Relation between total and ionized plasma calcium
concentration
The plasma (or serum) calcium concentration measured in the laboratory is
usually reported in units of mg/dL in the United States. Some laboratories,
however, use different units of measurement. The relationship between these
units is related to the following equations:
mmol/L = [mg/dL x 10] ‖ mol
wt
meq/L = mmol/L x valence
Since the molecular weight of calcium is 40 and the valence is +2, 1 mg/dL is
equivalent to 0.25 mmol/L and to 0.5 meq/L. Thus, the normal range of total
plasma 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.
PLASMA CALCIUM CONCENTRATION ！ The total
plasma calcium concentration consists of three fractions [
1]:
• Approximately 15 percent is bound to multiple
organic and inorganic anions such as sulfate, phosphate, lactate, and citrate.
• About 40 percent is bound to albumin in a ratio
of 0.8 mg/dL (0.2 mmol/L or 0.4 meq/L) of calcium per 1.0 g/dL (10 g/L) of
albumin.
• The remaining 45 percent circulates as
physiologically active ionized (or free) calcium.
The ionized calcium concentration is tightly regulated by parathyroid hormone
and
vitamin
D. The wide range in the normal total plasma calcium concentration is
probably due to variations in the plasma concentration of albumin among normal
healthy individuals and to variations in the state of hydration that can alter
the albumin concentration.
The net effect is that measurement of the total plasma calcium concentration
alone can be misleading, since this parameter can change without affecting the
ionized fraction. This problem can occur in hypoalbuminemia and multiple
myeloma [
2]:
Hypoalbuminemia ！ The total calcium
concentration will change in parallel to the albumin concentration. Thus,
hypoalbuminemia due to hepatic or renal disease is associated with
hypocalcemia. On the other hand, dehydration or fluid movement out of the
vascular space due to a tight tourniquet can produce both an elevation in the
albumin concentration and pseudohypercalcemia [
3].
In comparison, globulins only minimally bind calcium and changes in the
globulin level are usually not associated with changes in the calcium
concentration with the occasional exception of marked hyperglobulinemia in
multiple myeloma.
In general, the plasma calcium concentration falls by 0.8 mg/dL (0.2 mmol/L)
for every 1.0 g/dL (10 g/L) fall in the plasma albumin concentration. The
measured plasma calcium concentration can be corrected for the presence of
hypoalbuminemia from the following equation:
Corrected [Ca] = Measured
total [Ca] + 0.8 x (4.5 - [alb])
where the plasma calcium and albumin concentrations are measured in units of
mg/dL and g/dL, respectively. Thus, if the measured values are 7.6 mg/dL and
2.5 g/dL:
Corrected [Ca] = 7.6 + 0.8 x 2 = 9.2
mg/dL
Multiple myeloma ！ Myeloma can induce
pseudohypercalcemia by a second mechanism. Rarely, a monoclonal myeloma
protein can bind calcium with high affinity, potentially leading to a marked
elevation in the plasma calcium concentration [
4,5,6].
The absence of hypercalcemic symptoms is the major clue suggesting that the
ionized fraction is normal in this setting and that therapy aimed at
correcting the hypercalcemia is not indicated. The hyperproteinemia in myeloma
can also cause a spurious elevation in the plasma phosphate concentration,
perhaps by interfering with the normal assay used to measure to plasma
phosphate concentration [
7].
On the other hand, physiologically important changes in ionized calcium can be
produced without change in the total calcium concentration by
altering the affinitity of albumin for calcium. Two factors can act by this
mechanism to change the amount of calcium bound: the extracellular pH and
parathyroid hormone (PTH).
Respiratory alkalosis ！ An elevation in
extracellular pH increases the binding of calcium to albumin, thereby lowering
the plasma ionized calcium concentration [
8].
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 [
8].
Thus, acute respiratory alkalosis, as in the hyperventilation syndrome, can
induce symptoms of hypocalcemia, including cramps, paresthesias, tetany, and
seizures. The alkaline pH may also contribute to these symptoms.
There is also a significant fall in the ionized calcium concentration in
chronic respiratory alkalosis. However, this abnormality is not due to
increased calcium binding, since the renal adaptation lowers the plasma
bicarbonate concentration and minimizes the rise in extracellular pH. (
See
"Simple and mixed acid-base disorders"). The hypocalcemia in
this setting is due both to relative hypoparathyroidism and to renal
resistance to PTH, with resultant hypercalciuria [
9].
Why these changes occur is not well understood.
Parathyroid hormone ！ Parathyroid hormone
decreases the binding of calcium to protein and therefore increases ionized
calcium at the expense of the protein bound fraction. As a result, patients
with hyperparathyroidism may have an elevated ionized but normal total calcium
concentration, a syndrome previously called "normocalcemic
hyperparathyroidism" [
10].
Acute hyperphosphatemia (as with phosphate release from cells with any cause
of a marked increase in cell breakdown) also can reduce ionized calcium by
binding to circulating calcium. The total 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").
SUMMARY ！ In the settings noted above,
measurement of the total plasma calcium concentration may not be sufficient to
determine the presence or absence of a disturbance in calcium homeostasis.
Thus, the plasma calcium concentration should be correlated with
simultaneously measured concentrations of albumin and phosphate. Direct
measurement of the ionized calcium concentration should be obtained in
patients with borderline hypercalcemia and in those with symptoms of
hypocalcemia but a normal total calcium concentration.