CAUSES
. Solid tumors:
. 80% have increased levels of nephrogenous cyclic AMP, reflecting activity of ectopic parathormonerelated peptide(s). True ectopic PTH production is exceedingly rare.
. PTH-related protein has been found to be a major mediator of hypercalcemia in malignancy, and appears to influence bone metastases, especially in breast cancer
. Lung cancer (25% of cases usually squamous, less common are adenocarcinoma and large cell, rarely small cell)
. Squamous carcinoma of head, neck, esophagus, female genital tract (20% of cases)
. Renal cell carcinoma (8% of cases)
. Myeloma, lymphoma, breast cancer with osseous metastases, and others. Tumors may induce hypercalcemia by one or more of the following mechanisms:
. Nephrogenous cyclic AMP is reduced, refl ecting suppression of PTH by nonparathyroid hypercalcemia
. Factors implicated include interleukin-1, interleukin-6, tumor necrosis factor,macrophage colony stimulating factor, prostaglandin (E series), lymphotoxin, vascular cell adhesion molecule-1, hepatocyte growth factor, and others
. Direct resorption of bone by metastatic tumor (controversial)
. 1-alpha hydroxylase activity of some lymphomas, causing tumoral production of 1,25-dihydroxyvitamin D
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DIFFERENTIAL DIAGNOSIS
(not including benign familial hypercalcemia)
β’ Vitamins A and D
β’ Immobilization
β’ Thyrotoxicosis
β’ Addison disease
β’ Milk-alkali syndrome
β’ Inflammatory disorders
β’ Neoplastic-related disorders
β’ Sarcoidosis, TB, and other granulomatous diseases
β’ Thiazides, lithium; theophylline and aspirin toxicity
β’ Rhabdomyolysis
β’ AIDS
β’ Paget disease
β’ Parenteral nutrition
β’ Hyperparathyroidism
LABORATORY
β’ Serum calcium: Total calcium level depends on binding proteins. Adjusted calcium can be estimated by: Ca(adj) = Ca(tot) - 0.8 x (albumin - 4)
β’ Ionized calcium: Physiologically most important, affected by pH. May be measured directly if specimen is collected under anaerobic conditions and analyzed promptly.
β’ PTH assay: Intact molecule (especially two-site, noncompetitive) methods have greatest specifi city, almost always suppressed, in malignancy. If elevated
in a cancer patient, suspect concomitant hyperparathyroidism.
β’ PTH-related peptide: Assays now are clinically available; often elevated in hypercalcemia of malignancy
β’ 25-hydroxyvitamin D: May be elevated in vitamin D intoxication
β’ 1,25-dihydroxyvitamin D: Elevated in up to 50% of hypercalcemic patients with lymphoma
SPECIAL TESTS Staging techniques as necessary to determine extent of malignancy
IMAGING If there is laboratory evidence of primary hyperparathyroidism, imaging (such as ultrasound, CT, MRI, or nuclear parathyroid scans) may be required in patients with previous neck surgery, prior to re-exploration