27th February 2025

Increased PTH or PTHrP release

Primary hyperparathyroidism

Hypercalcaemia with an ‘inappropriately normal’ or raised PTH in a patient with normal renal function (i.e., tertiary hyperparathyroidism has been excluded) who does not take lithium points to a probable diagnosis of primary hyperparathyroidism (PHPT). Over 80% of cases are due to a solitary adenoma, with nodular hyperplasia and multiple adenomas forming most of the remainder. Parathyroid malignancy accounts for ≤1% of PHPT, usually with calcium and PTH levels far higher than typical PHPT. Gathering a family history is important as inherited conditions are implicated up to 10% with PHPT, with familial isolated hyperparathyroidism, multiple endocrine neoplasia (MEN), and hyperparathyroidism-jaw tumour syndrome (HPT-JT) the three most notable (all inherited in an autosomal dominant pattern).

Familial hypocalciuric hypercalcaemia

For a diagnosis of PHPT to be confirmed, familial hypocalciuric hypercalcaemia (FHH) must be excluded via urinary tests to rule out hypocalciuria (24-hour urinary calcium excretion, random renal calcium:creatinine excretion ratio, or random calcium:creatinine clearance ratio). In contrast to PHPT, however, FHH is almost always asymptomatic with little clinical significance and so is unlikely in symptomatic hypercalcaemia. This autosomal dominant condition occurs via an inactivating mutation in the calcium-sensing receptor (CaSR) gene, reducing receptor sensitivity to calcium. Higher than normal calcium levels are therefore required to suppress PTH secretion, and defective CaSR in renal tubules leads to increased reabsorption of calcium with subsequent hypocalciuria.

Hypercalcaemia of malignancy

Hypercalcaemia is seen in around 20% of cancer patients, with humoral hypercalcaemia of malignancy accounting for 80% of these. A history highly suspicious of cancer is often the primary concern when hypercalcaemia is incidentally noted. Given the limited physiological role of PTH-related protein (PTHrP), elevated PTHrP warrants urgent investigation for a causative malignancy. These are most often solid tumours, with lung primaries accounting for nearly 30% of cases. Negative feedback on PTH release results in a biochemical picture resembling PHPT except for a normal or low PTH rather than normal or raised.

Management of primary hyperparathyroidism

Referral to an endocrinologist is warranted in patients with PHPT if symptomatic, their serum calcium is ≥2.85 mmol/L, there is concurrent CKD stage ≥III, or they have developed renal stones or are at an increased risk of renal stones (e.g. obesity, gout, diabetes mellitus, Crohn’s disease, structural ureteric abnormalities).

Total or subtotal resection of the parathyroid glands is first-line in primary and tertiary hyperparathyroidism. If surgery is unsuccessful or not possible, calcimimetics such as cinacalcet can be used if serum calcium is >2.85 mmol/L with symptoms or >3.0 mmol/L regardless of symptoms, where it acts to increase CaSR sensitivity and, therefore, decrease PTH levels. Bisphosphonates are considered in moderate or severe hypercalcaemia refractory to IV fluids and in those with an increased risk of fractures.