Six o’clock blood result – hypercalcaemia
Consultant in chemical pathology and metabolic medicine, Professor Martin Crook, outlines the clinical implications surrounding hypercalcaemia.
Control of plasma calcium concentration
Calcium is involved in numerous cellular physiological processes, such as membrane function, enzyme activity, clotting pathways, muscle contraction, and excitation-stimulus response coupling. The plasma concentration of calcium is tightly controlled in humans to about 2.25 to 2.55mmol/l, and homeostatic mechanisms involved usually depend upon a suitable intake of calcium and vitamin D, and the normal functioning of the intestine, kidneys, bones, and parathyroid glands.
It is useful to consider the main controlling mechanisms of calcium homeostasis, as this helps explain the pathophysiology of hypercalcaemia. Parathyroid hormone (PTH) is normally released when the plasma calcium concentration falls. PTH increases plasma calcium through the stimulation of osteoclastic bone resorption and by causing increased renal reabsorption of calcium.
Simultaneously, it causes a decrease in plasma phosphate concentration by decreasing the renal tubular reabsorption of phosphate, causing phosphaturia. Calcitonin is produced by the C cells of the thyroid gland, and opposes the actions of PTH. Plasma concentrations of calcitonin may be raised in patients with medullary carcinoma of the thyroid.
In humans, vitamin D is derived from ergocalciferol (vitamin D2), obtained from the diet, and cholecalciferol (vitamin D3), formed mainly in the skin by the action of ultraviolet light on 7-dehydrocholesterol. Vitamin D is transported plasma bound to specific carrier proteins and binds to a specific receptor – the vitamin D receptor (VDR). In the liver, cholecalciferol is hydroxylated to 25-hydroxycholecalciferol (25-OHD3) by the enzyme 25-hydroxylase. This is the main circulating form and store of vitamin D, and the form that is usually measured by the laboratory to assess vitamin D status.
The calcium-sensing receptor (CaSR) facilitates parathyroid cells and those of the ascending loop of Henle to respond to changes in extracellular calcium concentrations. PTH-related protein (PTHrP) has a similar amino acid sequence to PTH. However, its function is currently unclear, and it may become de-repressed in certain tumours, such as small cell lung cancer.
Other hormones influencing calcium metabolism include thyroxine, and growth hormone. These may increase bone calcium reabsorption, 1,25-(OH)2D3 production, and increase calcium absorption during pregnancy, lactation and growth.
Causes of hypercalcaemia
Overall, thiazide diuretics are one of the most common causes of mild hypercalcaemia likely to be seen in primary care. However, severe hypercalcaemia is usually due to either primary hyperparathyroidism or malignancy. Some causes of hypercalcaemia are shown in box 1 (see below). These can be conveniently divided into two main groups: those with hypercalcaemia and inappropriately-raised or ‘normal’ plasma PTH levels, and those with hypercalcaemia and appropriately-suppressed plasma PTH levels.
Some causes of hypercalcaemia
Inappropriate PTH secretion
- Primary hyperparathyroidism, such as adenoma, hyperplasia, carcinoma or associated with MEN syndrome
- Tertiary hyperparathyroidism, although secondary hyperparathyroidism per se is not associated with hypercalcaemia
- Bony metastases, including breast, lung, prostate, kidney, and thyroid
- Tumours with humoral effects, ectopic PTH, or PTH-RP secretion
- Haematological tumours, like multiple myeloma-inducing osteolytic bone lesions
Conditions with high bone turnover
- Immobilisation, like with Paget’s disease
Inappropriately-elevated vitamin D
- Vitamin D toxicity
- Granulomatous disease, for example, sarcoidosis, tuberculosis, leprosy, and histoplasmosis
- Milk-alkali syndrome
Familial hypocalciuric hypercalcaemia
Other endocrine causes
- Adrenal insufficiency
Rarer causes, including
- Williams-Beuren syndrome
- HIV infection
- Vitamin A toxicity
Hypercalcaemia and inappropriately-raised PTH
Primary hyperparathyroidism occurs through inappropriate secretion of PTH by the parathyroid glands, causing hypercalcaemia. It is usually caused by one or more parathyroid adenomas, but is occasionally due to hyperplasia of all four parathyroid glands, or rarely parathyroid carcinoma.
