What is the etiology of hypercalcemia and elevated vitamin D levels?

From the Guidelines

Hypercalcemia with elevated vitamin D levels is most commonly caused by excessive vitamin D supplementation, granulomatous disorders, lymphomas, and certain endocrine disorders, with management focusing on discontinuing vitamin D supplements, hydration, and treating the underlying condition. The etiology of elevated hypercalcemia and vitamin D levels can be multifactorial, including excessive vitamin D supplementation, granulomatous disorders like sarcoidosis and tuberculosis, lymphomas, and certain endocrine disorders. Vitamin D toxicity typically occurs with serum 25-hydroxyvitamin D levels above 150 ng/mL, usually from taking high-dose supplements (>10,000 IU daily for extended periods) 1.

Key Considerations

• Excessive vitamin D supplementation can lead to increased intestinal calcium absorption and bone resorption, resulting in hypercalcemia.
• Granulomatous diseases, such as sarcoidosis, can cause activated macrophages to produce 1,25-dihydroxyvitamin D outside of normal regulatory control, leading to hypercalcemia.
• Lymphomas can also produce 1,25-dihydroxyvitamin D autonomously, contributing to elevated calcium levels.
• Primary hyperparathyroidism can cause hypercalcemia with normal or slightly elevated vitamin D levels.

Management and Treatment

• Discontinuing vitamin D supplements is a crucial step in managing hypercalcemia with elevated vitamin D levels.
• Increasing hydration and limiting dietary calcium can help reduce calcium levels.
• Treating the underlying condition, whether it be a granulomatous disorder, lymphoma, or endocrine disorder, is essential for resolving hypercalcemia.
• In severe cases, medications like bisphosphonates, calcitonin, or glucocorticoids may be necessary to rapidly lower calcium levels, as seen in studies such as the PRIMO trial which highlighted the risks of hypercalcemia with paricalcitol treatment 1.

Monitoring and Follow-Up

• Regular measurements of calcium and vitamin D levels are necessary to monitor the effectiveness of treatment and ensure that levels normalize.
• The pathophysiology of hypercalcemia with elevated vitamin D involves excessive vitamin D promoting increased intestinal calcium absorption and bone resorption, which can overwhelm the kidney's ability to excrete calcium, resulting in hypercalcemia, a condition that can be managed with appropriate treatment and monitoring 1.

From the FDA Drug Label

Hypercalcemia associated with cancer The FDA drug label does not answer the question.

From the Research

Etiology of Elevated Hypercalcemia and Elevated Vitamin D

• Hypercalcemia can be caused by various factors, including primary hyperparathyroidism, malignancy, granulomatous disease, and excessive intake of vitamin D or calcium supplements 2, 3, 4, 5
• Elevated vitamin D levels can lead to hypercalcemia due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor 6, 5
• The pathophysiology of hypercalcemia from vitamin D intoxication results from the long-term effects of vitamin D storage in adipose tissue 6
• Hypercalcemia can also occur as a result of ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D] or impaired degradation of 1,25(OH)2D 5

Causes of Hypercalcemia

• Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia, accounting for approximately 90% of cases 2, 4
• Malignancy is another common cause of hypercalcemia, often associated with elevated levels of parathyroid hormone-related protein (PTHrp) 2, 3
• Granulomatous disease, such as sarcoidosis, can also cause hypercalcemia due to the ectopic production of 1,25(OH)2D 3, 5
• Excessive intake of vitamin D or calcium supplements can lead to hypercalcemia, particularly in individuals with impaired renal function or other underlying medical conditions 2, 6, 5

Diagnosis and Treatment

• The diagnosis of hypercalcemia involves measuring serum calcium levels, parathyroid hormone (PTH) levels, and other biochemical markers 2, 3, 4
• Treatment of hypercalcemia depends on the underlying cause and severity of the condition, and may involve hydration, bisphosphonates, glucocorticoids, and other medications 2, 3, 6, 4