Disorders of Calcium: Physiology

Form

mg/dL

Percentage of total

Total

100

Ionized

Protein-bound

Complexed

Ca²⁺ plays a significant role in cellular metabolic functions; such as muscle and nerve contraction, activation of enzyme, blood coagulation, and cell growth. Consequently, low plasma [Ca²⁺] (hypocalcemia) or high plasma [Ca²⁺] (hypercalcemia) may lead to severe cellular dysfunction.

Ca²⁺ Homeostasis

The plasma [Ca²⁺] is maintained within narrow limits by the interplay between resorption and formation of Ca²⁺ by the intestine, bone, and kidney (Fig. 17.1). The daily intake of Ca²⁺ is approximately 1,000 mg. Of this amount, about 400 mg is absorbed by the intestine, and 200 mg is secreted into the intestine from the extracellular Ca²⁺ pool. This 200 mg of secreted Ca²⁺ plus the nonreabsorbed Ca²⁺ from the diet (600 mg) to a total of 800 mg is eliminated in the feces. Formation (deposition) and resorption (mobilization) of 500 mg also occurs in the bone. Therefore, the bone does not lose Ca²⁺ in a normal state. In the kidney, the filtered Ca²⁺ amounts to 60 % of the total Ca²⁺. If the GFR is 180 L per day and filterable Ca²⁺ is 60 % (6 mg/dL or 60 mg/L), the filtered load of Ca²⁺ is 10,800 mg (60 mg/L × 180 L = 10,800 mg). In order to maintain Ca²⁺ balance, 98 % of the filtered Ca²⁺ must be reabsorbed by the kidney, and only 200 mg is excreted in the urine. Thus, the interplay among the three organs maintains plasma Ca²⁺ level within a narrow range.

Fig. 17.1

Processes involved in Ca²⁺ homeostasis in an adult subject. (*Of 10 mg/dL plasma Ca²⁺, only 6 mg/dL are filtered which amount to the filtered load of 10,800 mg/day (60 mg/L × 180 L = 10,800 mg; modified with permission from Nordin B.E.C., (ed.). Calcium, Phosphate, and Magnesium Metabolism. Churchill Livingston, Edinburgh, 1976))

Three hormones and a Ca²⁺-sensing receptor system maintain Ca²⁺ homeostasis:

Ca²⁺-sensing receptor

Parathyroid hormone (PTH)

Active vitamin D₃ (1,25-dihydroxycholecalciferol, or calcitriol or 1,25(OH)₂D₃)

Calcitonin

Ca²⁺-Sensing Receptor (CaSR)

Ca²⁺-sensing receptor (CaSR) is expressed in the plasma membranes of cells that are involved in Ca²⁺ homeostasis. Its expression is highest in parathyroid glands and kidneys. The presence of CaSR has also been demonstrated in bone cells, thyroid, brain, gut, and other organs.

The CaSR exerts three important functions on parathyroid glands: (1) PTH synthesis; (2) PTH secretion, and (3) parathyroid cellular proliferation. In humans, the CaSR senses the circulating levels of Ca²⁺ and translates this information via a complex of signaling pathways either to inhibit or stimulate secretion of PTH by chief cells of the parathyroid gland. Low serum Ca²⁺ levels inhibit the CaSR so that PTH is secreted, whereas high levels of Ca²⁺ activate the CaSR and inhibit PTH secretion.

In the kidney, activation of CaSR in the thick ascending limb of Henle’s loop inhibits paracellular transport of Ca²⁺, resulting in hypercalciuria. In the inner medullary collecting duct, CaSR is localized in the endosomes that contain vasopressin regulated water channel, aquaporin 2. Activation of CaSR causes a reduction in vasopressin-stimulated water absorption, resulting in defective urinary concentration. This results in polyuria, particularly in conditions of hypercalcemia due to which, the development of nephrocalcinosis and nephrolithiasis is prevented .

In the bone, CaSR inhibits the formation and activity of osteoclasts and stimulates the osteoblasts. In thyroid C cells, activation of CaSR by high serum Ca²⁺ stimulates the secretion of calcitonin, which promotes bone formation by taking up Ca²⁺. Thus, CaSR plays an important role in Ca²⁺ homeostasis .

PTH

Active PTH is a large polypeptide containing 84 amino acids. PTH is secreted by the parathyroid gland. The secretion of PTH is primarily regulated by extracellular ionized Ca²⁺. As little as a 10 % increase or a decrease in plasma [Ca²⁺] either inhibits or stimulates PTH secretion. This response of PTH to changes in Ca²⁺ is mediated, as stated earlier, by CaSR. Other modulators of PTH secretion are calcitriol and Mg²⁺. Calcitriol and hypomagnesemia inhibit both the secretion and synthesis of PTH. PTH regulates plasma [Ca²⁺] by three mechanisms: (1) it stimulates bone resorption (demineralization) by activating osteoclasts (cells that break down bone mineral); (2) it increases the synthesis of calcitriol by enhancing the activity of 25-hydroxycholecalciferol-1α–hydroxylase (1,α–hydroxylase); and (3) it increases Ca²⁺ reabsorption in the distal tubule. Calcitriol increases bone resorption in concert with PTH and also promotes Ca²⁺ absorption from the intestine.

Calcitriol

As stated earlier, calcitriol is an active form of vitamin D₃. It is formed from 25-dihydroxyvitamin D (25(OH)D₃) by the enzyme 1,α-hydroxylase in the proximal tubule cells. PTH stimulates the activity of 1,α-hydroxylase, whereas hypercalcemia and hyperphosphatemia inhibit this enzyme’s activity. In the intestine, calcitriol promotes Ca²⁺ absorption .

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