Vitamin D Review Plan
Introduction
Health is a very important factor in life. There are various types of vitamins that should be consumed by an individual to stay healthy and firm and each vitamin has different functions. One of these is Vitamin D also known as calciferol, is a fat-soluble vitamin which is attained through diet or simply by exposure to sun light. The human body can generate Vitamin D; sunlight produces a reaction creating vitamin D3 (cholecalciferol) converted by the liver and kidneys into biologically active metabolites. This procedure is so resourceful that according to the UK Government's Committee on Medical Aspects of Food Policy Panel on Dietary Reference Values 'No dietary intake (of Vitamin D) is essential for individuals living a regular lifestyle. The primary goal of this research is to conduct a review plan about vitamin D, its functions, and importance.
Sources and forms of Vitamin D
Humans acquire vitamin D from food sources making this vitamin a unique one among the major vitamins. There are two sources and forms of vitamin D. These are the exogenous, wherein vitamin D is produce from food sources (diet) and the endogenous wherein vitamin D is taken from sunlight.
1.1.1 Exogenous (diet)
The exogenous Vitamin D2 is a form of Vitamin D which is derived from plan and produced exogenously by irradiation of ergosterol and enters the ciculation of the body through diet (Wolpowtiz & Gilchrest, 2006). The primary function of Vitamin D in human body is to keep the right balance of calcium and phosphorous to sustain the bone that promotes strong bones. Similar to large amount of nutrients, vitamin D does not work without help. This is most efficient when cooperating with other vitamins, minerals and hormones to develop bone mineralization. The most frequent food source of vitamin D is milk. This is not a usual incidence; milk is fortified with vitamin D. Milk is loaded in calcium; therefore it is vital to make sure enough vitamin D helps your body absorb the calcium. In the study of Nowson and his collegues (2004), margarine is the only food in Australia which is widely utilised and consists of vitamin D via fortification.
1.1.2 Endogenous
Some studies have noted that vitamin D is not a real vitamin because of the fact that sufficient amounts can only be achieved completely all the way through non-food sources. For example, many farmers and other outdoors workers get their needed vitamin D straight from the sun throughout definite times of year. Accordingly, the main source of vitamin D is the exposure to sunlight. For instance, in Australia, there are seasonal variations in the status of Vitamin D, such that serum 250HD degrees are considered to be lower at the end of winter as compared to the end of summer (Nowson et al, 2004). In the study made among Australians. It has been found that exposure of the whole body surface for 10-15 minutes in noonday sunlight is comparable to taking around 15000 IU of oral vitamin D.
1.2 Vitamin D Metabolism
Vitamin D metabolism occurs in different organs and parts of the body. In this regard, this part of the review highlights Vitamin D metabolism in the skin, liver and kidneys. Further, this part will also discuss the regulation of vitamin D metabolism with regards to PTH, Calcium, Acidosis, Phosphate insulin and IGF1, the transport of vitamin D and Vitamin D receptor.
1.2.1 Skin
The overview of the metabolism of Vitamin D is given in Figure 1. According to studies, Vitamin D3 can be developed and synthesized in the skin from 7-dehydrocholesterol in a reaction which is catalyzed by ultraviolet lights (Helmut, Koeffler & Norman, 1989; Holick, 1981). Alternatively, Vitamin D3 which comes from the food we eat is taken up into the bloodstream from the intestines, it is noted that Vitamin D2 which metabolically behaves like Vitamin D3 is only provided by dietary sources. According to Helmut and his colleagues (1989), the transport of vitamin D metabolites in the blood is attained mostly through non-covalent binding to vitamin D called binding protein: this protein was originally known as group-specific components or Gc protein by human geneticists (Helmut, Koeffler & Norman, 1989). This Vitamin D-Binding protein is noted to be structurally homologous to two other blood proteins which are albumin and α-fetoprotein (Gibbs & Dugaiczyk, 1987).
1.2.2 Liver
Furthermore, Vitamin D metabolism process also occurs in the liver which has been regarded as the major area of the hydroxylation of Vitamin D3. It gathers very rapidly in the liver where it go through 25-hydroxylation, yielding 25-OH-D3, (Wootton, 2005; Cashman, 2007). Consequently, such metabolic step is not believed to be subject to specifically tight regulation. As mentioned in the study, circulating 25-OH-D3 concentrations are noted to be a reflection of the availability of Vitamin D3 and are determined to be the best indicator of vitamin D levels (Helmut, Koeffler & Norman, 1989). Some studies have shown that the Vitamin D 25-hydroxilation is governed to some level by 1,25-OH-D3. Herein, the ingestion of large amount of Vitamin D have lead to a clear increase or augmentation in the serum levels of 1,25-OH-D3, however, the concomitant administration of 1,25-OH-D3 with Vitamin D prohibited such increase (Trang et al, 1998: Hollis, 2004). Other studies have investigated that hypocalcaemia and the ensuing increase in the serum concentrations of 1,25-OH-D3 that results in accelerated degradation and biliary excretion of 25-OH-D3 hence, decreasing to some level the amount of 25-OH-D3 accessible for activation in the kidney (Wootton, 2005).
