High Ionized Calcium in the General Population and Risk of Primary Hyperparathyroidism

Although it is generally held that in otherwise healthy individuals, primary hyperparathyroidism is the most likely cause of persistent hypercalcemia, solid research supporting this assumption is absent. We aimed to examine the relative and absolute risk of primary hyperparathyroidism associated with an incidental high ionized calcium in the general population.

We used the Danish Copenhagen General Population Study, a prospective cohort study with inclusion in 2003-2015, to investigate the association of ionized calcium on continuous and categorical scales with primary hyperparathyroidism using Cox regression and competing-risk regression. Hazard ratios and absolute 10-year risks of primary hyperparathyroidism were calculated.

In 106 588 individuals, 2497 (2.5%) had moderately high (1.33-1.40 mmol/L) or high (>1.40 mmol/L) plasma ionized calcium at baseline and 441 (0.4%) were diagnosed with primary hyperparathyroidism during follow-up. The multivariable adjusted hazard ratios for primary hyperparathyroidism for moderately high and high plasma ionized calcium vs low normal ionized calcium were 65 (95% confidence interval: 46-92) and 350 (251-489). Stratified on sex, the corresponding hazard ratios were 63 (42-95) and 326 (221-482) for women and 73 (37-145) and 490 (256-935) for men. For women and men above 65 years, absolute risks of primary hyperparathyroidism were 7.9% and 3.3% in those with moderately high plasma ionized calcium and 44% and 21% in those with high plasma ionized calcium.

High ionized calcium found in 1:40 in the general population conferred absolute 10-year risks of primary hyperparathyroidism of up to 44%. These findings support further diagnostic workup following an incidentally observed high plasma ionized calcium in otherwise healthy individuals.