What is the pathophysiology of hypercalcemia associated with malignancy?

Updated: Apr 29, 2020
  • Author: Thomas E Green, DO, MPH, MMM, CPE, FACEP, FACOEP; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Malignancy-associated hypercalcemia occurs in up to 20-30% of patients at some course within their disease. Most episodes occur with advanced disease and patients typically have a poor prognosis (with up to a 50% 30-day mortality). There are two generally recognized forms of this disorder, one in which hypercalcemia is the result of tumor secretion of a humoral factor (usually PTHrP) and one is the result of excessive bone metastases. [9] Common malignancies include multiple myeloma, breast cancer, or lung cancer. Multiple factors for osteolysis are responsible for this action, which is produced by or in response to the myeloma cells in the marrow. These are collectively referred to osteoclast-activating factors. [10]

Multiple endocrine neoplasia (MEN) are a group of disorders associated with hyperfunction of two or more endocrine glands and can be a cause of hypercalcemia (which may be milder and even asymptomatic). Finally, tamoxifen-linked hypercalcemia is hypercalcemia in association with the use of estrogen or antiestrogen therapy for therapy for carcinoma of the breast. The severity of hypercalcemia is variable, but it can be fatal. The mechanism by which tamoxifen and similar agents cause hypercalcemia is unclear but prostaglandins may be the main mediator of the response. [11] Other causes that are non-malignancy-related include milk-alkali syndrome (which involves large intake of calcium in association with volume contraction, systemic alkalosis and renal insufficiency) and medication-induced hypercalcemia (especially chronic lithium therapy). [9]

The emergency physician should be concerned about any patient with a history of cancer who presents with lethargy or altered mental status. Granulomatous disorders with high levels of calcitriol may be found in patients with sarcoidosis, berylliosis, tuberculosis, leprosy, coccidioidomycosis, and histoplasmosis. [4]

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