1.2.3 Kidney
Studies revealed that the second essential site of the transformation of Vitamin D is the kidney. Where the enzyme 25-OH-D3 goes on to the kidney where it undertakes one of two hydroxylations. If there is a biological need for calcium or for phosphate the kidney is stimulated to translate 25-OH-D3 to the 1,25-(OH)2-D3, a calcium and phosphate assembling hormone. If the animal has enough storage of calcium and phosphate, the l-hydroxylase is lock up and as an alternative the 25-OH-D3 is exchanged to a 24,25-(OH)2D3. The function of the 24, 25-(OH)2D3 is not yet known; it possibly a transitional in the inactivation-excretion devices. 1,25-(OH) 2D3 keeps going to intestine where it stimulates intestinal calcium transportation and intestinal phosphate transportation. It also arouses bone calcium mobilization and most likely has further results yet to be determined in such tissues as muscle. The 25-OH-D3-l-hydroxylase, which is positioned exclusively in renal mitochondria, has been shown to be a three component system relating a flavoprotein, an iron-sulfur (Iqbal, 1994) protein (renal ferredoxin), and a cytochrome P-450. This scheme has been effectively solubilized, the mechanisms isolated, and represented. The 24-hydroxylase, on the other hand, has not yet been carefully deliberated... 1, 25-(OH)2D3 is required for the manifestation of the 24-hydroxylase; parathyroid hormone contains 24-hydroxylation. It is probable that the 24-hydroxylase stands for the main synchronized enzyme, thus, its occurrence or absence may establish whether 1,25-(OH)2D3 is attained (Helmut, Koeffler & Norman, 1989).
Two metabolic passageways for 1,25-(OH)2D3 are recognized, alteration by the 24-hydroxylase to 1, 24, 25-(OH) 3D3, and translation of 1,25-(OH)2D3 to an unidentified matter. In the final example, there arises failure of a side series part, plus no less than one of the 26 and 27 carbons. Whether 1,25-(OH)2D3 have to be metabolized more before it brings out all of its purposes has yet to be found. The major emission way of vitamin D3 is through the bile into the feces. Urinary excretion comes out little in amount and no emission materials have yet been recognized completely (Omdahl, Morris & May, 2002).
Much remains to be studied regarding the metabolism and purpose of vitamin D and its metabolites. Then must therefore, confirm to be a productive part of examination for numerous years to come, particularly since 1,25-(OH)2D3, 25-OH-D3, and lalpha-OH-D3 have been revealed to be efficient in a number of metabolic bone disorder states.
Figure 1 shows how vitamin D regulates body levels and control mineral metabolism.
1.2.4 Regulation of Vitamin D Metabolism
1.2.4.1 PTH and Calcium
In a study conducted by Duso and his associates (2005), they have noted that Vitamin D and PTH are main hormones that regulate calcium metabolism. Also, the serum level of phosphorus is known to change according to the level of calcium and to regulate the vitamin D and PTH. Recently, cloning of 1alpha- hydroxylase cDNA which is the key enzyme in vitamin D metabolism enabled us to examine the effects of phosphorus in vitamin D metabolism at a molecular level. Furthermore, the direct effect of phosphorus in PTH synthesis is being elucidated in recent reports. In this paper, we summarized the regulation of vitamin D and PTH by phosphorus (Duso, Brown & Slatopolsky, 2005). In a study conducted by Hewison and his colleagues (2000), they have mentioned that the noticeable widespread distribution of mRNA and protein for 1_-Ohase in both extra-renal and renal tissues has raised essential issues which concern the local enzyme activity at this region. The connection between actual synthesis of 1,25-(OH)2D3 and expression of 1_-OHase in a specific tissue probably involves two particular mechanisms. These include the substrate access and the auto regulation of 1_-OHase function by 1,25-(OH)2D3 itself.
The previous questions the notion that, in common with other steroid hormones 1,25(OH)2D3 enter cells through a passive mechanism by virtue of the so-called lipophilic nature. The latter provides the plausibility that local 1_-OHase functions in extra-renal tissues is under even firmer control than that observed with the endocrine enzyme and, hence, local generation of 1,25-(OH)2D3 in vivo may be complex to identify various of serum proteins, however, by far the most essential of these is the vitamin D-binding protein (DBP), that is synthesized in the liver part. Previous investigations in vitro have recommended that DBP-bound vitamin D metabolites have restricted access to target cells and with these, the free formations of Vitamin D metabolites, with greater obvious accessibility target cells are more biologically functional and operational (Hewison et al, 2000; Dusso, Brown & Slatopolsky, 2005). However, studies of the D-Binding protein null mouse have noted that the animals in the investigation were less susceptible than the considered wild kind to vitamin D-induced hypercalcaemia (Safadi et al. 1999). In this regard, the D-binding protein null mice also generated vitamin D deficiency much earlier than the experimented normal litter-mates. With these findings, it is recommended that that, in addition to the role it plays as a transport protein, D-binding protein also plays an essential function in directing vitamin D responses. Specifically, because of its significantly high capability for binding 25-(OH)2D3, D-Binding protein is probable to be a vital aspects of the availability of substrate to 1_-OHase. Current investigations have identified that D-binding protein and D-binding protein-bound vitamin D metabolites are strained through the glomerulus and readmitted via the endocytic receptor megalin which is located in the proximal tubules (Nykjaer et al. 1999).
Accordingly, megalin is included to the classification of low-density-lipoprotein receptor gene and is represented in various types of tissues (Saito et al. 1994; Lundgren et al. 1997). Furthermore, megalin has also been identified to be found in the brush border membrane which is located in the proximal tubules, whereas those cells of distal nephron are seen to be considered as megalin-negative (Lundgren et al. 1997). Hence, megalin-mediated endocytosis of D-binding protein bound 25(OH)D can function as an additional system that control specific tissue synthesis of 1,25(OH)2D3 by modifying the accessibility of substrate to the 1_-OHase protein. Such result may give a partial explanation for the inconsistency between more discrete patterns of actual enzyme activity in vivo and widespread 1_-OHase protein expression along the nephron.
