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Key Clinical Questions

  • image How is serum calcium regulated?

  • image What are the causes of hypercalcemia in hospitalized patients?

  • image How is hypercalcemia diagnosed and managed?

  • image What causes hypocalcemia in hospitalized patients? How is it diagnosed and managed?

Abnormalities of calcium metabolism are common in hospital practice. Hypercalcemia has a prevalence of 0.1% in the general population and 1% among hospitalized patients. In the inpatient setting, hypercalcemia often portends serious illness, especially malignancy. Hypocalcemia is also common in the hospital, especially in patients with chronic renal failure or sepsis. Hypocalcemia may also be a manifestation of vitamin D deficiency, which has a prevalence of up to 80% on specialized geriatric inpatient units.


Precise regulation of calcium homeostasis is essential because of the critical role of calcium in many physiological activities. It is the major mineral of bone. It also plays major roles in neuronal transmission, muscle contraction, and blood coagulation. Calcium is also required for the proper functioning of many enzymes, endocrine secretory processes, and biochemical signaling pathways.


A typical laboratory range for serum total calcium concentration is between 8.4 and 10.2 mg/dL. Approximately half of this total amount is bound to albumin, with the remainder in free (ionized) form. The normal free calcium concentration range is 4.5 to 5.3 mg/dL. A small fraction (10%) of circulating calcium is complexed with anions, such as citrate and phosphate.


The three organ systems that together regulate serum calcium are the gastrointestinal tract, kidneys, and skeleton. The two principal regulatory hormones are parathyroid hormone (PTH) and 1,25-­dihydroxyvitamin D3. PTH is a peptide secreted from the parathyroid glands in its active full-length configuration, known as PTH(1-84). Its plasma half-life is very short, on the order of 3 to 5 minutes. The major regulator of PTH secretion is the free calcium concentration in extracellular fluid. Elevated levels of free or ionized calcium promptly block secretion of PTH, while reduced serum ­calcium levels promptly increase secretion of PTH.

1,25-dihydroxyvitamin D3 is produced by a sequence of activation steps (Figure 240-1), starting with the generation of cholecalciferol (vitamin D3) through exposure of skin to ultraviolet light of a specified wavelength (90-315 nm). Cholecalciferol or its plant analogue, ergocalciferol (vitamin D2), can also be obtained by dietary sources or in nutritional supplements. Cholecalciferol or ergocalciferol is converted in the liver to a hydroxylated form, 25-hydroxyvitamin D3 or 25-hydroxyvitamin D2. The 25-hydroxylated forms of vitamin D are converted to their active forms by a second hydroxylation step in the kidney leading to 1,25-dihydroxyvitamin D2 or D3. Both dihydroxylated forms of vitamin D are active in human subjects, although there is controversy over whether vitamin D3 is more potent than vitamin D...

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