Normocalcaemic Primary Hyperparathyroidism

Normocalcaemic primary hyperparathyroidism is persistently raised parathyroid hormone with normal albumin adjusted and ionised calcium, after excluding every cause of secondary hyperparathyroidism.

Reported prevalence varies widely, from under 1% to several percent, depending on the population and the exclusions applied. It is often found during workup of osteoporosis or kidney stones.

A minority later develop hypercalcaemia over several years, and complications such as fracture or stones can occur at normal calcium.

Pathophysiology.

Early autonomous parathyroid function, or end organ resistance to parathyroid hormone, raises the hormone while calcium is held within range by the tissue response. Many patients have a hyperfunctioning adenoma.

Secondary causes are the main source of misdiagnosis, so exclusion comes first.

• Usually found on screening. Features overlap with primary hyperparathyroidism: osteoporosis, fragility fracture, kidney stones and fatigue.
• Hypercalcaemic symptoms are not present.

• Parathyroid hormone raised on at least two occasions over 3 to 6 months with normal albumin adjusted and ionised calcium.
• Exclude secondary causes: vitamin D deficiency (replace to at least 75 nmol/L, 30 ng/mL before accepting the diagnosis), eGFR under 60 mL/min, low calcium intake, malabsorption, renal calcium leak (hypercalciuria), and drugs (thiazide, loop diuretic, lithium, bisphosphonate, denosumab, phosphate).
• Phosphate, magnesium, 24-hour urinary calcium, DXA and renal imaging.
• Localisation imaging only if surgery is being considered.

Differential diagnosis.

• Secondary hyperparathyroidism (vitamin D deficiency, kidney disease, malabsorption, drugs).
• Idiopathic hypercalciuria with raised parathyroid hormone.
• Familial hypocalciuric hypercalcaemia (calcium eventually raised) and early primary hyperparathyroidism.

• Replace vitamin D and dietary calcium first, then repeat the tests.
• Most patients without osteoporosis, fracture, stones or progression are observed.
• Surgery is considered for osteoporosis, fragility fracture, kidney stones, nephrocalcinosis, hypercalciuria, or rising calcium and parathyroid hormone.
• Osteoporosis: alendronate 70 mg weekly or an alternative bone agent. Cinacalcet is not used while calcium is normal.
• Avoid thiazide diuretics. Correct dehydration.

Monitoring. Calcium, parathyroid hormone, creatinine and 25-hydroxyvitamin D yearly. DXA every 1 to 2 years. Renal imaging if symptoms develop.

Referral and escalation. Endocrinology; endocrine surgeon if a surgical indication appears.