Some studies have noted that, during the sufficient status of vitamin D, 1,25-(OH)2D3 generation by the kidneys is regulated very tightly, however there is a remarkable up-regulation of 1_-OHase activity in proximal tubule cells in vitamin D-deficient states (Hewison et al, 2000). This reaction appears to be an activity of several direct and indirect systems which include changes in accessory proteins like ferrodoxin, or changes in VDR or 24-OHase expression. Some studies in vivo suggest that the vital activator of 1_-OHase is a PTH and that this impact is mediated, at least in the region, by target-cell induction of cAMP (Henry & Luntao, 1989).
Latest studies give emphasis capable cAMP reaction components in downstream regions that are PTH receptive in promoter-reporter assays (Kong et al. 1999; Brenza et al. 1998,). In these researches, the authors have not been able to show any self-regulation of basal CYP1_ promoter function, and no vitamin D response elements (VDREs) were also determined in the 1·4 kb fragment. But, in each condition 1,25-(OH)2D3 was able to suppress PTH induced trans-activation. Such findings recommends either that the CYP1_ gene promoter has a nonconforming VDRE, or that 1,25(OH)2D3 attains its effects through indirect mechanism. Such result contrast with investigation of the murine promoter (Murayama et al. 1998), that demonstrated both positive (PTH) and negative (1,25-(OH)2D3) receptiveness in a region downstream of -0·9 kb. Herein, calcitonin was identified to be a potent stimulator of 1_-OHase expression that support previous studies in which calcitonin was shown to stimulate 1_-OHase mRNA and operates under normocalcaemic situations (Shinki et al. 1999).
The study recommends that calcitonin, acting through distal sites of the nephron, may play an essential role in the ‘fine-tuning' of serum 1,25-(OH)2D3 degrees in time of vitamin D sufficiency. Along with the most important inhibitors of 1_-OHase are phosphate, calcium, and 1,25-(OH)2D3 itself, the latter also invigorating an increase in 24-OHase function (Murayama et al. 1999).
In this study, it shows that most of these impacts s are mediated indirectly via modulation of PTH production and secretion. But, as a result of the tight regulation of 1,25-(OH)2D3 production, the result of the specific mechanisms involved in manipulating 1_-OHase has proven to be difficult. In addition, utilising a transformed human proximal tubule cell line, HKC-8, the studies confirmed the cAMP mediated up-regulation of 1_-OHase expression and inhibition of expression by 1,25-(OH)2D3 (Bland et al. 1999). Nevertheless, the study also noted that the most forceful and fast modulation of 1_-OHase expression and operation happened as a follow-up to changes in extra-cellular calcium. Comparatively high levels of calcium (2 mM versus 1 mM) decreased the synthesis of 1,25(OH)2D3, while significantly low levels (0·5 mM versus 1 mM) increased the enzyme activity. Such reactions happened within 4 h but were transitory, with operations returning to normal at 24 h. These experiments, coupled with the broad range expression of calcium-sensing receptors, along the nephron recommend that alterations in local calcium sensing may perform as a major variable of tissue-specific 1,25(OH)2D3 production. Moreover, another approach to the in vitro investigation of 1_-OHase has been to utilise preparations of keratinocytes or activate macrophages as oneo f the sources of 1_-OHase activity. In this regard, the major complexity connected with these model systems is that present evidence recommends that there are substantial discrepancies between the regulation of 1_-OHase in the kidney and that in extra-renal regions. For instance, , the synthesis of 1,25(OH)2D3 by activated macrophages is not repressed by 1,25(OH)2D3, and this seems to be the basis for the unregulated 1_-OHase operation connected with granulomatous diseases including sarcoidosis, and which often leads to hypercalcaemia in these victims. This is not easy to explain, specifically in view of recent researches which suggest that renal and extra-renal 1_-OHase is due to the equal gene product. Macrophage-like cells are considered to express VDR, and few groups have shown functional responses to 1,25(OH)2D3 in these cells (Hewison & O'Riordan 1997). Hence, the most likely illustration is that induction of extra-renal 1_- OHase engages regulatory pathways that is not the same from renal, cAMP-mediated mechanisms and are less sensitive to auto-regulation by 1,25(OH)2D3. Consequently, induction of extra-renal 1_-OHase often involves antigenic activators like lipopolysaccharide or inflammatory mediators like interferon. Since these agents signal via nuclear factor _B, Hewison and his colleagues (2000) can postulate that this direction activates 1_-OHase in a way unlike that of calciotrophic aspects and, as a effect, shows differential sensitivity to feedback control by 1,25(OH)2D3. In addition, analysis of the signal-transduction directions involved in regulating 1_-OHase will be critical to the comprehension of the way in which 1,25(OH)2D3 functions in extra-renal tissues (Hewison et al, 2000).
1.2.4.2 Acidosis and Phosphate
It has been known that metabolic acidosis is an essential acid-base disturbance among humans. It is described by a principal decrease in human body bicarbonate stores and is noted to induce metabolic alterations and multiple endocrine changes (Hosking, 1999). It induces nitrogen wasting and decreases protein metabolism. According to some studies, the acidosis-induced changes in different endocrine systems involve decreases in IGF-1 degrees due to peripheral development hormone insensitivity, a slight form of principle hypothyroidism and hyperglucocorticoidism. In addition, it also induces a negative calcium balance which is also known as resorption from bone with hypercalciurua and a tendency to build up kidney stones. Acidosis also results in hypophosphataemia because of the renal phosphate wasting (Hosking, 1999). Phosphate depletion and negative balance combine to persuade a metabolic bone diseases which exhibits features of both Osteomalacia and osteoporosis in humans at least 1,25-(OH)2, Vitamin D degrees increase, plausible through phosphate depletion-induced motivation of 1-alpha hydroxylase. The generation of 1,25-(OH)2 vitamin is therefore motivated and parathyroid hormone eventually reduces (Thomas & Demay, 2000). Some studies have supported the idea that even slight degrees of acidosis including those that occurs by ingestion of a high animal protein diet, encourages some of endocrine and metabolic effects.