Ectopic PTH secretion by tumours may also occur but is rare, as discussed below. Primary hyperparathyroidism may be associated with the multiple endocrine neoplasia (MEN) syndrome, including pituitary and pancreatic adenomas (MEN type I), or with phaeochromocytoma and medullary carcinoma of the thyroid (MEN type II).
The treatment of primary hyperparathyroidism is often surgical, with the removal of the parathyroid gland(s), particularly if patient is symptomatic, and has renal calculi or poor renal function. However, asymptomatic ‘mildly’ hypercalcaemic patients are sometimes treated conservatively. Tertiary hyperparathyroidism occurs if the parathyroid glands have been subjected to prolonged and sustained positive feedback by chronic hypocalcaemia of secondary hyperparathyroidism, and – unlike secondary hyperparathyroidism – is associated with hypercalcaemia. A common cause is chronic kidney disease.
Possible clinical features of hypercalcaemia
Renal damage, such as nephrocalcinosis and renal calculi
- Depression of neuromuscular excitability and hypotonia
- ECG abnormalities, with shortening of the QT interval and T wave broadening
- Sudden cardiac arrest or ventricular arrhythmias
- Tissue calcification
- Bone and joint pain
- Peptic ulceration
- Anorexia, nausea and vomiting
- Acute abdomen, constipation and abdominal pain
Hypercalcaemia and appropriately suppressed PTH levels
Hypercalcaemia of malignancy
Malignant disease involving bone
Some patients with multiple bony metastases – typically breast, lung, prostate, kidney, and thyroid tumours – or with multiple myeloma show hypercalcaemia usually associated with hyperphosphataemia. The hypercalcaemia is caused by osteoclastic action due to the local action of tumour cells and cytokine activation. Some tumours show ectopic 1-alpha hydroxylase activity. Elevated plasma alkaline phosphatase activity may be a clue to malignant deposits in bone.
Humoral hypercalcaemia of malignancy
PTHrP is synthesised by some malignant tumours, and is not subject to normal feedback control by the high plasma-free ionised calcium concentration. PTHrP is not usually detected by standard PTH assays.
Drugs or medications associated with hypercalcaemia
Various medications can cause hypercalcaemia, such as thiazides (which decrease calcium renal excretion), lithium (which may stimulate PTH release), and vitamin A excess (which increases osteoclastic bone activity). Vitamin D excess may be caused by the inappropriate use of vitamin D supplements, resulting in hypercalcaemia.
Sarcoid granuloma tissue synthesises 1.25-(OH)2D3, causing an increase in calcium absorption from the intestinal tract. Chronic beryllium poisoning produces a granulomatous reaction very similar to that of sarcoidosis, and may also be associated with hypercalcaemia, as can tuberculosis, histoplasmosis, HIV, and leprosy.
Other endocrine causes of hypercalcaemia
Prolonged and severe hyperthyroidism may be associated with the histological appearance of osteoporosis with hypercalcaemia is a very rare complication. Other rare endocrine causes of hypercalcaemia include acromegaly, Addison’s disease and phaeochromocytoma.
This occurs with the excessive use of calcium-containing antacids for dyspepsia, for example, calcium hydroxide. It is also associated with a metabolic alkalosis. This is now rarely seen since the use of PPIs.
Familial hypocalciuric hypercalcaemia
Hypercalcaemia with an inappropriately-high plasma or normal PTH concentration in the presence of hypocalciuria has been reported in some families, and is sometimes called familial benign hypercalcaemia. This can ‘mimic’ primary hyperparathyroidism, and is usually inherited as an autosomal dominant trait that is thought to be due to a defect on the CaSR.
This is also sometimes called infantile hypercalcaemia, which is a rare autosomal dominant condition caused by a microdeletion at 7q11.23. In addition to hypercalcaemia, this is associated with a dysmorphic face, abnormal dentition, cataracts, hypotonia, short stature, and supraventricular aortic stenosis.
