In a large prospective cohort of over 106,000 individuals, elevated plasma ionized calcium levels were associated with markedly increased relative and absolute risks of developing primary hyperparathyroidism over 10 years. High ionized calcium (>1.40 mmol/L) conferred up to a 350-fold increased hazard and absolute 10-year risks as high as 44% in older women.
Background
Primary hyperparathyroidism is characterized by autonomous parathyroid hormone overproduction leading to hypercalcemia, with higher incidence in elderly and female populations. Although persistent hypercalcemia is commonly attributed to primary hyperparathyroidism in otherwise healthy individuals, robust population-based evidence supporting this is lacking. Prior studies often relied on total or albumin-adjusted calcium rather than ionized calcium, the physiologically active form. This study leverages ionized calcium measurements in a general population cohort to clarify the risk association with primary hyperparathyroidism.
Data Highlights
Ionized Calcium Level (mmol/L)
Number of Individuals
Hazard Ratio (95% CI)
10-year Absolute Risk in Women >65
10-year Absolute Risk in Men >65
Low Normal
Not specified
Reference
Not specified
Not specified
Moderately High (1.33-1.40)
2497 (2.5%)
65 (46-92)
7.9%
3.3%
High (>1.40)
Included in 2497
350 (251-489)
44%
21%
Key Findings
Among 106,588 individuals, 2.5% had moderately high or high plasma ionized calcium at baseline.
During follow-up, 0.4% were diagnosed with primary hyperparathyroidism.
Multivariable adjusted hazard ratios for primary hyperparathyroidism were 65 for moderately high and 350 for high ionized calcium compared to low normal levels.
Hazard ratios stratified by sex showed similarly elevated risks: up to 490 in men with high ionized calcium.
Absolute 10-year risks of primary hyperparathyroidism reached 44% in women over 65 with high ionized calcium.
High ionized calcium was found in approximately 1 in 40 individuals in the general population.
Clinical Implications
These findings underscore the importance of measuring ionized calcium in clinical practice for accurate assessment of calcium status. Incidentally detected elevated ionized calcium in otherwise healthy individuals warrants further diagnostic evaluation for primary hyperparathyroidism, especially in older adults. Early identification may facilitate timely management and reduce overlooked cases.
Conclusion
Elevated plasma ionized calcium is a strong predictor of primary hyperparathyroidism risk in the general population, with substantial relative and absolute risks demonstrated. Routine measurement and follow-up of high ionized calcium can improve detection of this underdiagnosed condition.
References
Copenhagen General Population Study, 2003-2015 -- Association of Elevated Ionized Calcium Levels with Primary Hyperparathyroidism Risk
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