Relation between total and ionized serum calcium concentrations

INTRODUCTION — The plasma (or serum) calcium concentration is usually reported in units of mg/dL in the United States, in mmol/L in many other countries, and in mEq/L by some laboratories. The relationship between these units is defined by the following equations:

Since the molecular weight (Mol wt) of calcium is 40 and the valence is +2, 1 mg/dL is equivalent to 0.25 mmol/L and 0.5 mEq/L. Thus, the normal range of total serum calcium concentration of 8.8 to 10.3 mg/dL is equivalent to 2.2 to 2.6 mmol/L and 4.4 to 5.2 mEq/L.

DETERMINANTS OF THE SERUM CALCIUM CONCENTRATION — The total serum calcium concentration consists of three fractions [1,2]:

●Approximately 15 percent is bound to multiple organic and inorganic anions such as sulfate, phosphate, lactate, and citrate.

●Approximately 40 to 45 percent is bound to proteins, primarily albumin.

●The remaining 40 to 45 percent circulates as physiologically active ionized (or free) calcium. The ionized serum calcium concentration is tightly regulated by parathyroid hormone (PTH) and vitamin D, and can be modified by a variety of factors. (See 'Change in ionized fraction but not total calcium' below.)

The wide range in the normal total serum calcium concentration is probably due to variations in the serum concentration of albumin and variations in the state of hydration.

Thus, measurement of the total serum calcium concentration alone is frequently misleading since this parameter can change without affecting the concentration of ionized calcium [3]. In addition, the ionized fraction can change without an alteration in the total serum calcium concentration.

Change in total but not ionized calcium — An abnormal total serum calcium concentration in the presence of a normal ionized calcium concentration can occur in patients with hypoalbuminemia, hyperalbuminemia, and multiple myeloma. If the total serum calcium is low but the ionized calcium is normal, it is called pseudohypocalcemia. If the total serum calcium is high in the setting of a normal ionized calcium, it is called pseudohypercalcemia.

Hypoalbuminemia — The total serum calcium concentration will change in parallel to the albumin concentration. Thus, hypoalbuminemia due to hepatic or kidney disease is associated with hypocalcemia. By comparison, globulins only minimally bind calcium, and changes in the globulin level are usually not associated with dramatic changes in the calcium concentration, with the occasional exception of marked hyperglobulinemia in multiple myeloma.

In the setting of hypoalbuminemia, clinicians have attempted to estimate total serum calcium concentrations using a variety of correction formulas that take into account albumin concentrations. Traditionally, one of the most widely utilized equations to estimate the total calcium concentration in clinical practice assumes the serum calcium to fall by 0.8 mg/dL (0.2 mmol/L) for every 1.0 g/dL (10 g/L) fall in the serum albumin concentration. Thus, in this calculation, the measured serum calcium concentration would be corrected for the presence of hypoalbuminemia using the following equation, where the serum calcium (Ca) and albumin (Alb) concentrations are measured in units of mg/dL and g/dL, respectively:

Despite widespread use of this formula in clinical practice over the last several decades, more contemporary studies suggest the accuracy of this estimate is quite poor in a variety of populations, including patients hospitalized with critical illness and patients with advanced-stage chronic kidney disease (CKD) [4-10]. The poor performance of calcium-correction formulas in patients with critical illness and CKD may be partially explained by the presence of metabolic acidosis, which can lead to an underestimate of the ionized calcium (see 'Acid-base disorders' below). Alternative formulas have been developed to predict ionized calcium from a number of routine laboratory measurements [11-14]. While these newer strategies may provide improved accuracy over traditional methods of predicting ionized calcium, further validation of their efficacy in other clinical scenarios, institutions, and patient populations is necessary to justify their incorporation into routine clinical practice. Thus, based upon the potential inaccuracies of calcium-correction formulas, measurement of ionized calcium remains the gold standard for evaluating calcium status.

Hyperalbuminemia — An elevation in serum albumin, leading to a rise in serum calcium, can be induced by extracellular volume depletion or by fluid movement out of the vascular space due, for example, to a tight tourniquet [15]. Hyperalbuminemia has also been reported in athletes who consume very-high-protein diets (more than 2 g of protein per kg of body weight per day) [16].

Multiple myeloma — Myeloma can induce pseudohypercalcemia by a mechanism other than hyperalbuminemia. Rarely, a monoclonal myeloma protein binds calcium with high affinity, potentially leading to a marked elevation in the total serum calcium concentration [17-19]. Since multiple myeloma is commonly associated with true hypercalcemia related to osteolytic lesions, measurement of the ionized calcium can help to differentiate these entities. Likewise, the absence of hypercalcemic symptoms is often a major clue suggesting that the ionized fraction is normal in pseudohypercalcemia and that therapy aimed at correcting the hypercalcemia is not indicated.

