What is the evaluation of hypercalcemia (elevated calcium levels)?

From the Guidelines

Evaluation of high calcium should prioritize avoiding hypercalcemia, especially in patients with chronic kidney disease (CKD), as it may be harmful in all GFR categories, and treatment approaches should focus on maintaining calcium levels while addressing elevated parathyroid hormone levels, as recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) 2017 clinical practice guideline update 1.

Key Considerations

• Hypercalcemia may be harmful in all GFR categories of CKD, prompting the recommendation to avoid inappropriate calcium loading in adults whenever possible 1.
• Treatment approaches for CKD–MBD should be based on serial assessments of biochemical variables (serum phosphate, calcium, and PTH) taken together 1.
• The current recommendation is to treat patients with PTH values that are progressively increasing or persistently above the upper limit of normal and not to base treatment on a single elevated value 1.
• Calcimimetics, calcitriol, and vitamin D analogues are acceptable first-line options in patients receiving dialysis, while treatment approaches for SHPT in patients not receiving dialysis should not include routine use of calcitriol or vitamin D analogues due to the increased risk for hypercalcemia 1.

Diagnostic Approach

• Evaluation of high calcium should begin with confirmation through repeat testing, as values above 10.5 mg/dL require investigation.
• Measuring parathyroid hormone (PTH) levels is crucial to distinguish between PTH-dependent causes (like primary hyperparathyroidism) and PTH-independent causes (such as malignancy).
• Additional first-line tests include comprehensive metabolic panel, phosphorus, magnesium, 25-hydroxyvitamin D, and urinary calcium excretion.

Treatment

• Severe hypercalcemia (>12 mg/dL) requires urgent treatment with IV fluids, calcitonin, bisphosphonates, or denosumab depending on severity, while addressing the underlying cause.
• Family history should be obtained to identify potential hereditary disorders like Multiple Endocrine Neoplasia.
• A systematic approach, considering the patient's overall clinical context and the potential risks and benefits of treatment, ensures proper diagnosis and management of hypercalcemia.

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

In the absence of a direct measurement of free-ionized calcium, measurement of the serum albumin concentration and correction of the total serum calcium concentration may help in assessing the severity of hypercalcemia.

To evaluate high calcium, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions. However, if ionized calcium levels are not available, total serum calcium levels can be used, and it is essential to correct for albumin levels to accurately assess the severity of hypercalcemia 2.

• Serum albumin concentration should be measured to correct total serum calcium levels.
• Corrected serum calcium levels can help assess the severity of hypercalcemia. In patients with hypercalcemia of malignancy, correction of excessive bone resorption and adequate fluid administration are essential to manage hypercalcemia 2.
• Adequate fluid administration is necessary to correct volume deficits.
• Correction of excessive bone resorption can help decrease serum calcium levels.

From the Research

Causes of Hypercalcemia

• Primary hyperparathyroidism and malignancy are responsible for greater than 90% of all cases of hypercalcemia 3, 4, 5
• Other causes of hypercalcemia include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements like calcium, vitamin D, or vitamin A 5
• Hypercalcemia has also been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes 5

Symptoms of Hypercalcemia

• Mild hypercalcemia is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people 5
• Severe hypercalcemia can cause nausea, vomiting, dehydration, confusion, somnolence, and coma 5
• Hypercalcemia of malignancy is typically rapid in onset, with higher serum calcium levels, and more severe symptoms 3

Diagnosis of Hypercalcemia

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 5
• An elevated or normal PTH concentration is consistent with primary hyperparathyroidism, while a suppressed PTH level indicates another cause 5

Treatment of Hypercalcemia

• Mild hypercalcemia usually does not need acute intervention, but may be managed with parathyroidectomy or observation with monitoring 5
• Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 3, 4, 6, 5
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas) 3, 5
• Denosumab and dialysis may be indicated in patients with kidney failure 5, 7