Calcidiol plasma concentration

Unlike the other fat-soluble vitamins, there is litde or no storage of vitamin D in the liver, except in oily fish. In human liver, concentrations of vitamin D do not exceed about 25 nmol per kg. Significant amounts may be present in adipose tissue, but this is not really storage of the vitamin, because it is released into the circulation as adipose tissue is catabolized, rather than in response to demand for the vitamin. The main storage of the vitamin seems to be as plasma calcidiol, which has a half-life of the order of 3 weeks (Holick, 1990). In temperate climates, there is a considerable seasonal variation, with plasma concentrations at the end of winter as low as half those seen at the end of summer (see Table 3.2). The major route of vitamin D excretion is in the bile, with less than 5% as a variety of water-soluble conjugates in urine. Calcitroic acid (see Figure 3.3) is the major product of calcitriol metabolism but, in addition, there are a number of other hydroxylated and oxidized metabolites. 

Sunlight is not strictly essential for cutaneous synthesis of cholecalciferol, because UV-B penetrates clouds reasonably well complete cloud cover reduces the available intensity by about 50%. It also penetrates light clothing. However, low-intensity irradiation (below 20 ml per cm in vitro) does not result In significant photolysis of 7-dehydrocholesterol to previtamin D. Acute whole-body exposure to UV-B irradiation below 18 ml per cm does not result in any detectable increase in plasma cholecalciferol or calcidiol. In temperate regions (beyond about 40°N or S), the intensity of UV-B is below this threshold in winter, so there is unlikely to be any significant cutaneous synthesis of the vitamin in winter, and plasma concentrations of calcidiol show a marked seasonal variation in temperate regions (Holick, 1995 see Table 3.2). 

Calcidiol la-hydroxylase also acts on 24-hydroxycalcidiol, yielding cal-citetrol indeed, it has a relatively low specificity and will act on any secosteroid with hydroxyl groups at C-3 and C-25. Calcitriol has a short metabolic half-life after injection of the order of 4 to 6 hours (Holick, 1990). But, under normal conditions, the regulation of its synthesis means that the plasma concentration remains fairly constant, depending on the state of calcium balance (Hewison et al., 2000). 

Elderly people are at risk of osteomalacia, because of both decreased synthesis of 7-dehydrocholesterol in the skin with increasing age and low exposure to sunlight. Plasma concentrations of calcidiol below 10 nmol per L are commonly seen in people over 75 years of age, not rising above 20 nmol per L at any time of the year. Histologically proven osteomalacia is observed in 2% to 5% of elderly people presenting to the hospital in Britain. 

The plasma concentration of calcidiol is the most sensitive and usefiil index of vitamin D status, and is correlated with elevated plasma parathyroid hormone and alkaline phosphatase activity (Table 3.4). As shown in Table 3.2, the reference range of plasma calcidiol is between 20 to 150 nmol per L, with a twofold seasonal variation in temperate regions. Concentrations below 20 nmol per L are considered to indicate impending deficiency, and osteomalacia is seen in adults when plasma calcidiol falls below 10 nmol per L. In children, clinical signs of rickets are seen when plasma calcidiol faUs below 20 nmol per L. The plasma concentration of calcitriol does not give a useful indication of vitamin D status. The reference range is between 38 to 144 pmol per L and is maintained because of the stimulation of calcidiol 1-hydroxylation by parathyroid hormone secreted in response to faUing concentrations of calcium (Holick, 1990). 

Tabie 3.4 Plasma Concentrations of Calcidiol, Alkaline Phosphatase, Calcium, and Phosphate as Indices of Nutritional Status... 

Dietary vitamin D makes little contribution to status, and the major factor is exposure to sunlight, a conclusion that is supported by the two-fold seasonal variation in plasma calcidiol in temperate regions (see Table 3.2). There are no reference intakes for young adults in the United Kingdom and Europe for house-bound elderly people, the reference intake is 10 /rg per day, based on the intake required to maintain a plasma concentration of calcidiol of 20 nmol per L (see Table 3.5). This will almost certainly require supplements of the vitamin, because average intakes are less than half this amount. The U.S./Canadian adequate intake is 5 /xg per day up to age 50, increasing to 10 /xg between 51 to 70, and 15 /xg over 70 years of age (Institute of Medicine, 1997). 

A number of studies have suggested that the cholecalciferol content of human mUk is inadequate to meet the requirements of hreast-fed infants without exposure to sunlight, especially during the winter, when the mother s reserves of the vitamin are low. Infant formulae normally provide 10 /xg of cholecalciferol per day, and a similar amount is recommended for hreast-fed infants. Supplements of 10 /xg per day are also recommended for children between 3 months and 3 years, because of the relatively high requirement during the phase of maximum bone development and the limited exposure to sunlight in temperate regions. Such supplements maintain the plasma concentration of calcidiol above 20 mnol per L. 

The U.S. /Canadian report (Instimte of Medicine, 1997) quotes a no adverse effect level of 60 /rg per day, leading to a tolerable upper level of intake of 50 /xg per day (and 25 /xg per day for infants). The toxic threshold for adults has not been established, but reports of hypercalcemia in adults have involved intakes in excess of 1,000 /xg per day. There is no evidence of adverse effects at plasma concentrations of calcidiol lower than 140 nmol per L, which requires an intake in excess of 250 /xg per day, suggesting that the currently accepted no adverse effect level is lower than necessary (Vieth, 1999). 

Plasma Concentrations of Calcium and Phosphate Although the mean response to changes in plasma cedcium is a chemge in the secretion of peuathyroid hormone, the activity of calcidiol 1-hydroxyleise in kidney slices is decreased directly by high concentrations of cedcium in the incubation medium. Cedcium heis no direct effect on the activity of calcidiol 24-hydroxylase under these conditions. Strontium and cadmium edso inhibit ctdcidiol 1-hydroxylase. 

It is difficult to determine requirements for dietary vitamin D, as the major source is synthesis in the skin. The main criterion of adequacy is the plasma concentration of calcidiol. In elderly subjects with little sunlight exposure, a dietary intake of 10 fg of vitamin D per day results in a plasma calcidiol concentration of 20 nmol/L, the lower end of the reference range for younger adults at the end of winter. Therefore, the reference intake for the elderly is 10 Jg/day. Average intakes of vitamin D are less than 4 Jg/day, so to achieve an intake of 10 Xg/day will almost certainly require either fortification of foods or the use of vitamin D supplements. 

Parathyroid hormone is secreted in response to a fall in plasma calcium. In the kidney it acts to increase the activity of calcidiol 1-hydroxylase and decrease that of the 24-hydroxylase. This is not an effect on protein synthesis, but the result of changes in the activity of existing enzyme protein, mediated by cAMP (section 10.3.2). In turn, both calcitriol and high concentrations of calcium repress the synthesis of parathyroid hormone. 

Dawson-Hughes B, Harris SS, and Dallal GE (1997) Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. American Journal of Clinical Nutrition 65 65-71. 

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