Why is hypercalcemia associated with high albumin levels?

Relationship Between Albumin and Calcium Levels

High albumin levels can cause falsely elevated total serum calcium values due to the binding relationship between calcium and albumin, necessitating the use of correction formulas to determine the true calcium status. 1

Physiological Basis

Calcium in the blood exists in three forms:

• Ionized calcium (biologically active form): ~50%
• Protein-bound calcium (primarily to albumin): ~40%
• Complexed with anions: ~10%

When albumin levels are elevated, more calcium becomes protein-bound, leading to an increase in total serum calcium while ionized calcium (the physiologically active form) remains normal. This creates a laboratory artifact rather than a true hypercalcemic state.

Correction Formulas

The relationship between albumin and calcium is so significant that standard laboratory practice includes formulas to adjust total calcium based on albumin levels:

• Standard correction formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] 1

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

These formulas help clinicians distinguish between true hypercalcemia (elevated ionized calcium) and pseudohypercalcemia due to high albumin levels.

Clinical Implications

Diagnostic Considerations

• Without albumin correction, hypercalcemia may be overdiagnosed in patients with high albumin levels 2, 3
• Conversely, true hypercalcemia may be masked in patients with hypoalbuminemia 4
• In one study, 79% of apparently abnormal calcium values were actually normal after albumin adjustment 4

Monitoring Considerations

• Albumin-adjusted calcium provides more stable measurements for monitoring patients over time
• The within-person standard deviation for calcium measurements decreases from 0.148 mmol/L to 0.100 mmol/L when adjusted for albumin 4

Best Practices for Calcium Assessment

1. Measure ionized calcium when available, as it's the gold standard for assessing calcium status 5
2. Always adjust total calcium for albumin when ionized calcium is unavailable 1
3. Be aware of the method used to measure albumin, as different methods (colorimetric vs. electrophoretic) can yield different corrected calcium values 2
4. Consider the clinical context when interpreting calcium values, especially in conditions that affect protein binding (e.g., pH changes)

Pitfalls to Avoid

• Don't rely solely on total calcium values without considering albumin levels
• Don't assume hypercalcemia based on total calcium alone in patients with elevated albumin
• Don't overlook true hypercalcemia in patients with hypoalbuminemia, as low albumin can mask elevated calcium 4
• Be cautious with correction formulas in extreme cases of hypo- or hyperalbuminemia, as the relationship may not be perfectly linear at extremes

By understanding the relationship between albumin and calcium, clinicians can avoid misdiagnosis of calcium disorders and ensure appropriate management based on the patient's true calcium status.