Normocalcaemic hyperparathyroidism: raised PTH with normal calcium

The parathyroid glands sit in the neck and control calcium levels in the blood by releasing parathyroid hormone (PTH). The NHS explains that hyperparathyroidism happens when the body produces too much PTH, and that the primary form is caused by a non-cancerous growth (adenoma) on the parathyroid glands. In classic primary hyperparathyroidism the calcium in the blood is high as well.

In the normocalcaemic form, calcium stays in the normal range while PTH is raised. The 2022 review in Archives of Endocrinology and Metabolism calls it a newer phenotype, first formally recognised at the Third International Workshop on asymptomatic primary hyperparathyroidism in 2008, and notes that it is increasingly diagnosed during evaluation for kidney stones or metabolic bone disease.

The review says the diagnosis is made in individuals with an elevated PTH on multiple occasions at least three months apart, with consistently normal calcium, and that it requires exclusion of secondary causes. These must be considered carefully because secondary causes of a raised PTH are common.

• Vitamin D deficiency, a common secondary cause, which can take months to resolve after treatment. The review notes that people with a classic form may become hypercalcaemic once vitamin D deficiency is corrected.

• Reduced kidney function, because PTH rises as the estimated glomerular filtration rate falls.

• Medicines, including bisphosphonates and denosumab, which can raise PTH by blocking calcium release from bone.

• Malabsorption, and excess calcium loss in the urine (hypercalciuria).

• Normal total calcium that is in fact slightly high when ionised calcium is measured. The review says 4% to 64% of people labelled normocalcaemic can be reclassified as having the classic form with ionised calcium testing.

NICE guideline NG132 is about primary hyperparathyroidism in general. It recommends measuring albumin-adjusted serum calcium for people with symptoms of hypercalcaemia such as thirst, frequent urination or constipation, osteoporosis or a previous fragility fracture, a renal stone, or an incidentally raised calcium of 2.6 mmol/litre or above. It recommends repeating abnormal measurements, and measuring PTH when the calcium is raised on at least two occasions, or at 2.5 mmol/litre or above with suspected primary hyperparathyroidism. Specialist advice is advised for certain PTH results.

NICE also says not to measure ionised calcium when testing for primary hyperparathyroidism, which differs from the approach described in the international review for normocalcaemic disease. For people with a probable diagnosis it recommends measuring vitamin D, and after a confirmed diagnosis, assessment of symptoms and comorbidities, kidney function, a DXA bone scan and a renal tract ultrasound. These points show how the investigation is organised, and whether normal-calcium disease is handled within the same pathway is a matter for your endocrinologist.

The NHS lists symptoms of hyperparathyroidism as tiredness, aches and pains, muscle weakness, feeling and being sick, loss of appetite, constipation, tummy pain, thirst, passing more urine and low mood, but notes that many people have no or very mild symptoms. Untreated hyperparathyroidism can lead to osteoporosis and kidney stones, among other complications.

For the normocalcaemic form, the review says the rates of bone and kidney complications differ between studies, probably because of the lack of rigorous diagnostic criteria and selection bias in the groups studied. In other words, it is not yet clear how much risk the condition carries on its own.

Because the natural history is unknown, management is individualised. The review says that bisphosphonates are presumed to be as effective in normocalcaemic disease as in other people with osteoporosis, and that antiresorptive treatment may be considered if there is osteoporosis or osteopenia with a raised fracture risk. Its authors give their opinion that using cinacalcet in normocalcaemic disease is unreasonable, given the small evidence available.

For surgery (parathyroidectomy), the review says the Fourth International Workshop recommended it if the person developed disease progression, such as worsening bone density, or new symptoms such as fractures or kidney stones, and a European Society of Endocrinology consensus stated that surgery should be considered only after experienced endocrine review and with compelling indications and a surgical target. The review also stresses that discussion should be individualised and take patient expectations into account.

Sensible steps in the meantime include checking vitamin D status, reviewing medicines and monitoring calcium, PTH, kidney function and bone density at intervals set by the specialist. The NHS advises that you should not change your diet to try to lower calcium unless a specialist tells you to, because this could make things worse.

See a GP if you develop thirst, passing more urine, constipation, bone pain, new tiredness or low mood, or if you have a fracture or kidney stone, because these can be signs of high calcium or bone and kidney complications. If you already have a diagnosis and your calcium rises, your endocrinology team will reassess the diagnosis, since the review notes that some people classified as normocalcaemic are later found to have the classic hypercalcaemic form.