How do I differentiate between primary hyperparathyroidism and malignancy as the cause of hypercalcaemia?

To differentiate between primary hyperparathyroidism and malignancy as causes of hypercalcaemia, the key diagnostic step is measuring parathyroid hormone (PTH) levels concurrently with albumin-adjusted serum calcium.

In primary hyperparathyroidism, PTH levels are typically elevated or inappropriately normal despite hypercalcaemia, whereas in malignancy-associated hypercalcaemia, PTH levels are usually suppressed (below the lower limit of the reference range) due to negative feedback from high calcium levels.

Specifically, measure albumin-adjusted serum calcium first; if elevated (≥2.6 mmol/L on at least two occasions), measure PTH concurrently. If PTH is above the midpoint of the reference range or inappropriately normal with hypercalcaemia, primary hyperparathyroidism is likely. If PTH is low with hypercalcaemia, malignancy or other causes should be considered and investigated further.

Additional investigations to support differentiation include assessing for symptoms and signs of malignancy, reviewing clinical context, and considering imaging or specialist referral. In malignancy, hypercalcaemia is often more severe and associated with symptoms requiring urgent management.

Referral to an endocrinologist is recommended if primary hyperparathyroidism is suspected, and urgent specialist assessment is needed if malignancy is suspected or hypercalcaemia is severe.