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 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).