1.2.4.3 Insulin and IGf-1
According to studies, there are several aspects which are known to be included in the Vitamin D regulation. It has been mentioned that serum insulin-like growth factor-1 also known as IGF-1 was found to be an independent predictors of total bone density. Accordingly, the systems of IGF-1 are positively connected with concentrations of Vitamin D. Insulin-like growth factor-1 is known as a polypeptide protein hormone which is common in molecular structure to insulin (Holick, 2005). 1,25-(OH)2D3 has been determined to the operation of IGF-I by enhancing IGF-I receptors and IGF-I can also increase 1,25-(OH)2D3 concentrations by triggering the hydroxylation of 25-(OH)2D3 in the active 1,25-(OH)2D3 hormone. It has also been noted that IGF-I relatively increased renal 1α-hydroxylase expression and serum 1, 25-(OH)2D3 concentrations.
1.2.4.4. 1,25(OH)2D3
In a study undertaken by various scholars, they have mentioned that the potentials of 1,25(OH)2D3 in increasing serum calcium and phosphate levels needs a mechanism to calm its operation and activity. In this regard, it is accomplished within nearly all target cells by the 1,25(OH)2D3-inducible vitamin D 24-hydroxylase, that catalyzes a sequence of oxidation reactions at carbons 24 and 23, which lead to side chain cleavage as well as inactivation. In a study wherein they investigated mice, these animals have been discovered to lack a functional 24-hydroxylase gene have high serum 1,25(OH)2D3 levels because of the decreased capacity to degrade or reduced it (St-Arnaud, Arabian and Glorieux, 1996). 24-Hydroxylase has been regulated in a reciprocal manner to 1_-hydroxylase. Such function and expression are augmented by phosphate (Tanaka & DeLuca, 1973) and decreased by PTH (Henry & Norman, 1984). Furthermore, the 24-hydroxylase gene composes at least two unique vitamin D response components which mediate the impact of 1,25(OH)2D3 through its receptor on transcription (Chen & DeLuca, 1995). In addition, study revealed also that 1,25(OH)2D3 can also be transformed to the 1,25(R)-(OH)2D3-23(S),26-lactone (Ishizuka & Norman, 1987). Such metabolite has been considered to have mild antagonist operation toward 1,25(OH)2D3 action, and more capable lactone analogs have now been established and formulated. In some investigations, the authors have revealed that the 3_-hydroxyl group of 1,25(OH)2D3 can be epimerized to the 3_ position (Brown et al, 1999) in a cell-specific manner. In this study, they found that 1,25(OH)2-3-epi-D3 have shown to be catabolized slower than the parent hormone and sustains relative biological operation. Herein, the essence of the 3-epimerase is unclear, yet its cell-specific expression shows that this direction may operate to prolong the function of 1,25(OH)2D3 in cells which contain such enzyme. With this, the authors have found that differential rates of 3-epimerization of vitamin D analogues may give a system for their selective operations in vivo area. Moreover, studies recommends that 3-epimerization of select vitamin D analogues may augment their proapoptotic operation (Nakagawa et al, 2001).
1.2.5 Transport of Vitamin D
Like any other vitamins, Vitamin D flows into the body with its own transport system. Accordingly, Vitamin D metabolites are also known as lipophilic molecules with low aqueous solubility which must be carried in the circulation bordered towards plasma proteins. Herein, the most essential protein carrier is the vitamin D-binding protein (DBP), that binds the metabolites with high resemblance and likeness in the order 25(OH)D_24,25(OH)2D _ 1,25(OH)2D _ vitamin D (Cooke & Haddad, 1989). Research shows that the DBP Plasma levels are 20 times higher than the total quantity of vitamin D metabolites. In this regard, 99% of circulating vitamin D components are protein bound, mostly to D-binding protein, even though albumin and lipoproteins also contribute to lesser levels. Such findings have a major effect in line with their pharmacokinetics. D-binding protein metabolites have restricted access to target cells (Cooke & Haddad, 1989), hence these are less vulnerable to subsequent biliary excretion and hepatic metabolism, which leads to longer circulating half-life.
Previous research recommended that only the small fraction of boundless and limitless metabolites passively go through target cells to be further developed metabolized or to give biological function. For those activated vitamin D components which is 1,25(OH)2D3 and other analogues, biological function has a relation with the concentration of free hormone (Bikle & Gee, 1989; Brown et al, 1993). Hence, D-binding protein appears to safeguard the free levels of active vitamin D components, protecting them against vitamin D intoxication (Bouillon, et al, 1981). D-binding protein levels are not synchronized by vitamin D however; they are reduced by, nephrotic syndrome, liver disease and malnutrition and eventually increased in times of pregnancy and estrogen therapy. The focus of free 1,25(OH)2D3, but, remains constant when D- binding proteins levels alters, an instance of the tight self- adjustment of vitamin D metabolism.