Clinical consequences of hypercalcaemia
‘Bones, moans, groans and stones’ is a useful mnemonic to remember some of these clinical consequences of hypercalcaemia.
Severe hypercalcaemia causes ECG abnormalities, with shortening of the QT interval and T wave broadening. If plasma concentrations exceed about 3.5mmol/l, there is a risk of sudden cardiac arrest, ventricular arrhythmias, or seizure. For this reason, severe hypercalcaemia should be treated as a matter of urgency.
Renal damage such as nephrocalcinosis with calcification of the tubular cells can cause polyuria. The impairment of renal concentrating ability due to inhibition of the tubular response to antidiuretic hormone (ADH) leads to fluid loss and dehydration. Renal calculi can also occur.
Hypercalcaemia can also directly inhibit potassium reabsorption from the renal tubules, resulting in hypokalaemia, often with a metabolic alkalosis. A depression of neuromuscular excitability may produce hypotonia, and seizures may also occur. In addition, depression, anorexia, nausea and vomiting can also be associated with hypercalcaemia.
There is an association between chronic hypercalcaemia and peptic ulceration, probably due to calcium-stimulating gastrin secretion. The patient may also complain of constipation and abdominal pain. Severe hypercalcaemia may also present as an acute abdomen, and hypercalcaemia is additionally associated with non-specific bone and joint pain.
Investigation of hypercalcaemia
It is important to establish whether the high plasma total calcium concentration is due only to a high protein-bound fraction, as about 50% of plasma calcium is albumin-bound). Most laboratories should now report albumin-corrected or adjusted calcium results. If not, this can be calculated by the following equation:
Plasma [corrected calcium] = Plasma [calcium] + (40 – [Plasma albumin] in g/l ) x 0.02mmol/L
Two main groups of causes can be differentiated for hypercalcaemia:
- Raised plasma-corrected calcium concentration due to inappropriately high PTH and usually hypophosphataemia
- Raised plasma-corrected calcium concentration due to other causes and associated with low or non-suppressed PTH concentrations and often hyperphosphataemia.
Plasma PTH is an important test and should be available to primary care. If you are considering this test, check with the laboratory for the optimal collection conditions, as PTH can be labile.
The following procedure may be useful to find the cause of unexplained hypercalcaemia, although the diagnosis may be obvious before all the steps have been followed.
Ensure the blood specimen is taken without venous stasis, preferably without a tourniquet, to eliminate artefactual haemoconcentration. A raised plasma albumin concentration plus a raised plasma urea concentration suggests dehydration, while a raised plasma albumin concentration in the presence of a normal urea concentration suggests stasis when taking the blood sample. If true hypercalcaemia, that is, a raised albumin-corrected calcium elevation is confirmed, a cause must be sought.
Take a careful history, with special reference to the drug history, such as vitamin D-containing preparations, calcium-containing antacids, lithium, and thiazide diuretics. Look for evidence of the milk-alkali syndrome, albeit rare, and if present, check acid-base status, as metabolic alkalosis shows a raised serum bicarbonate concentration. Hypercalcaemia associated with hyperparathyroidism tends to be associated with lower serum calcium concentrations, usually less than 3mmol/l, and also a longer duration of hypercalcaemia – greater than six months and with hypophosphataemia – than in malignant hypercalcaemia.
Apart from thiazide diuretic usage, the most common causes of hypercalcaemia are either primary hyperparathyroidism or malignancy. The latter may be obvious following clinical examination and radiological and laboratory tests, for example, abnormal chest X-ray, anaemia, and raised ESR. The assay of serum 25-OHD3 is useful to help exclude vitamin D toxicity.
It is crucial that primary hyperparathyroidism and malignant hypercalcaemia are distinguished. In the case of the latter, it is important to be alert for breast, lung, kidney, and prostate carcinoma or multiple myeloma. A normal or raised plasma PTH concentration is usually seen in primary hyperparathyroidism. Conversely, suppressed PTH levels are found in malignant states, and indeed in hypercalcaemia of many other causes. Specialist units may wish occasionally to have plasma PTHrP measured if ectopic secretion of this is suspected, for example, by a tumour.
