Hypercalcemia is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

  • A serum calcium >10.3 mg/dL with a normal serum albumin or an ionized calcium >5.2 mg/dL defines hypercalcemia.
  • Clinically significant hypercalcemia typically requires both an increase in ECF calcium and a decrease in renal calcium clearance. Underlying disturbances to calcium metabolism are thus often masked by compensatory mechanisms until the patient develops a concomitant disorder, such as decreased renal clearance from volume depletion. More than 90% of cases are due to primary hyperparathyroidism or malignancy.
  • Primary hyperparathyroidism causes most cases of hypercalcemia in ambulatory patients. It is a common disorder, especially in elderly women, in whom the annual incidence is approximately 2 in 1000. Nearly 85% of cases are due to an adenoma of a single gland, 15% to hyperplasia of all four glands, and 1% to parathyroid carcinoma.
  • Malignancy is responsible for most cases of hypercalcemia among hospitalized patients. Patients usually have advanced, clinically obvious disease. In these patients, hypercalcemia may develop from stimulation of osteoclast bone resorption from tumor cell products, tumor-derived PTH-related peptides (PTHrPs), and tumor calcitriol production.
  • Less common causes account for about 10% of cases of hypercalcemia:
    • Increased vitamin D activity occurs with exogenous exposure to vitamin D or increased generation of calcitriol in chronic granulomatous diseases (e.g., sarcoidosis, tuberculosis).
    • The milk-alkali syndrome describes the acute or chronic development of hypercalcemia, alkalosis, and renal failure that may result from the ingestion of large quantities of calcium-containing antacids.
    • Other. Hyperthyroidism, adrenal insufficiency, prolonged immobilization, Paget disease, and acromegaly may be associated with hypercalcemia. Familial hypocalciuric hypercalcemia is a rare, autosomal dominant disorder of the calcium-sensing receptor, which is characterized by asymptomatic hypercalcemia from childhood and a family history of hypercalcemia.

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