What are the laboratory diagnostic criteria for Hypercalcemia (elevated calcium levels)?

From the Guidelines

Hypercalcemia is diagnosed through laboratory testing that reveals an elevated serum calcium level above 10.5 mg/dL (2.6 mmol/L), and the initial diagnostic approach should include measurement of total serum calcium, interpreted in the context of serum albumin levels, as well as ionized calcium measurement for a more accurate assessment of calcium status. The diagnostic approach to hypercalcemia involves several key steps, including:

• Measurement of total serum calcium, which should be interpreted in the context of serum albumin levels, since approximately 40% of calcium is bound to albumin 1.
• Adjustment of total calcium for every 1 g/dL decrease in albumin below 4 g/dL, by adding 0.8 mg/dL to the total calcium level.
• Ionized calcium measurement, which provides a more accurate assessment of calcium status, especially in patients with abnormal protein levels, and is considered the gold standard. Once hypercalcemia is confirmed, further laboratory evaluation should include:
• Intact parathyroid hormone (PTH) to distinguish between PTH-dependent causes (primary hyperparathyroidism) and PTH-independent causes (malignancy, granulomatous diseases) 1.
• 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, magnesium, blood urea nitrogen, creatinine, and alkaline phosphonate to evaluate for other potential causes of hypercalcemia. Additional tests may include PTH-related protein (PTHrP) if malignancy is suspected, serum and urine protein electrophoresis to evaluate for multiple myeloma, and thyroid function tests to rule out hyperthyroidism 1. Urinary calcium excretion over 24 hours can help differentiate familial hypocalciuric hypercalcemia from primary hyperparathyroidism 1. It is essential to base treatment on trends in laboratory values rather than a single abnormal result and to be cautious to avoid hypercalcemia when treating secondary hyperparathyroidism 1.

From the Research

Hypercalcemia Lab Diagnosis

• Hypercalcemia is defined as a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values 2.
• The diagnostic workup of hypercalcemia requires a thorough patient history, a focused clinical examination, as well as a step-by-step laboratory diagnostic approach 3.
• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 4.
• An elevated or normal PTH concentration is consistent with primary hyperparathyroidism (PHPT), while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause 4.

Causes of Hypercalcemia

• Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy 4, 3.
• Other causes of hypercalcemia include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A 4.
• Hypercalcemia has 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 4.

Laboratory Tests

• Measurement of serum calcium in correlation with the parathyroid hormone level is essential to detect the exact aetiology of hypercalcemia 3.
• Parathyroid hormone-related protein shares molecular mechanisms of action with PTH and is the most common cause of hypercalcemia of malignancy 5.
• Other laboratory tests, such as serum intact PTH, ionized calcium, and 24-hour urine calcium, may be useful in the evaluation of hypercalcemia 4, 2.