PTH Responds to Ionized Calcium, Not Total Calcium
PTH secretion is directly regulated by ionized (free) calcium levels through the calcium-sensing receptor (CaR) on parathyroid chief cells, not by total calcium measurements. 1
Physiological Mechanism
Depression in serum levels of ionized calcium stimulates PTH secretion through the calcium-sensing receptor (CaR) in the parathyroid gland within seconds, triggering release of preformed PTH. 1
The calcium-sensing receptor on the parathyroid chief cell surface is the principal regulator of PTH synthesis and secretion, responding specifically to extracellular ionized calcium concentrations. 2
PTH biosynthesis increases over 24 to 48 hours following persistent hypocalcemia, eventually leading to parathyroid gland hypertrophy and hyperplasia if the stimulus continues. 1
Clinical Evidence Supporting Ionized Calcium as the Active Regulator
In hemodialysis patients, intact PTH proved most reliable in detecting changes in parathyroid hormone secretion in response to variations in ionized calcium induced by dialysis, demonstrating the direct ionized calcium-PTH relationship. 3
Dynamic testing in both normal volunteers and patients with secondary hyperparathyroidism showed that PTH levels respond directly and rapidly to changes in ionized calcium concentrations, with PTH rising 396% in normal subjects when ionized calcium decreased by 0.21 mmol/L during citrate infusion. 4
A hysteretic relationship exists between ionized calcium and intact PTH levels, where PTH responds differently depending on whether calcium is rising or falling, further confirming ionized calcium as the direct regulatory signal. 5
Why Total Calcium Measurements Are Used Clinically Despite This Physiology
Total calcium reflects ionized calcium levels when plasma protein concentrations are normal, making it a practical surrogate measure. 1
Ionized calcium measurement has worse reproducibility than total calcium, is more time-consuming, and more expensive, which is why clinical guidelines base recommendations on corrected total calcium. 1
When albumin is low, measured total calcium must be corrected using formulas such as: Corrected Ca = measured Ca + 0.8 × [4 - serum albumin (g/dL)]. 1
Critical Clinical Caveats
Acid-base status affects ionized calcium independent of total calcium: a fall in pH of 0.1 unit causes approximately 0.1 mEq/L rise in ionized calcium as hydrogen ions displace calcium from albumin, while alkalosis decreases free calcium by enhancing calcium-albumin binding. 1
Hyperphosphatemia leads to secondary hyperparathyroidism partly by lowering ionized calcium levels, not through effects on total calcium. 1
In patients with abnormal protein levels, complexed calcium, or acid-base disturbances, direct ionized calcium measurement should be obtained when subtle changes are expected or total calcium measurements are inadequate. 1
The calcium fraction distribution in blood is: 40% protein-bound, 48% free (ionized), and 12% complexed with anions (phosphate, lactate, citrate, bicarbonate). 1
Practical Implications for PTH Interpretation
When evaluating PTH levels, consider the ionized calcium concentration as the true physiologic regulator, even when using corrected total calcium for clinical decision-making. 1
In chronic kidney disease patients, free ionized calcium levels may be decreased despite normal total serum calcium due to increased calcium complexed with anions. 1
Calcimimetic agents like cinacalcet work by increasing calcium-sensing receptor sensitivity to extracellular ionized calcium, directly lowering PTH through the same ionized calcium-CaR pathway. 2