usually recommended for surgery.
Parathyroid surgery
Parathyroidectomy should always be performed by an experienced surgeon. Minimally invasive approaches are used, and many centres now use intra-operative PTH assay to confirm successful removal of the parathyroid adenoma. The aim of surgery is to normalise serum calcium and reverse symptoms. Complications of parathyroid surgery include infection, bleeding and recurrent laryngeal nerve palsy, which is usually temporary. In patients with severe hypercalcaemia, postoperative hypocalcaemia can occur, termed ‘hungry bone syndrome’. In patients with ectopic parathyroid adenoma, thoracotomy may be required. In four-gland hyperplasia (e.g. MEN-1), total parathyroidectomy may be necessary followed by lifelong vitamin D and calcium replacement.
Non-surgical approaches
Medical management or simple observation can be an alternative for those patients unable to undergo surgery. Prevention of dehydration and treatment of osteoporosis with bisphosphonates is a common approach. Calcimimetic drugs (e.g. cinacalcet) are effective in lowering calcium in primary hyperparathyroidism but do not have an effect on bone mineral density. They act on the calcium sensing receptor to reduce PTH.

Acute severe hypercalcaemia
This is a medical emergency. Patients present with profound dehydration and renal impairment, requiring urgent treatment and consideration of the cause (Chapter 40).