As noted, D-binding protein null mice lack any sign of rickets, in spite of its very low total degrees of 25(OH)D and 1,25(OH)2D, which supports the free hormone hypothesis for the operations of 1,25(OH)2D3 and its analogues. Conversely, it is now apparent that 25(OH)D do not merely diffuse into the proximal tubule cells that contains 1_-hydroxylase. Mice without the endocytic receptor megalin were unpredictably discovered to produce vitamin D deficiency and rickets due to a loss of D-binding protein and its bound vitamin D metabolites in the urine (Nykjaer et al, 1999). Hence, the entrance of 25(OH)D into the proximal tubule cells is not through diffusion athwart the basolateral region but through receptor-mediated uptake of D-binding protein in the brush border. Such system denotes the discoveries that D-binding protein-null mice are resilient to vitamin D intoxication (Safadi et al, 1999). Nonetheless, due to the fact that DBP-null mice do not show vitamin D deficiency, DBP-independent uptake of 25(OH)D should also happen.
1.2.6 Vitamin D receptor
It has been noted that during the past 10 years, receptors for 1,25-(OH)2 vitamin D3 (1,25-(OH)2D3) have been described in fetal rat calvaria (Stern, 1990), in primary cultures of calvarial cells with predominantly osteoblastic characteristics from both neonatal mice (Chen, Hirst & Feldman, 1979) and fetal rats (Stern, 1990), in rat and human osteogenic sarcoma cell lines and in cloned mouse osteoblastic cells. The binding sites have sedimentation coefficients of approximately 3.2 S, and high affinities for 1.25-(OH)2D3, with Kd's in the 0.1 to 0.3 nM range (Stern, 1990). The concentration of binding sites was generally found to be less than 100 fmol/mg cytosolic protein. Receptor densities were highest at the start of culture (Stern, 1990). Examination of the time course of receptor binding indicated that in cell derived from neonatal mouse bone there was a correlation with the stage of the cell cycle, the number of receptors being highest during the log phase and lowest at confluence. In contrast, in bone cells from fetal rats the receptor concentration did not correlate with the cell cycle, showing a somewhat inverse correlation with thymidine incorporation. At the times when receptor density was highest, the concentration of binding sites in the rat bone cells was approximately 1/5 that in the mouth cells (Stern, 1990).
The binding sites in the various bone cells exhibit saturation. The selectivity for the ligand is consistent with the biological potencies of the various analogs and metabolites, 1,25-(OH)2D3 being the most potent with 25-OH-D3 and 24,25-(OH)2D3 being at least two orders of magnitude significantly affected the concentration of binding sites, however, the effects of glucocorticoid treatment on receptor number were again different in cells derived from mouse and rat tissues. In mouse bone cells, dexamethasone, 130 nM, decreased the receptor number, both in the log phase of growth and at confluence (Stern, 1990). Incorporation of C-thymidine was markedly inhibited by dexemethasone at the log phase but not at confluence. In contrast, glucocorticoids increased the density of 1,25-(OH)2D3 receptors in cells derived from fetal rat bone and in fetal rat calvarial cells. In the rat bone cells, the effect was consistent throughout the cycle, with no effects of glucocorticids on thymidine incorporation. It was proposed that glucocorticoids maintain the content of 1,25-(OH)2D3 receptors in rat bone cells by inhibiting their degradation.
The biochemical receptor studies suggest that the osteoblast is a target cell for 1,25-(OH)2D3 . in addition, thaw-mount autoradiographic studies in 18 to 20 day old rat fetuses injected with 3H-1,25-(OH)2D3 demonstrated the presence of radioactivity in the nuclei of osteoblasts and osteoprogenitor cells (Stern, 1990). This accumulation of radioactivity was selectively blocked by 1,25-(OH)2D3. In contrast, no labeling was observed in mature multinucleated osteoclasts. Other evidence suggesting that the osteoblast rather than the osteoclast is the target for 1,25-(OH)2D3 action was obtained with enriched populations of mature rat osteoblasts incubated on inert surfaces. The addition of 1,25-(OH)2D3 was ineffective in increasing the motility of isolated mature osteoclasts (Stern, 1990). However, the osteoclasts were activated to resorbed cortical bone slices when co-cultured with osteoblastic cells, in addition to 1,25-(OH)2D3 (Stern, 1990). The effect was abolished by inhibitors of macromolecular factor that promotes bone resorption was released when osteoblasts were treated with 1,25-(OH)2D3 (McSheehy & Chambers, 1989). These results in isolated cell populations would be consistent with the model of Rodan and Martin, whereby the effects of 1,25-(OH)2D3 to elicit resorption by a direct effect on bone (Stern, 1990) could be elicited by an initial effect on the osteoblast, which would then activate the osteoclast to produce a local humorial mediator.
