What is the difference between ionized calcium and serum calcium in clinical practice?

Difference Between Ionized Calcium and Serum Calcium in Clinical Practice

Ionized calcium is the biologically active form representing about 50% of total serum calcium, while serum (total) calcium includes both ionized calcium and calcium bound to proteins (primarily albumin) and anions, making ionized calcium measurement more clinically accurate for assessing true calcium status. 1, 2

Key Differences

Composition and Biological Activity

• Ionized calcium (iCa):

  • Represents approximately 50% of total serum calcium
  • Biologically active form that participates in physiological processes
  • Normal range: 1.15-1.36 mmol/L
  • Not affected by serum protein levels 1, 2

• Total serum calcium (tCa):

  • Includes:
    • Ionized calcium (50%)
    • Protein-bound calcium (primarily to albumin) (40%)
    • Calcium bound to organic and inorganic anions (8-10%) 2
  • Normal range: 8.5-10.5 mg/dL

Clinical Relevance

When to Measure Ionized Calcium

Ionized calcium measurement is preferred in:

• Critically ill patients
• Patients with altered protein levels (especially hypoalbuminemia)
• Acid-base disturbances (pH affects calcium binding to proteins)
• Suspected hypocalcemia with normal total calcium
• Post-surgical patients, especially after neck surgery
• Patients receiving massive transfusions
• Patients with 22q11.2 deletion syndrome 1

Impact of pH on Ionized Calcium

• An increase of 0.1 units in pH decreases ionized calcium by approximately 0.05 mmol/L
• Acidosis increases ionized calcium
• Alkalosis decreases ionized calcium 1

Clinical Discordance

Discordance between ionized and total calcium measurements is common:

• In patients with abnormal calcium states, total calcium frequently disagrees with ionized calcium in classifying calcium status 3
• Reliance on total calcium alone can miss up to 45% of cases with ionized hypercalcemia 3
• In primary hyperparathyroidism, 41% of cases may present with isolated ionized hypercalcemia with normal total calcium 3

Correcting Total Calcium for Albumin

When ionized calcium measurement is unavailable, total calcium should be corrected for albumin using:

• Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)]
• Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.0704 × [34 - Serum albumin (g/L)] 1

However, these formulas have limitations:

• Calculated surrogates for ionized calcium, including albumin-adjusted calcium, have consistently shown insufficient accuracy in detecting hypocalcemia 4
• Direct measurement of ionized calcium is superior to calculated surrogates, particularly in research settings and for detecting mild hypo- or hypercalcemia 4

Clinical Pitfalls

1. Hypoalbuminemia: Low albumin levels lead to decreased total calcium but may not affect ionized calcium, potentially masking normal calcium status if only total calcium is measured 1, 5

2. Acid-base disturbances: Changes in pH alter calcium binding to proteins, affecting ionized calcium levels without changing total calcium 1

3. Critical illness: In ICU settings, hypocalcemia is common but may reflect disease severity rather than a primary calcium disorder; attempted correction of low ionized calcium may not be beneficial and could potentially be harmful 6

4. Renal failure: In patients with chronic kidney disease, albumin-corrected calcium and ionized calcium measurements can lead to different calcium classifications, potentially affecting treatment decisions regarding vitamin D supplementation and phosphate binder selection 5

5. Transfusions: Massive blood transfusions can cause hypocalcemia due to citrate binding calcium, which may not be accurately reflected by total calcium measurements 1, 7

For accurate assessment of calcium status, especially in complex clinical scenarios, direct measurement of ionized calcium provides the most reliable information about the physiologically active calcium fraction.