Hypercalcaemia

This includes the commonest underlying diagnosis: primary hyperparathyroidism, and all other causes of hypercalcaemia.

Baseline investigations

Full blood count

Anaemia raises the possibility of malignancy or other chronic disease.

Erythrocyte sedimentation rate

Useful indicator of general health and underlying disease, particularly useful if there is clinical suspicion of renal or inflammatory disease.

Urea and electrolytes

Hypercalcaemia may be associated with dehydration and renal failure.

Liver function test

This is a simple screen for underlying malignancy.

Bone profile

Baseline calcium level needs to be interpreted with albumin to determine corrected calcium. 

Alkaline phosphatise (ALP) and serum phosphate levels may also give an indication of the likely cause of hypercalcaemia. Low phosphate and normal ALP are consistent with primary hyperparathyroidism, whereas an elevated ALP may indicate malignancy with bone metastases.

Thyroid stimulating hormone, free thyroxine

Untreated hyperthyroidism may cause hypercalcaemia though this is generally not severe.

Prolactin

Hypercalcaemia is often the earliest manifestation of MEN1. For this reason, it is prudent to consider this diagnosis at presentation even in patients who give no obvious suggestive history.

Vitamin D

Vitamin D deficiency is common and can lead to diagnostic confusion. This usually occurs in the context of a low or normal calcium, with PTH elevation or secondary hyperparathyroidism.

With hypercalcaemia, it is also important to document that vitamin D levels are normal. Uncorrected vitamin D defficiency not only confuses the biochemical picture, but may also lead to profound hypocalcaemia after parathyroid surgery.

Parathyroid hormone

PTH is normal or elevated in primary hyperparathyroidism, in familial hypocalciuric hypercalcaemia, and in lithium associated hypercalcaemia. Low PTH levels imply an alternative cause of hypercalcaemia for example malignancy, or granulomatous disease.

Bisphosponates are commonly prescribed in patients with osteoporosis and have a very long half life. It is standard practise to stop bisphosphonate treatment for at least six weeks prior to testing, as they lead to further elevation of PTH with little effect on serum calcium.

Calcium to creatinine clearance ratio

24hr urinary collection for calcium and creatinine, with a paired serum sample for calcium and creatinine is required. This demonstrates the level of hypercalciuria which is a useful indicator of the risk of renal stone formation, and allows calculation of the calcium to creatinine clearance ratio. This may be calculated using the following formula: 

Urine Calcium (mmol/l) x [Plasma Creatinine (micromol/l)/1000] divided by Plasma Calcium (mmol/l) x Urine Creatinine (mmol/l)

A web-based tool is also available to calculate this ratio. Ratios below 0.01 are consistent with familial benign hypocalciuric hypercalcaemia. This condition generally requires no specific treatment. 

24hr urinary collection for calcium, creatinine and magnesium

In cases with borderline results, it may be worth repeating the calcium:creatinine clearance ratio on three occasions, and also calculate the magnesium:creatinine clearance ratio in the same way.

Further investigations

Serum and urine protein electrophoresis

Where serum PTH is undetectable, other causes of hypercalcaemia should be sought, for example haematological malignancy.

Chest radiograph

Perform a chest XR if the patient is a smoker, or if the patient has any respiratory symptoms or signs that might suggest a lung malignancy or sarcoidosis. Also perform in all patient with a low PTH.

Abdominal radiograph

Abdominal radiograph is a useful low cost screen to detect asymptomatic renal tract calcification.

Calcium sensing receptor gene sequencing

If the results of three 24hr collections are still equivocal, consider sequencing of the calcium sensing receptor to seek genetic confirmation of familial benign hypocalciuric hypercalcaemia.

Bone densitometry

This is not necessary in other causes of hypercalcaemia and is not mandatory in hyperparathyroidism. However, if the patient is not already known to have osteoporosis it can be a useful adjunct to the decision making process. Furthermore, if the patient does not proceed to surgery, they may benefit from specific treatment for newly diagnosed osteoporosis.

Neck ultra-sound scan

In patients with confirmed primary hyperparathyroidism, who are suitable for surgery, localisation is attempted using a combination of neck USS and MIBI. Where the results are concordant no further localisation is necessary and minimally invasive parathyroid surgery may be arranged.

Neck sesta-MIBI scan

In patients with confirmed primary hyperparathyroidism, who are suitable for surgery, localisation is attempted using a combination of neck USS and MIBI.

Where the results are concordant no further localisation is necessary and minimially invasive parathyroid surgery may be arranged. Where results are discordant, either selective venous sampling to aid localisation or bilateral neck exploration may be considered.

Selective venous sampling of the neck

Where repeat surgery is contemplated, and in selected cases where localistion of the parathyroid is difficult, consider selective venous sampling of the neck and mediastinum.

Skeletal survey

In the presence of specific bony pain, or with elevated erythrocyte sedimentation rate and protein electrophoresis consider performing a skeletal survey prior to haematology referral.

Liver ultrasound

If ALP and other liver enzymes are elevated and the PTH is low, consider liver ultrasound to seek evidence of metastatic disease.

Oesophagogastroduodenoscopy

If the patient complains of severe upper gastroinstestinal symptoms and has other warning features, such as anaemia, weight loss or a low PTH, consider direct visualisation of the upper gastrointestinal tract for malignancy.  

Serum ACE

If there is any suspicion of sarcoidosis, it is worth documenting a baseline serum ACE before referring to the relevant specialist, although this is not a specific screen for the disease.