How does adrenal insufficiency cause hypercalcemia?

From the Guidelines

Adrenal insufficiency can cause hypercalcemia due to the loss of cortisol's regulatory effects on calcium metabolism, leading to increased bone resorption, decreased renal calcium excretion, and increased intestinal calcium absorption, as noted in patients with primary adrenal insufficiency 1. The pathophysiology of hypercalcemia in adrenal insufficiency involves multiple mechanisms.

• Cortisol normally suppresses bone resorption, so its deficiency leads to increased osteoclast activity and release of calcium from bone into the bloodstream.
• Cortisol deficiency results in decreased renal calcium excretion, as cortisol typically promotes calcium elimination through the kidneys.
• Cortisol normally reduces intestinal calcium absorption, so its absence can increase calcium uptake from the gut. Additionally, volume depletion, which commonly occurs in adrenal insufficiency due to mineralocorticoid deficiency, leads to hemoconcentration that can further elevate measured serum calcium levels, as seen in 10% to 20% of patients with primary adrenal insufficiency who present with mild or moderate hypercalcemia 1. Treatment of hypercalcemia in adrenal insufficiency involves hormone replacement therapy with glucocorticoids, such as hydrocortisone 15-25 mg daily in divided doses, and mineralocorticoids, such as fludrocortisone 0.05-0.2 mg daily, as recommended for patients with primary adrenal insufficiency 2. Once appropriate hormone replacement is initiated, calcium levels typically normalize within days as these pathophysiological mechanisms are reversed.
• It is essential to monitor serum electrolytes, including calcium levels, during follow-up of patients with primary adrenal insufficiency, as recommended at least annually 2.
• The diagnosis of primary adrenal insufficiency should be considered in patients presenting with unexplained hypercalcemia, hypotension, vomiting, or diarrhea, and the diagnostic test for primary adrenal insufficiency should include paired measurement of serum cortisol and plasma ACTH 2.

From the Research

Adrenal Insufficiency and Hypercalcemia

• Adrenal insufficiency can cause hypercalcemia, although it is a rare and often underdiagnosed condition 3, 4, 5, 6, 7.
• The exact mechanisms of hypercalcemia in adrenal insufficiency are complex and not fully understood, but may involve decreased glomerular filtration rate and increased calcium reabsorption 3.
• Hypercalcemia can be a presenting feature of adrenal insufficiency, particularly in cases of acute adrenal crisis 7.
• Symptoms of hypercalcemia in the setting of adrenal insufficiency include fatigue, weakness, nausea, vomiting, constipation, abdominal pain, confusion, and dehydration 6.

Diagnosis and Treatment

• Diagnosis of adrenal insufficiency-related hypercalcemia requires a thorough clinical history and laboratory evaluation, including measurement of cortisol and adrenocorticotropic hormone (ACTH) levels 4, 5.
• Treatment typically involves correcting the underlying adrenal insufficiency with hormone replacement therapy, along with measures to lower calcium levels in the blood, such as hydration 3, 6.
• In some cases, hypercalcemia may resolve rapidly with treatment of the underlying adrenal insufficiency 5.

Clinical Considerations

• Adrenal insufficiency should be considered in the differential diagnosis of parathyroid hormone-independent hypercalcemia 4.
• A high index of suspicion is required to diagnose adrenal insufficiency-related hypercalcemia, as the symptoms can be non-specific and similar to those of other conditions 7.
• Early recognition and treatment of adrenal insufficiency-related hypercalcemia are crucial to prevent complications such as kidney damage, bone loss, and cardiac arrhythmias 6.