Hyperparathyroidism is inappropriate overactivity of the parathyroid glands resulting in parathyroid hormone (PTH) levels in the blood plasma which are in excess of what a normally functioning plasma ionized calcium regulator (or homeostat, or negative feedback mechanism) would produce. Normal parathyroid glands measure the ionized calcium (Ca²⁺) concentration in the blood plasma and secrete parathyroid hormone accordingly: if the ionized calcium rises above normal the secretion of PTH is decreased, whereas when the Ca²⁺ level falls, parathyroid hormone secretion is increased. In primary hyperparathyroidism, the release of parathyroid hormone into the blood is no longer determined by the current plasma Ca²⁺ level, but is persistently above what is appropriate. This may be due to a parathyroid adenoma which secretes PTH independently of changes in the plasma ionized calcium concentration. This leads to hypercalcemia (abnormally high plasma calcium levels). Secondary hyperparathyroidism occurs if the plasma ionized calcium level does not respond to changes in PTH secretion from normal glands, and therefore remains abnormally low (hypocalcemia). The normal glands respond by secreting parathyroid hormone at a persistently high rate. This typically occurs when the 1,25 dihydroxyvitamin D₃ levels in the blood are low or absent. 1,25 Dihydroxyvitamin D₃ (or calcitriol) is the active hormone which determines the quantity of calcium absorbed from the duodenum. Its absence therefore causes hypocalcemia, to which the parathyroid glands respond by secreting large quantities of PTH into the blood (i.e. "secondary hyperparathyroidism"). A lack of 1,25 dihydroxyvitamin D₃ can result from a deficient dietary intake of vitamin D, or from a lack of exposure of the skin to sunlight, so that the body cannot make its own vitamin D from cholesterol. The resulting hypovitaminosis D is usually due to a partial combination of both factors. Vitamin D is converted to vitamin D₃ (or cholecalciferol) by the liver, from where it is transported via the circulation to the kidneys where it is converted into the active hormone, 1,25 dihydroxyvitamin D₃. Thus a third cause of secondary hyperparathyroidism is chronic kidney disease. Here the ability to manufacture 1,25 dihydroxyvitamin D₃ is compromised, resulting in hypocalcemia. In both primary and secondary hyperparathyroidism, the high plasma PTH levels erode the skeleton, predisposing it to fractures and bone deformities, necessitating interventions to reverse the high PTH levels in the blood.