In favor of more ionized-calcium measurement

The calcium present in blood plasma comprises two almost equal fractions: half is bound to albumin and the remainder is unbound, free ionized calcium. Only the free ionized calcium is physiologically active. There are two ways of assessing patient blood calcium status. 

The first – at one time the only available method – is to measure total calcium (unbound plus ionized calcium); and the second is to measure only the physiologically active, clinically important ionized calcium fraction (iCa). This second method, which was made possible by the relatively recent development of reliable calcium-specific electrodes, is utilized in point-of-care analyzers, including some blood gas analyzers. 

Measurement of total calcium (tCa) is more widely applied, being the method of choice in routine clinical laboratories. It has the advantage of being cheaper and more convenient for the high throughput of samples required in the routine clinical laboratory. 

The validity of measuring tCa as a proxy for the clinically significant iCa fraction depends crucially on the amount of calcium bound to albumin remaining constant in health and disease, so it is vital to correct the tCa result for abnormal plasma albumin concentration.

Current wisdom suggests that when this is done, there is clinically acceptable correlation between iCa and tCa, so that in most (but not all) clinical circumstance it is considered immaterial which method is used. A recent study was designed to test this widely held general view. 

The study population comprised 5490 ambulatory patients attending the outpatients department of a hospital in Perth, Western Australia for suspected bone or calcium metabolism disorder during 2006-2008. 

Blood was sampled from each for both tCa (albumin corrected) and iCa measurement. Discordance between tCa and iCa in classifying calcium status (i.e. normocalcemia, hypocalcemia or hypercalcemia) was evident in 12.6 % of cases overall, but discordance rates were much higher in hypercalcemia (49 % of cases only tCa or iCa increased) and in hypocalcemia (92 % of cases only tCa or iCa decreased).  

In a second part of the study investigators compared iCa and tCa in 143 patients with increased parathyroid hormone (PTH) and biopsy-proven primary hyperparathyroidism, the most common cause of hypercalcemia. In 107 (75 %) cases both iCa and tCa indicated hypercalcemia, but in 34 cases (24 %) only iCa was increased. 

In these 34 cases primary hyperparathyroidism would have been excluded on the basis of normal tCa. The authors of the study conclude that for accurate diagnosis of primary hyperparathyroidism and assessment of calcium status generally, measurement of ionized calcium is required. In discussion of their findings they consider the barriers that must be overcome for there to be more widespread use of iCa measurement.