Approach

Generally, evaluation of hypercalcaemia begins subsequent to an incidental report from blood analysis and is followed by a consideration of possible aetiologies.[10]

Clinical presentation

Important points to cover in the history include:

  • Bone pain: may suggest metastases in long bones

  • Renal stones: typical in hyperparathryoidism

  • Lethargy, easy fatigue

  • Confusion

  • Depression, irritability

  • Constipation: classic gastrointestinal symptoms may also be present (nausea, vomiting, abdominal pain, peptic ulcer disease, pancreatitis)

  • Polyuria, polydipsia

  • Weight loss: would identify malignancy as more likely than hyperparathyroidism

  • Timing of symptoms: chronic symptoms are more consistent with hyperparathyroidism, whereas recent onset of symptoms suggests malignancy

  • Drugs, including supplements and non-prescription drugs

  • Family history: hypocalciuric hypercalcaemia.

'Bones, stones, groans and moans' is a useful aide-memoire for some common symptoms of hypercalcaemia (bone pain, renal stones, abdominal pain, and psychiatric symptoms).[21]

Examination is usually not helpful in confirming the diagnosis.

Investigations

The most common causes of hypercalcaemia are primary hyperparathyroidism and malignancy, together accounting for 90% of cases.[2][10]

They can be distinguished by ordering a serum parathyroid hormone (PTH) level and a simultaneous repeat calcium test.

Total serum calcium is usually satisfactory but if there is an elevated or markedly depressed plasma protein concentration, the physiologically important fraction is ionised calcium. Normal serum or plasma total calcium should be 2.13 to 2.63 mmol/L (8.5 to 10.5 mg/dL); ionised calcium should be 1.15 to 1.27 mmol/L (4.6 to 5.1 mg/dL).[3]

PTH is elevated in primary hyperparathyroidism, despite elevated calcium indicating a disconnect between the regulating hormone and the ion. In malignancy, calcium is elevated either due to humoral abnormality with a PTH-related protein, or bone destruction in metastases.[14] In cases of malignancy, the PTH might be very low or barely detectable since the elevated calcium should inhibit PTH secretion.[22]

Step by step

Incidental hypercalcaemia

  • A history should be taken and calcium and PTH drawn simultaneously. If both are elevated, the cause is primary hyperparathyroidism. If PTH is normal to low in the face of hypercalcaemia, the most likely cause is malignancy.

Symptomatic metabolic bone disease

  • Bone imaging (including skeletal survey and x-rays of painful areas)

  • PTH measurement should be drawn simultaneously with calcium

  • Bone densitometry.

Coma

  • Investigations include calcium and electrolytes, glucose, urea, haematocrit, and an ECG. Calcium levels should be >3.25 mmol/L (>13 mg/dL) to explain coma. Hypercalcaemia may be a part of dehydration and not the direct or immediate cause of the diminished consciousness.

Primary hyperparathyroidism, if suspected, can be differentiated from familial hypocalciuric hypercalcaemia by measuring 24-hour urinary calcium excretion.[9]

Further tests to consider are: vitamin D levels for vitamin D intoxication; creatinine levels and kidney ultrasound for chronic renal failure and secondary hyperparathyroidism; and chest x-ray for sarcoidosis (if there are pulmonary symptoms, e.g., cough and dyspnoea).

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