An alternative pathway for the direct effects of 1,25-(OH)2D3 on bone could be through increases in the numbers of osteoclasts. Evidence from several models indicated that osteoclasts arise from mononucleated hematogenous precursor cells that also develop into cells of the monocyte-macrophage lineage (Stern, 1990). Furthermore, 1,25-(OH)2D3 promotes the differentiation of monocytic cells, such as normal mouse alveolar macrophages and HL-60 promyelocytic leukemia cells, as well as primate marrow mononuclear cells with osteoclast characteristics including multinuclearity and tartrate-resistant acid phosphatase activity (Abe et al, 1983; Roodman et al, 1985). These findings support the possibility that the direct effect of 1,25-(OH)2D3 on bone resorption could be mediated through an effect on osteoclast differentiation and maturation. This model would appear to be inconsistent with the results of several recent studies in which 1,25-(OH)2D3 analogs with potencies greater than or equal to that of 1,25-(OH)2D3 on differentiation including 25-oxa-1α,25-(OH)2D3, 24,24-dihimo-1,25-(OH)2D3 and ∆22-24, 24 trihoma-1,25-(OH)2D3, MC 903 and 1, 25-dihydroxy-16-ene-23-yne-vitamin D3. These compounds have greater relative effects on differentiation than on bone resorption in vitro or production of hypercalcaemia in vivo, some even being inactive in eliciting resorptive and calcemic responses at concentrations several orders of magnitude higher than maximally effective concentrations of 1,25-(OH)2D3. 1,25-(OH)2D3 receptors have been shown to interact with DNA cellulose and as will described several of the effects of 1,25-(OH)2D3 on bone have been shown to be mediated through genomic actions. The report of a rapid transient effect of low concentrations of 1,25-(OH)2D3 to increase intracellular calcium in mouse osteoblasts raises the possibility of the existence of non-genomic second messenger effects. But, in another study, short term treatment with this metabolite failed to increase calcium influx in bone cells.
1.3 Biological Actions of Vitamin D on target tissues and Systems
1.3.1 Intestine
The maintenance of serum calcium and phosphate levels as well as the provision of minerals for bone formation by 1,25(OH)2D3 is largely mediated by the hormone's intestinal activities. One if the best-defined effects of 1,25(OH)2D3 is the stimulation of the intestinal lumen-plasma flux of calcium and phosphate. Extensive evidence exists for an interaction of 1,25(OH)2D3 with an intestinal receptor and for genome-mediated up-regulation of a calcium-binding protein, known a s calbindin-D. The amounts of calbindin-D in the intestinal mucosa in both humans and animals are positively correlated with the rate of calcium transport or absorption; however, studies have not yet defined the exact role of calbindin-D in this process (DeLuca, Krisinger & Darwish, 1990). In addition to the genomic actions of the hormone, emerging evidence supports the existence of a nongenomic stimulation of intestinal calcium transport by 1,25(OH)2D3 that is very rapid.
Bone tissue undergoes construct remodelling, in that under normal conditions the osteoclast-mediated resorption of bone is in approximate equilibrium with the osteoblast-mediated formation of new bone material. A variety of local and systemic hormonal modulators have been implicated in the short-term and long-term regulation of these dual processes, 1,25(OH)2D3 is well characterized as an essential hormone for the regular mineralization of new bone and as a potent bone-resorptive agent.
The 1,25(OH)2D3 -induced stimulation of bone growth and mineralization probably is not mediated through a direct effect on osteoblasts. Evidence suggests that 1,25(OH)2D3 stimulates bone mineralization indirectly by providing minerals for incorporation into bone matrix through increased intestinal absorption of calcium and phosphorus. On the other hand, osteoblasts, which possess 1,25(OH)2D3 receptors, are probably the primary target cells for 1,25(OH)2D3 in bone. Accordingly, a spectrum of osteoblast-related functions has been shown to be influenced by 1,25(OH)2D3 (Reichel et al, 1989). For example, 1,25(OH)2D3 modulated the proliferation of and alkaline phosphatase production in cultured osteoblasts, increased the synthesis of osteoblasts-derived bone y-carboxyglutamic acid protein (osteocalcin) and of matrix y carboxyglutamic acid protein, and down-regulated the production of type I collagen by fetal rat calvaria. Recently, investigators have demonstrated a 1,25(OH)2D3-mediated increased of receptors for epidermal growth factor B-like activity of osteoblast. Thus, 1,25(OH)2D3 seems to play a part in the regulation of osteoblast function; however, the physiologic relevance of such interactions (e.g., for osteoblast- mediated processes of bone remodelling) must be defined more precisely (Reichel et al, 1989)..
The bone-resorbing effects of 1,25(OH)2D3 probably can be divided into short-term and long-term actions. There is evidence the neither effect is exerted directly on the mature osteoclast. With respect to ling-term effects, investigators have shown that the administration of 1,25(OH)2D3 to rats results in an increased formation of osteoclasts in vivo over a period of several days. Studies in vitro have indicated that the number of osteoclast-like cells increased in long-term culture of primate bone marrow cells after exposure to 1,25(OH)2D3 for 14 to 21 days. Most of the available data suggest that the osteoclast originates from a hematopoietic cells of macrophage lineage. Therefore, the increase in osteoclast induced by 1,25(OH)2D3 may indicate a maturational effect of the hormone on myeloid hematopoietic precursor cells, in that these cells are prompted to different entiate toward functional osteoclasts. Consistent with the postulate that 1,25(OH)2D3 alters the number but not the function of the osteoclasts, chicken osteoclasts have been reported not to contain 1,25(OH)2D3 receptors. These findings may represent a case in which the ability of 1,25(OH)2D3 to induce cellular differentiation is closely linked to its effects on mineral metabolism.
The short-term effects of 1,25(OH)2D3 on bone resorption have been demonstrated in organ cultures of bone; the 1,25(OH)2D3-mediated release of calcium from bone was demonstrable after several hours. This effect was too rapid to be explained by the ability of the hormone to increase the pool of osteoclasts. The exact mechanism of this short-term mobilization of calcium from bone is not known but evidence suggests that 1,25(OH)2D3 induces the release of osteoblast-derived resorption factors that stimulate osteoclast activity.
