What are the etiologies of Hypercalcemia (elevated calcium levels)?

From the Guidelines

Hypercalcemia is most commonly caused by primary hyperparathyroidism and malignancy-associated hypercalcemia, with other significant etiologies including medications, granulomatous diseases, endocrine disorders, and excessive vitamin D intake or production, as supported by recent studies 1. The etiologies of hypercalcemia can be broadly categorized into parathyroid-mediated and non-parathyroid causes. Parathyroid-mediated causes include primary hyperparathyroidism, where parathyroid glands produce excessive parathyroid hormone, and tertiary hyperparathyroidism, which occurs in the context of renal failure. Non-parathyroid causes include malignancy-associated hypercalcemia, which occurs through direct bone destruction or production of parathyroid hormone-related protein, as well as other conditions such as granulomatous diseases, endocrine disorders, and excessive vitamin D intake or production. Some of the key etiologies of hypercalcemia include:

• Primary hyperparathyroidism, where parathyroid glands produce excessive parathyroid hormone 1
• Malignancy-associated hypercalcemia, which occurs through direct bone destruction or production of parathyroid hormone-related protein 1
• Medications, such as thiazide diuretics, lithium, and vitamin A derivatives 1
• Granulomatous diseases, such as sarcoidosis and tuberculosis 1
• Endocrine disorders, such as thyrotoxicosis and adrenal insufficiency 1
• Excessive vitamin D intake or production 1
• Immobilization, which can cause hypercalcemia in patients with high bone turnover 1
• Milk-alkali syndrome, which results from excessive calcium and absorbable alkali consumption 1
• Renal failure, which can lead to tertiary hyperparathyroidism 1 Measuring intact parathyroid hormone levels is essential in distinguishing parathyroid-mediated from non-parathyroid causes of hypercalcemia, as recommended by recent guidelines 1.

From the Research

Hypercalcemia Etiologies

• Hypercalcemia can be caused by various factors, including primary hyperparathyroidism (PHPT) and malignancy, which account for approximately 90% of cases 2
• 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 2
• 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, although these account for less than 1% of cases 2
• The etiology of hypercalcemia can be classified into PTH-dependent and PTH-independent causes, with serum intact parathyroid hormone (PTH) being the most important initial test to evaluate hypercalcemia 2

Classification of Hypercalcemia

• Hypercalcemia can be classified into mild, moderate, and severe, depending on calcium values, with mild hypercalcemia being usually asymptomatic and severe hypercalcemia causing nausea, vomiting, dehydration, confusion, somnolence, and coma 3
• The classification of hypercalcemia is important for determining the appropriate treatment, with mild cases often not requiring acute intervention and severe cases requiring immediate treatment 2

Pathophysiology of Hypercalcemia

• Calcium homeostasis is regulated by three factors: calcitonin, vitamin D, and parathyroid hormone (PTH) 3
• Various mechanisms are involved in the pathophysiology of hypercalcemia, including excessive PTH production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion 3
• The pathophysiology of hypercalcemia is complex and involves multiple factors, making it essential to identify the underlying cause of hypercalcemia and treat it accordingly 2, 3, 4, 5