Normocalcemic primary hyperparathyroidism: an update on diagnostic and management challenges

Normocalcemic primary hyperparathyroidism (NPHPT) is defined by persistently elevated parathyroid hormone (PTH) levels in the presence of normal total and ionized serum calcium after excluding secondary causes of PTH elevation. Increasing use of biochemical screening has led to growing recognition of this phenotype, yet uncertainties remain regarding its natural history, diagnostic criteria, and optimal management.

NPHPT shares several clinical features with hypercalcemic primary hyperparathyroidism (HPHPT). Substantial rates of osteoporosis, fragility fractures, and nephrolithiasis are reported. Diagnosis requires repeated biochemical measurements, confirmation of normal ionized calcium, and rigorous exclusion of secondary causes such as vitamin D insufficiency, chronic kidney disease, malabsorption, and medication effects. Preoperative localization may also be more difficult than in HPHPT due to smaller adenomas and higher prevalence of multigland disease.

Parathyroidectomy appears safe and effective in selected individuals. However, NPHPT may carry a greater risk of recurrence than HPHPT. Improvements in bone mineral density (BMD) and quality of life (QOL) have been reported after surgery, although renal outcomes remain less certain.This review summarizes current evidence on the epidemiology, diagnosis, clinical manifestations, and management of NPHPT and highlights key areas requiring further study.