Should hypercalcemia be a concern if ionized calcium levels are within normal limits?

From the Guidelines

If ionized calcium is normal, you generally do not need to be concerned about an abnormal total serum calcium level. Ionized calcium is the physiologically active form that matters most clinically, representing about 50% of total calcium in the blood. When ionized calcium is normal but total serum calcium is abnormal (either high or low), the discrepancy is usually due to changes in albumin levels or acid-base status affecting protein binding. For example, low albumin can cause falsely low total calcium readings while ionized calcium remains normal. Similarly, changes in blood pH can alter calcium binding to proteins without affecting the ionized fraction. This is why many clinicians prefer measuring ionized calcium directly when evaluating calcium disorders, as supported by the K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease 1. However, if clinical symptoms of calcium imbalance exist despite normal ionized calcium, further investigation may still be warranted to rule out rapid changes in calcium homeostasis or laboratory error. In most cases though, a normal ionized calcium level provides reassurance that calcium-dependent physiological functions are intact regardless of total serum calcium values. Some key points to consider include:

• The importance of maintaining normal serum levels of corrected total calcium, as hypocalcemia can cause secondary hyperparathyroidism and have adverse effects on bone mineralization 1.
• The need to avoid high calcium intake, as it can lead to hypercalcemia and soft-tissue calcification, particularly in patients with chronic kidney disease (CKD) 1.
• The use of calcium infusion and oral calcium supplements to maintain normal ionized calcium levels, with adjustments as necessary to prevent hypercalcemia or hypocalcemia 1.
• The consideration of dialysate calcium concentration in patients with CKD, with a typical concentration of 2.5 mEq/L, but with potential adjustments based on individual patient needs and response to treatment 1.

From the FDA Drug Label

Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations

If ionized calcium is normal, you should still be concerned about serum calcium because total serum calcium levels may not reflect the severity of hypercalcemia due to concomitant hypoalbuminemia.

• Ionized calcium levels are ideal for diagnosing and following hypercalcemic conditions, but if they are normal, it does not necessarily rule out hypercalcemia of malignancy.
• Corrected serum calcium (CSC) may be used in place of ionized calcium measurement, taking into account differences in albumin levels 2.

From the Research

Ionized Calcium and Serum Calcium Concerns

• If ionized calcium is normal, the concern about serum calcium may be minimal, as ionized calcium is the biologically active form of calcium and is often measured in patients admitted to ICUs 3.
• However, abnormal values of ionized calcium are likely a marker of disease severity in critical illness and most often normalize spontaneously with resolution of the primary disease process 3.
• In some cases, low ionized calcium levels in critical illness may be protective, and attempted correction of low levels may be harmful 3.

Diagnosis and Management of Hypocalcemia

• Hypocalcemia is a condition where serum calcium levels are low, and it can be caused by various disorders, including parathyroid hormone (PTH) and non-PTH mediated disorders 4.
• The diagnosis and management of hypocalcemia involve measuring serum calcium levels, identifying the underlying cause, and providing appropriate treatment, such as intravenous calcium infusion or oral calcium and vitamin D supplementation 4.

Vitamin D Supplementation and Hypercalcemia

• Vitamin D supplementation can exacerbate hypercalcemia, nephrolithiasis, and renal impairment in patients with granulomatous disease, and therefore, it should be used with caution in these patients 5.
• The formation of granulomas can lead to the conversion of inactive vitamin D to active vitamin D, causing significant hypercalcemia and derivative disease 5.

Ionized Calcium Measurement

• The optimal specimen type for measuring ionized calcium is whole blood, either with balanced heparin (BH) or lithium heparin (LH) 6.
• The reference interval for serum is similar to that of whole blood, but the reference interval for plasma is dramatically lower 6.
• pH adjustment of ionized calcium measurements should be used with caution, as it can introduce bias and affect the accuracy of the results 6.