Differential diagnosis of hypercalcemia: a mechanistic approach

Malignant disease and primary hyperparathyroidism are the most common causes of hypercalcemia, but there are many minor causes. Mechanical or humoral factors, or both, may underlie the increase in bone resorption. Parathyroid hormone (PTH) is a major mediator of bone resorption, but many other humoral agents have the same effect, eg, prostaglandin, osteoclast-activating factor, and thyroid hormone. Serial determination of total calcium concentration is the most important laboratory test in hypercalcemia. Other useful tests include the determination of serum and urinary phosphorus concentration, chloride/phosphate ratio, urinary cyclic adenosine 3',5'-monophosphate (cAMP) level; carboxyl-terminal PTH assay; corticosteroid challenge; and appropriate radiologic studies. Nephrogenous cAMP and urinary prostaglandin determinations are research tools that hold great promise in the future. Differentiation between PTH- and non-PTH-mediated hypercalcemia determines subsequent steps in diagnosis and treatment.