In a study conducted by various authors, they have mentioned that the most important effect of 1,25(OH)2D3 on the kidney is the inhibition of 25(OH)D3-l-α-hydroxylase activity, which result in a decrease of 1,25(OH)2D3 biosynthesis. This effect is accompanied by a stimulation of 25 (OH)D3-24-hydroxylase (Iqbal, 1994). The hormone has also been implicated in the regulation of renal calcium and phosphate excretion. There is controversy, however, about the direction (increased excretion vs. increased resorption) of a possible 1,25(OH)2D3 -mediated effect and on the conditions in which the hormone interferes with renal calcium and phosphate transport. Clearly, more research is needed to determine the effects of 1,25(OH)2D3 on the kidney in addition to its modulation of the 25(OH)D3-hydroxylases (Reichel et al, 1989).
1.3.4 Immunological system
Various studies have proposed about the interpretation of some epidemiologic information which supports a role of vitamin D and latitude in reducing the risks of MS is that Vitamin D enhances the immunological system's capacity to fight the impacts of infectious diseases. These diseases are noted to be the most common diseases in winter and more common among children and adolescents who still do not have a well-developed immunological system (Grant, 2006). Recent studies that revealed that Vitamin D regulates the immune system administers cancer cell growth and controls the blood pressure hormone rennin provides an explanation for why the sufficiency of vitamin D has been observed to be so useful in the prevention of various chronic illness which plague both children and adults (Holick, 2005).
1.4 Factors influence Vitamin D levels
Vitamin D levels are said to be influenced by various factors. These factors are subdivided into two components, the biological and the physical factors. The biological factors include, age, gender, liver diseases, kidney diseases while the physical factors includes, sun protective agents, latitude or geographical aspects and seasonal variations. In this review, some studies which have shown how these factors have influenced the Vitamin D levels will be discussed.
1.4.1 Biological Factors
1.4.1.1 Age and Skin Colors, Kidney Disease and Liver Disease
It had been noted that the body should be able to maintain a specific Vitamin D levels (Barger-Lux et al, 1998). According to study, the most likely reason for this requirement is that necessarily every tissue and cell in the body has a VDR which needs Vitamin D. This vitamin is crucially essential for maintaining calcium metabolism and a good bone and skeletal health in life. With this, it is now noted that the maintenance of a serum 25(OH)D level of 80 nmol/L (32 ng/mL) or higher enhances the strength of the muscle (Bischoff-Ferrari, 2004) and adult's bone mineral density (Tangpricha et al, 2004). The effectiveness of vitamin D synthesis in the skin as well as the absorption of Vitamin D from the intestine is noted to decline with age. According to study, several aspects in addition to sun exposure or inadequate dietary intake are noted to predispose to vitamin D deficiency, which include severe liver or kidney disease. Stored Vitamin D may also be useless when DBP levels also decline substantially with the liver failure, severe malnutrition and nephrotic syndrome.
Aside from these factors, aging is also considered as one of the factors that affects the status of Vitamin D (Salamone, 1993). Studies have shown that 7-dehydrocholesterol status in the skin decline or decreases as individual ages. For instance, a 70 year old person has 25% of the capability to generate cholecalciferol as compared with a healthy young adult (McLaughlin & Holick, 1985: Holick, Matsuoka & Wortsman, 1989).
Some information from other nations suggest that the occurrence of having low 25-OHD status in the elderly people is more typical than was thought to be the condition, reaching 80% in 80-year-old women living in elder people's homes in the Netherlands (Lips, Van Ginkel and Jongen, 1988). In addition, in line with healthy young adult the status of vitamin D may reach 42% utilising a cut-off point of 20 ng/ml (50 nmol/L) for serum 25-OHD (Gordon et al, 2004). In some nations like Australia, an investigation carried out with men whose age is over 60 years of age, which include 41 participants with fractures of the femoral neck, 41 hospitalized men for other reasons and 41 outpatients. Herein, the study revealed that the mean serum 25-OHD levels were relatively lower in the patients with fractures of the femoral neck (18.2 ng/ml, or 45.5 nmol/L) and also lower in those hospitalized for other reasons (24.4 ng/ml, or 61 nmol/L) or in the outpatients (25.4 ng/ml, or 63.5 nmol/L).
Subclinical vitamin D deficiency which is commonly defined as a serum 25-OHD level below 20 ng/ml, or 50 nmol/L happened in 63% of the patients having fractures of the femoral neck, as compared with 25% of the outpatients. Int his regard, analysis shows that in relation to other risk factors for osteoporosis such as age, body weight, concomitant morbid conditions, alcohol intake, smoking and use of corticoids, sub-clinical vitamin D deficiency was the most essential aspects in predicting the risk of fractures of the femoral neck (Diamond et al, 1998).
In a cross-sectional study conducted at In Wolverhampton, England, the researchers compared 98 patients from the ethnic Asian community, which were being followed up in rheumatology clinics and they also use 36 control individuals. In this study, the participants were matched with regards to gender, age and BMI. With this, most of the patients were noted to be vegetarians and had a diet low which is low in calcium.
The emergence of severe vitamin D deficiency was founded to be 78% and 58%, respectively among the two sub-groups. On one hand, the color of the skin, which limits the penetration of sunrays, and usual clothes that covers a large entity of the body site in a region with a low quantity of sunlight, both provide to the high frequency of extreme vitamin D deficiency among these people (Serhan, Ali & Newton, 1999). In a study conducted by Harris and his collegues (2000), they used a population of non-institutionalised low-income elderly people in Boston USA, whose age are raging from 64-100 years. The study evaluated and assessed the serum 25-OHD levels of 308 people in the Boston Low Income Osteoporosis Study. Int his study, they found out that twenty-eight black patients (21% of 136) and 12 white individuals (11% of 110) had vitamin D levels regarded as very low (< 10 ng/ml). One on hand, 73% of the black and 35% of the white patients had 25-OHD status lower than 20 ng/ml (50 nmol/L). While in these patients or participants of both Asian and Hispanic origin, they found out a similar Vitamin D levels to those of the white patients. In this regard, the serum PTH status was considerably higher in the patients with vitamin D deficiency, specifically the black individuals (Harris et al, 2000).
