How does calcium bind to albumin?

Calcium Binding to Albumin: Mechanism and Clinical Implications

Calcium binds to albumin through specific binding sites on the albumin molecule, with approximately 40% of total serum calcium being protein-bound (primarily to albumin) while the remaining calcium exists as ionized calcium (50%) or bound to organic and inorganic acids (8-10%). 1

Mechanism of Calcium-Albumin Binding

• Calcium binding to albumin occurs at specific binding sites on the albumin molecule
• Approximately 40% of total serum calcium is protein-bound (primarily to albumin) 1
• 50% of total serum calcium exists in the ionized form, representing the biologically active part 1
• 8-10% of serum calcium is bound to organic and inorganic acids 1

Calcium-Albumin Binding Ratio

The binding ratio of calcium to albumin is not fixed but varies inversely with albumin concentration:

• At lower albumin levels (1.7 g/dL), binding can be as high as 2.1 mg calcium/g albumin 2
• At higher albumin levels (3.1 g/dL), binding decreases to approximately 1.0 mg calcium/g albumin 2
• This variable binding ratio explains why fixed correction formulas can lead to clinical errors

Clinical Implications of Calcium-Albumin Binding

Correction Formulas

Traditional correction formulas assume a fixed binding ratio, but this assumption can lead to significant clinical errors:

• Standard formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] 3, 4
• Alternative formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.0704 × [34 - Serum albumin (g/L)] 3, 4

Limitations of Albumin-Adjusted Calcium

• Albumin-adjusted calcium can overestimate hypercalcemia and miss hypocalcemia in critically ill patients 5
• Using a fixed binding ratio (0.88 mg calcium/g albumin) can lead to major errors in estimating ultrafilterable calcium 2
• In hypoalbuminemic patients, correction formulas may give an erroneous impression of normocalcemia 2

Best Practice for Calcium Assessment

• Direct measurement of ionized calcium is recommended for accurate assessment of calcium status, especially in:
  • Patients with abnormal albumin levels
  • Critically ill patients
  • Patients with kidney disease 4, 5
• Ionized calcium is the biologically active form and represents approximately 50% of total serum calcium 1
• Normal ionized calcium range is 4.6-5.4 mg/dL (1.15-1.36 mmol/L) 4

Pitfalls to Avoid

• Relying solely on total calcium or albumin-adjusted calcium in critically ill patients 4, 5
• Using fixed binding ratio formulas for calcium correction in hypoalbuminemia 2, 6
• Treating low total calcium without confirming low ionized calcium 4
• Overlooking that the calcium binding ratio increases during hypoalbuminemia 2
• Failing to recognize that different analyzers may yield different correlations between albumin and ionized calcium 7

Recent research suggests that unadjusted total calcium may actually have better diagnostic accuracy than several commonly used adjustment formulas, particularly in patients with reduced kidney function (eGFR <60 mL/min/1.73 m²) 8.