What Causes Hypercalcemia? Understanding the Underlying Factors Behind Elevated Calcium Levels

Hypercalcemia, a condition characterized by abnormally high levels of calcium in the blood, can lead to a range of health complications if left untreated. While mild cases may go unnoticed, more severe forms can impact bone health, kidney function, and even cardiovascular and neurological systems. Understanding the root causes is essential for timely diagnosis and effective management.

Primary Causes of Hypercalcemia

Elevated calcium levels in the bloodstream are not a standalone disease but rather a symptom of underlying medical conditions. Several key factors contribute to the development of hypercalcemia, with varying degrees of prevalence and severity.

1. Primary Hyperparathyroidism (PTH-Dependent Hypercalcemia)

This is the most common cause of hypercalcemia, particularly in outpatient settings. It occurs when one or more of the parathyroid glands become overactive and secrete excessive parathyroid hormone (PTH), which increases calcium release from bones, enhances calcium reabsorption in the kidneys, and boosts intestinal calcium absorption via vitamin D activation.

Primary hyperparathyroidism can be categorized into two main types: sporadic (occurring without family history) and familial (inherited forms such as in multiple endocrine neoplasia syndromes). Women over the age of 50 are at higher risk, and the condition often progresses slowly, sometimes being detected incidentally during routine blood tests.

2. Malignancy-Related Hypercalcemia

Cancer is the second leading cause of hypercalcemia and is typically associated with more acute and severe symptoms. There are several mechanisms through which malignancies elevate calcium levels:

Osteolytic hypercalcemia: Occurs when cancer spreads to bones (metastases), causing bone breakdown and releasing calcium into the bloodstream.
Humoral hypercalcemia of malignancy: Tumors (especially lung, head, and neck cancers) secrete substances like PTH-related peptide (PTHrP), which mimic the action of PTH.
Production of ectopic PTH: Rarely, some tumors produce actual parathyroid hormone, further disrupting calcium balance.

This form of hypercalcemia is considered a medical emergency and requires prompt treatment to prevent organ damage.

3. Endocrine Disorders

Several hormonal imbalances can indirectly influence calcium metabolism and contribute to hypercalcemia. These include:

Hyperthyroidism: Excess thyroid hormone accelerates bone turnover, leading to increased calcium release.
Pheochromocytoma: This rare adrenal tumor may affect calcium regulation through catecholamine-induced bone resorption.
Adrenal insufficiency: Low cortisol levels can reduce renal calcium excretion.
Acromegaly: Growth hormone excess has been linked to elevated calcium levels in some patients.
VIPomas: Tumors secreting vasoactive intestinal peptide can disrupt electrolyte balance, including calcium.

Managing the underlying endocrine condition often helps normalize calcium levels.

4. Granulomatous Diseases

Conditions involving granuloma formation can lead to dysregulated vitamin D metabolism. In these diseases, activated immune cells within granulomas produce 1,25-dihydroxyvitamin D (the active form) independently of normal regulatory mechanisms, resulting in increased intestinal calcium absorption.

The most notable examples include:

Sarcoidosis (most common)
Tuberculosis
Wegener's granulomatosis (now known as granulomatosis with polyangiitis)
Leprosy and other chronic infections

Patients with sarcoidosis should be monitored regularly for signs of hypercalcemia, especially when exposed to sunlight or taking vitamin D supplements.

5. Medication-Induced Hypercalcemia

Certain drugs can significantly alter calcium homeostasis. The most well-known culprit is vitamin D toxicity, often due to excessive supplementation, leading to uncontrolled calcium absorption from the gut.

Other medications associated with elevated calcium levels include:

Thiazide diuretics: Reduce calcium excretion by the kidneys.
Lithium carbonate: Used in bipolar disorder, it increases PTH secretion and reduces calcium sensitivity in the parathyroid glands.
Estrogens and anti-estrogen therapies: Can influence bone metabolism, especially in postmenopausal women.
Androgens and anabolic steroids: May increase bone resorption in certain cases.
Theophylline: A bronchodilator that may interfere with calcium regulation.
Growth hormone therapy: Long-term use has been linked to mild hypercalcemia in some individuals.

It's crucial for healthcare providers to review all medications during the evaluation of unexplained hypercalcemia.

Conclusion

Hypercalcemia arises from a complex interplay of physiological and pathological processes. While primary hyperparathyroidism and malignancy top the list of causes, endocrine disorders, granulomatous diseases, and certain medications also play significant roles. Early recognition, accurate diagnosis, and targeted treatment are vital to preventing long-term complications such as kidney stones, osteoporosis, arrhythmias, and cognitive disturbances. If you experience symptoms like fatigue, nausea, confusion, or frequent urination, consult a healthcare professional for proper evaluation.