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The serum calcium concentration is tightly regulated by the kidney, intestinal tract, and bone through multiple hormonal pathways. Over 98% of total body calcium is deposited in bone along with phosphate as hydroxyapatite [Ca10(PO4)10(OH)2]. About 1% of calcium circulates in the plasma in 3 different forms: about 50% is a physiologically active form as ionized free calcium (Ca2+), about 40% of calcium is inert as it is bound to albumin and globulins, and about 10% is complexed with citrate, sulfate, or phosphate. Total plasma calcium measures free and bound calcium. Measuring only total plasma calcium concentration is usually sufficient for clinical purposes since its values correlate with free Ca2+ levels. However, in the presence of hypoalbuminemia, acid-base disorders, or chronic kidney disease, the serum calcium and Ca2+ levels may or may not correlate. Thus, acidosis decreases calcium binding to albumin, thus causing increased free Ca2+ concentrations; alkalosis increases calcium binding to albumin thus having the opposite effect.

Ca2+ is an intercellular and intracellular messenger that is necessary for neuronal and neuromuscular communication, muscular contraction, cardiac rhythmicity, enzyme function, clotting, protein synthesis and secretion, and cellular proliferation. Intracellularly, Ca2+ is a second messenger that propagates signals that control cellular activities such as gene transcription, cell division, growth, movement, and function.

Serum Ca2+ levels are maintained within narrow limits by the plasma membrane Ca2+ sensing receptor (CaSR), parathyroid hormone (PTH) and the PTH/PTH-related protein (PTHrP) receptor, calcitonin and its receptor, as well as vitamin D, which regulates intestinal tract, bone, and kidney absorption of Ca2+ (Fig. 535-1).

Figure 535-1

Regulation of calcium and phosphate homeostasis. In response to calcitriol [1,25(OH)2D3] and parathyroid hormone (PTH), Ca2+ is absorbed from the intestinal tract, renal tubule, and bone. Calcitonin inhibits resorption of bone calcium. The Ca2+-sensing receptor (CaSR) modulates the activity of the parathyroid glands and the renal tubules. PTH, hypocalcemia, and hypophosphatemia stimulate renal tubular synthesis of calcitriol. PTH inhibits renal tubular reabsorption of phosphate, as does fibroblast growth factor-23 (FGF23), a phosphatonin secreted by osteoblasts. FGF23 also inhibits renal tubular synthesis of calcitriol. VDR, vitamin D nuclear receptor.

An increase in serum Ca2+ concentration activates the CaSR on the plasma membrane of the chief cell of the parathyroid gland (PTG), which decreases PTH synthesis and release. PTH stimulates bone reabsorption, increases renal tubular synthesis of calcitriol [1,25(OH)2D3] and intestinal absorption of calcium. Increased serum Ca2+ concentrations also activate the CaSR in the distal renal tubule, which decreases tubular reabsorption of Ca2+ and increases its urinary excretion.

Ca2+ enters cells through transmembrane calcium channels and is bound intracellularly to Ca2+ binding proteins, including calbindin ...

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