The hyperproteinemia in myeloma can also cause a spurious elevation in the serum phosphate concentration [20]. The mechanism involves interference with the molybdate assay commonly used to measure the serum phosphate concentration.

Change in ionized fraction but not total calcium — Physiologically important changes in the ionized calcium concentration may occur without an alteration in the total serum calcium concentration.

Acid-base disorders — Acid-base disorders can lead to changes in the ionized calcium concentration. An elevation in extracellular pH (alkalemia) increases the binding of calcium to albumin, thereby lowering the serum ionized calcium concentration [21]. The fall in ionized calcium with acute respiratory alkalosis is approximately 0.16 mg/dL (0.04 mmol/L or 0.08 mEq/L) for each 0.1 unit increase in pH [21]. Thus, acute respiratory alkalosis, as in the hyperventilation syndrome, can induce symptoms of hypocalcemia, including cramps, paresthesias, tetany, and seizures, although the alkalosis is likely to be of primary importance. The same relationship is true in vitro when the pH is changed in specimens of whole blood or serum [22].

There is also a significant fall in the ionized calcium concentration in chronic respiratory alkalosis. However, the fall in ionized calcium in this setting is not due to increased calcium binding since the renal adaptation lowers the serum bicarbonate concentration and minimizes the rise in extracellular pH. The hypocalcemia in this setting is due both to relative hypoparathyroidism and to renal resistance to PTH, with resultant hypercalciuria [23]. Why these changes occur is not well understood. (See "Simple and mixed acid-base disorders".)

In chronic metabolic acidosis, the increase in ionized calcium due to less albumin binding may not be recognized by measurement of total calcium concentrations [4,5]. In one study, for example, the total serum calcium underestimated the diagnosis of hypercalcemia in incident kidney transplant recipients [5]. This was explained primarily by the high prevalence of metabolic acidosis in these patients.

The binding of calcium to albumin that is induced by an elevation in extracellular pH may be important in patients with severe CKD who often have both hypocalcemia and metabolic acidosis, which will tend to raise the ionized calcium concentration. Treatment of the metabolic acidosis with bicarbonate therapy or dialysis can lower the ionized calcium concentration [24,25], which may exacerbate preexisting hypocalcemia and precipitate symptoms such as tetany [25].

Parathyroid hormone — PTH may decrease the binding of calcium to albumin and therefore increase ionized calcium at the expense of the protein-bound fraction, resulting in an increased ratio of ionized to total calcium in patients with elevated levels of PTH [26]. On the other hand, the sensitivities of ionized and total calcium concentrations in the diagnosis of primary hyperparathyroidism were identical in a large cohort of patients [27], suggesting that this effect of PTH on protein binding of calcium does not have diagnostic implications. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Introduction'.)

Hyperphosphatemia — Acute hyperphosphatemia (as with phosphate release from cells due to a marked increase in cell breakdown) can reduce the ionized serum calcium concentration by binding to circulating calcium. The total serum calcium concentration will also fall in a short period of time as the calcium-phosphate precipitates and is deposited in soft tissues. (See "Etiology of hypocalcemia in adults".)

SUMMARY

●Determinants of the serum calcium concentration – The total serum calcium concentration consists of three fractions (see 'Determinants of the serum calcium concentration' above):

•15 percent is bound to organic and inorganic anions.

•40 to 45 percent is bound to albumin.

•40 to 45 percent is physiologically active ionized (or free) calcium.

●Change in total but not ionized calcium – Measurement of the total serum calcium concentration alone is often misleading; thus, measurement of ionized calcium remains the gold standard for assessing calcium status. Clinical scenarios in which total calcium can change without affecting the concentration of ionized calcium include:

•Hypoalbuminemia because a large fraction of calcium circulates while bound to albumin

•Hyperalbuminemia, as may occur with extracellular volume depletion or by fluid movement out of the vascular space due to a tight tourniquet, and can also result from a very-high-protein diet

•Some cases of multiple myeloma, in which calcium binds to the monoclonal immunoglobulin (see 'Multiple myeloma' above)

●Change in ionized fraction but not total calcium – The ionized fraction can change without an alteration in the total serum calcium concentration, as with:

•Acid-base disorders, in which an increase in blood pH may enhance binding of calcium to albumin, thereby decreasing the ionized fraction (see 'Acid-base disorders' above)

•Hyperparathyroidism, which increases the ionized calcium at the expense of that bound to albumin (see 'Parathyroid hormone' above)

•Hyperphosphatemia, which increases the fraction bound to inorganic anions, decreasing ionized calcium (see 'Hyperphosphatemia' above)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to an earlier version of this topic review.