What does hypercalcemia indicate?

From the Guidelines

A high serum calcium level typically indicates primary hyperparathyroidism, where overactive parathyroid glands secrete excessive parathyroid hormone, and can also be caused by malignancy, certain medications, granulomatous diseases, prolonged immobilization, and endocrine disorders. The most common cause of hypercalcemia is primary hyperparathyroidism, which occurs when parathyroid glands autonomously overproduce parathyroid hormone (PTH), typically resulting in hypercalcemia 1. Other significant causes of hypercalcemia include:

• Malignancy (particularly lung, breast, and blood cancers)
• Certain medications (thiazide diuretics, lithium, excessive vitamin D or calcium supplements)
• Granulomatous diseases like sarcoidosis
• Prolonged immobilization
• Endocrine disorders such as hyperthyroidism or adrenal insufficiency Symptoms of hypercalcemia may include:
• Fatigue
• Weakness
• Confusion
• Bone pain
• Kidney stones
• Increased urination
• Cardiac abnormalities Diagnosis requires confirmation with repeat testing and evaluation of parathyroid hormone levels, vitamin D status, and screening for malignancy 1. Treatment depends on the underlying cause and calcium level severity, ranging from increased hydration and discontinuation of contributing medications to bisphosphonates, calcitonin, or surgery for parathyroid adenomas. Severe hypercalcemia (>14 mg/dL) constitutes a medical emergency requiring immediate intervention to prevent serious complications like cardiac arrhythmias or coma. It is essential to avoid hypercalcemia in patients with chronic kidney disease (CKD) stages G3a to G5D, as higher serum calcium concentrations have been linked to increased mortality and nonfatal cardiovascular events 1.

From the FDA Drug Label

Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present.

A high serum calcium level, also known as hypercalcemia, can indicate:

• Malignancy: Hypercalcemia is often associated with malignancies, such as breast cancer, squamous-cell tumors of the lung or head and neck, renal-cell carcinoma, and certain hematologic malignancies.
• Bone resorption: Excessive bone resorption can lead to an increase in serum calcium levels.
• Dehydration: Progressive dehydration can contribute to worsening hypercalcemia.
• Renal impairment: Decreasing glomerular filtration rate can lead to increased renal resorption of calcium, exacerbating hypercalcemia. It is essential to note that total serum calcium levels may not accurately reflect the severity of hypercalcemia due to concomitant hypoalbuminemia. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions 2.

From the Research

High Serum Calcium Indications

A high serum calcium level, also known as hypercalcemia, can indicate several conditions. The following are some possible indications of high serum calcium:

• Primary hyperparathyroidism (PHPT) 3, 4, 5, 6, 7
• Malignancies 3, 5
• Granulomatous disease such as sarcoidosis 5
• Endocrinopathies such as thyroid disease 5
• Immobilization 5
• Genetic disorders 5
• Medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A 5
• Sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise 5

Hypercalcemia Classification

Hypercalcemia can be classified into three categories:

• Mild hypercalcemia: total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L) 5
• Moderate hypercalcemia: total calcium of 12-14 mg/dL (3-3.5 mmol/L) or ionized calcium of 8.0-10 mg/dL (2-2.5 mmol/L) 5
• Severe hypercalcemia: total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) 5

Clinical Manifestations

Clinical manifestations of hypercalcemia can vary depending on the severity of the condition. Some possible symptoms include:

• Fatigue 5
• Constipation 5
• Nausea 5
• Vomiting 5
• Dehydration 5
• Confusion 5
• Somnolence 5
• Coma 5
• Skeletal fragility 4, 6, 7
• Nephrolithiasis 4, 6, 7
• Nephrocalcinosis 4, 6, 7