From the Guidelines
Hypercalcemia is most commonly caused by primary hyperparathyroidism, where parathyroid glands produce excessive parathyroid hormone (PTH), leading to increased calcium absorption from bones and kidneys, as evident in the study by 1.
Etiology of Hypercalcemia
The etiology of hypercalcemia can be multifactorial, involving various conditions that disrupt the normal calcium homeostasis maintained by PTH, vitamin D, and calcitonin.
- Primary hyperparathyroidism is the most common cause, accounting for approximately 80% of cases, where a single parathyroid adenoma is usually the culprit, as noted in the study by 1.
- Malignancy is the second most common cause, either through direct bone destruction by metastatic tumors or through production of parathyroid hormone-related protein (PTHrP) by certain cancers like lung and breast cancer, as discussed in the study by 1.
- Other important causes include:
- Granulomatous diseases (sarcoidosis, tuberculosis) where activated macrophages produce excess vitamin D
- Medications (thiazide diuretics, lithium, excessive vitamin D or calcium supplements)
- Endocrine disorders (hyperthyroidism, adrenal insufficiency)
- Familial hypocalciuric hypercalcemia
- Immobilization in patients with high bone turnover
- Milk-alkali syndrome from excessive calcium and absorbable antacids
Underlying Mechanism
The underlying mechanism of hypercalcemia typically involves:
- Increased bone resorption
- Enhanced intestinal calcium absorption
- Decreased renal calcium excretion These mechanisms disrupt the normal calcium homeostasis, leading to elevated calcium levels in the blood, as explained in the study by 1. In clinical practice, it is essential to identify the underlying cause of hypercalcemia to provide appropriate treatment and prevent long-term complications, as emphasized in the study by 1.
From the FDA Drug Label
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts.
The etiology of hypercalcemia can be divided into two main groups:
- Humoral hypercalcemia: caused by factors such as parathyroid hormone-related protein, which stimulate osteoclasts and bone resorption
- Hypercalcemia due to tumor invasion of bone: caused by local tumor products that stimulate bone resorption by osteoclasts Key tumors associated with hypercalcemia include:
- Squamous cell malignancies of the lung or head and neck
- Genitourinary tumors such as renal cell carcinoma or ovarian cancer
- Breast cancer
- Multiple myeloma 2
From the Research
Hypercalcemia Etiology
Hypercalcemia can be caused by various factors, including:
- Primary hyperparathyroidism (PHPT) 3, 4, 5
- Malignancy 3, 4, 5
- Granulomatous disease such as sarcoidosis 3, 4
- Endocrinopathies such as thyroid disease 3, 4
- Immobilization 3, 4
- Genetic disorders 3
- Medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A 3, 4
- 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 causes 3
PTH-Dependent and PTH-Independent Causes
Hypercalcemia can be divided into PTH-mediated and PTH-independent variants:
- PTH-mediated causes include primary hyperparathyroidism, familial hypocalciuric hypercalcemia, familial hyperparathyroidism, and secondary hyperparathyroidism 5
- PTH-independent causes include malignancy-related hypercalcemia, which can be caused by direct osteolysis or production of humoral factors by the primary tumor 5
Diagnosis and Differential Diagnosis
The clinical laboratory plays a central role in the diagnosis and differential diagnosis of hypercalcemia, including:
- Measuring routine chemistry tests such as total calcium, phosphate, creatinine, and alkaline phosphate 4
- Quantification of ionized calcium, parathyroid hormone (PTH), and vitamin D metabolites 4
- Establishing accurate reference intervals for parathyroid hormone by excluding individuals who are vitamin D insufficient or deficient 4
- Harmonizing intact PTH immunoassays 4