Contents
Causes
Hypercalcaemia is an elevation of the corrected blood calcium above the upper limit of the normal range. This usually means a corrected calcium that exceeds 2.5mM or 2.6mM depending on the reference range of the local laboratory. There are numerous causes of hypercalcaemia.
- Primary hyperparathyroidism
- Malignancy: Bone metastases; Paraneoplastic syndromes; Myeloma
- Tertiary hyperparathyroidism
- Sarcoidosis
- Other granulomatous diseases
- Thyrotoxicosis
- Addison's disease
- Acromegaly
- Thiazide diuretics
- Lithium
- Vitamin D intoxication
- Vitamin A intoxication
- Milk-alkali syndrome
- Familial hypocalcuric hypercalcaemia
The most common causes are primary hyperparathyroidism and malignancy. Sarcoidosis is also an important cause.
The hypercalcaemia of sarcoidosis is due to the presence of the Vitamin D 1-alpha hydroxylase enzyme in the macrophages of the granulomas of sarcoidosis. This enzyme activates vitamin D and its behaviour is sarcoidosis may not be subject to the usual regulatory mechanisms. This mechanism applies to the hypercalcaemia of other granulomatous diseases, although they are much rarer causes of hypercalcaemia.
The hypercalcaemia of thyrotoxicosis and acromegaly reflects increased bone turnover.
Corticosteroids promote excretion of calcium by the kidney. If their levels are deficient, as in Addison's disease, mild hypercalcaemia can result.
Milk-alkali syndrome is a consequence of drinking large volumes of milk and alkaline antacids.
Familial hypocalcuric hypercalcaemia is an autosomal dominant condition in which the protein used by the parathyroid glands and kidney to detect calcium is defective. This leads the parathyroid glands and the kidney to behave as if calcium levels are low.
Clinical Features
The features of hypercalcaemia centre around the GI system, skeletal muscle, heart, brain and kidneys.
Nausea and vomiting occur. Constipation is present. Patients suffer from abdominal pain, which in some cases may be due to renal stones. The formation of renal stones is most likely to be secondary to the increased excretion of calcium in the urine and the accompanying dehydration that is provoked by the polyuria which is caused by the hypercalcaemia / hypercalcuria. Polydispia accompanies the polyuria. In severe cases, the hypercalcaemia can be sufficient to induce renal failure, which may in part be secondary to calcification within the kidney.
Hypercalcaemia can precipitate acute pancreatitis, which itself is a cause of abdominal pain.
Weakness, tiredness, lethargy, impaired concentration and an altered personality can be present. In severe cases coma develops.
Cardiac arrhythmias can occur and may reflect shortening of the QT interval.
In many cases of chronic hypercalcaemia (particularly due to primary hyperparathyroidism) there can be bone pain and fractures.
Cataracts can develop and the cornea may become calcified.
Calcium can be deposited in various soft tissues.
Investigations
The diagnosis of hypercalcaemia can be confirmed by measuring the blood corrected calcium. This test is often routinely accompanied by the alkaline phosphatase levels and sometimes the blood phosphate level.
The level of parathyroid hormone will be elevated in primary and tertiary hyperparathyroidism. It may also be raised in paraneoplastic hypercalcaemia, either due to secretion of parathyroid hormone itself by the neoplasm or because the tumour secretes a parathyroid hormone-like substance which gives a positive result in the test. In all other causes of hyperparathyroidism (except familial hypocalcuric hypercalcaemia), the parathyroid hormone level is very low because the hypercalcaemia suppresses the secretion of the hormone.
Activated vitamin D levels can be measured. These will be low, due to suppression of the activation of vitamin D by the hypercalcaemia, with the exception of sarcoidosis, other granulomatous diseases and vitamin D overdose.
The urea and electrolytes should be checked to assess renal function.
An ECG is vital to evaluate the cardiac rhythm.
Other investigations are reserved for situations where the above collection of tests has not determined the cause of the hypercalcaemia, or if the location and nature of the malignancy needs to be established.
Artefactual hypercalcaemia can be caused by leaving the tourniquet on for too long before taking the blood. This problem should be borne in mind if a one-off sample shows hypercalcaemia when the clinical context is not congruent. A repeat sample can resolve the issue.
Treatment
Rehydration with 0.9% saline is the first step in the initial correction of hypercalcaemia, followed by intravenous loop diuretics (usually frusemide). Loop diuretics promote calcium excretion by the kidney. The patient's hydration and renal function should be monitored.
Biphosphonates inhibit the resorption of calcium from bone and are popular in the treatment in the hypercalcaemia of malignancy.
Calcitonin can be given.
Plicamycin is another agent that suppresses the release of calcium from bone.
Glucocorticoids may be effective in some malignancies, sarcoidosis and vitamin D intoxication. They do not work in primary hyperparathyroidism.
If an underlying cause is present, this should be treated if possible.