If primary hyperparathyroidism due to an adenoma is found, it is important to exclude the associated MEN syndrome. Although this is more applicable to a specialist endocrine unit, imaging of the parathyroid glands is often needed to distinguish adenoma from hyperplasia of the parathyroid glands. Isotope subtraction scanning or ultrasound of the neck may help to localise the adenoma, as may venous sampling for PTH concentrations at operation.
To exclude a multiple myeloma or paraprotein, you should request both serum and urinary protein electrophoresis, and serum-free light chains. If the source of the hypercalcaemia is unclear look for evidence of sarcoidosis; here plasma ACE activity is often non-specifically raised and a chest X-ray may be helpful. Consider rare causes of hypercalcaemia such as acromegaly, Addison’s disease or thyrotoxicosis. A raised plasma alkaline phosphatase in the presence of hypercalcaemia suggests bony metastases, sarcoidosis, thyrotoxicosis, or Paget’s disease immobilisation.
Familial hypocalciuric hypercalcaemia can be associated with hypermagnesaemia and a family history of hypercalcaemia. It is important to distinguish primary hyperparathyroidism from familial hypocalciuric hypercalcaemia, as the treatments differ. In the case of the latter, plasma PTH may be normal or elevated, but – unlike other causes of hypercalcaemia – the calcium excretion index (CEI) is low. The CEI = [calcium] urine x [creatinine] plasma / [creatinine] urine, and requires a spot urine sample taken at the same time as a fasting plasma sample for calcium. Familial hypocalciuric hypercalcaemia is likely if this is less than 22umol/l filtrate.
Management of hypercalcaemia
The plasma albumin-adjusted or corrected calcium concentration at which urgent treatment is indicated because of the danger of cardiac arrest is usually above 3.5mmol/l. If in doubt, abnormalities associated with hypercalcaemia should be sought from symptoms and also on the ECG. Consider the following:
- Rehydration – the patient should be volume repleted intravenously with saline if necessary. The loop diuretic furosemide may also need to be given in an attempt to increase urinary calcium clearance and avoid fluid overload.
- Bisphosphonates – after rehydration and correction of any electrolyte abnormalities, consider bisphosphonates such as pamidronate or zolendronic acid.
- Steroids may sometimes lower the plasma calcium concentration in malignancy, and almost always in cases of sarcoidosis and vitamin D intoxication.
- Calcitonin is sometimes used to treat severe refractory hypercalcaemia.
- Cinacalcet hydrochloride is a calcimimetic (mimicking the action of calcium) agent that may reduce PTH levels in patients with secondary hyperparathyroidism.
- Haemodialysis or peritoneal dialysis may be indicated in patients with severe hypercalcaemia secondary to chronic kidney disease.
- Treating the cause of hypercalcaemia may be sufficient to restore plasma calcium concentrations in milder cases.
Summary of treatment of severe hypercalcaemia
- Rehydration with careful fluid replacement and with furosemide if required.
- After rehydration and correction of any electrolyte abnormalities, consider bisphosphonates such as pamidronate or zolendronic acid.
- Steroids may sometimes lower the plasma calcium concentration in malignancy and in cases of sarcoidosis and vitamin D intoxication.
- Calcitonin is sometimes used to treat severe refractory hypercalcaemia.
- Cinacalcet hydrochloride is a calcimimetic agent that may reduce PTH levels in some patients with hyperparathyroidism.
- Haemodialysis or peritoneal dialysis may be indicated in patients with severe hypercalcaemia secondary to chronic kidney disease
- Treat and manage the underlying cause of hypercalcaemia
Professor Martin Crook is a consultant in chemical pathology and metabolic medicine at University Hospital Lewisham and Guy’s and St Thomas’ Hospitals, and is a visiting professor at the University of Greenwich, London.
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5 NICE. Clinical knowledge summaries – hypercalcaemia. London: NICE; 2010