1.4.2 Physical factors
1.4.2.1 Sun Protective Agents
It has been noted that Vitamin D deficiency is an unrecognized epidemic in both children and adults all over the world (Nesby-O'dell et al, 2002), even in some of the regions with sunniest climates, which include Saudi Arabia and India (Sedrani, 1984: Sedrani et al, 1992). Some study of the intake of the Vitamin D in country like United States have showed that neither children nor adults are being able to receive the suggested AIs for vitamin D (Moore et al, 2004). It is noted that that general public health implications of the deficiency of vitamin D are incalculable. Such is specifically true for individuals who are more prone to the deficiency of vitamin D which include individuals with darker skin tone. Herein, studies have noted that African Americans are more active to enhancing colon; breast, prostate and other variety of cancers and such diseases are aggressive as compared with those people with white skin color. Furthermore, people with darker skin color are more likely to have type 1 diabetes and hypertension, with a high risk for vitamin D deficiency (Chiu et al, 2004). Hence, the level of vitamin D has such essential health consequences that a measurement of 25(OH)D must be part of a usual and customary physical examination for both children and adults at all ages. It is said that the sensible exposure of the sun in times of spring, the summer, and the fall but not during the winter unless one is located below 35° north, and education of the general public about the advantages of some limited sun exposure to satisfy the level of the vitamin D requirements should be focused and highlighted.
1.4.2.2 Latitude (Geographical) and Seasonal Differences
The differences in geographic location and seasonal differences in ultraviolet light exposure are associated with different rates of cutaneous vitamin D synthesis (Webb, JSline & Holick 1988). Accordingly, the levels and status of vitamin D also differ in individuals living at different latitudes (Webb, JSline & Holick 1988). Herein, the seasonal variations in ultraviolet light exposure is related with seasonal differences in vitamin D status and levels, with a peak at the end of summer and a nadir at the end of winter (Webb, JSline & Holick 1988). With the enhanced concern about the relation between UV light exposure and the generation of skin cancer, people who avoid sun exposure may not be able to synthesize sufficient amount of vitamin D all over the skin to sustain adequate amount of vitamin D levels. Herein, the extent to which high solar protection factor (SPF) sunscreens interfere with cutaneous vitamin D synthesis remains controversial (Holick, 1994). The lower level (OC25) showed a 6-fold difference between Asians and non-Asians in winter and 2-fold difference in summer (Asians vs non-Asian, winter 2·3 vs 13·4, summer 7·4 vs 13·4 ng/ml). Probability transformation analysis proves a significant discrepancy between Asians and non-Asians during both seasons. Information from other countries recommend that the happenings of low 25-OHD status in the elderly is more typical than was thought to be the situation, reaching 80% in 80-year-old women living in old people's homes in the Netherlands (Chapuy et al, 1994).
1.5 Vitamin D deficiency
1.5.1 Definition of vitamin D deficiency
Vitamin D Deficiency is a term used when vitamin D levels is insufficient or not enough. According to studies, it emerges when the focus of 25-hydroxy-vitamin D (25-OH-D) in an individual's blood serum happens at 12 ng/ml or less. It is said that an individual with a normal concentration of 25-hydroxy-vitamin D in their blood serum is 25-50 ng/ml (Fouda, 1999: Thomas & Demay, 2000). Scholars believed that the continuous deficiency of vitamin D for many months, especially among growing children, some diseases will occur and having a prolonged deficiency of the vitamin D among adults may result to disease like Osteomalacia (Thomas & Demay, 2000).
1.5.2 Criteria of definition of Vitamin D deficiency
There are various criteria of the deficiency of Vitamin D. First, Vitamin D deficiency may be caused by cases which result in an individuals' little exposure to sunlight. Such cases may include: living in northern regions; having dark skin; being an infant or being elderly, and having small exposure outside and lastly covering one's face and even the entire body, for religious purposes (Department of Health, 1998). For instance, many Arab women are covering their body with black cloth, and wear a veil and black gloves when they go outside since it is a part of their culture and religion. Such women may have deficiency of vitamin D, even if they live in a sunny climate. On one hand, other caused of Vitamin D deficiency is related to the food we eat. Most food has little or even no vitamin D. In this regard, sunlight is often a deciding criterion on the notion of having Vitamin D deficiency. Even though fortified infant formula and fortified milk are said to have high levels of vitamin D, the breast milk of mothers is rather low in the vitamin. With this, the term fortified is referred to vitamins which are added to the food by the producers (Department of Health, 1998).
1.5.3 Populations at risk for Vitamin D deficiency
It is said that Vitamin D deficiency affects different people from infancy to adulthood. This part of the review will provide discussion about the populations at risk for Vitamin D deficiency.
1.5.3.1 Infants and children
The deficiency of Vitamin D in infants and children has been considered as continuous problems in various countries (Lebrun et al, 1993). In a study conducted by Roth and his colleagues (2005) they reported that 34% of children with age 2-12 years in Edmonton had a deficient vitamin D status. Studies have also shown that skin production of vitamin D is diminished among infants, which contribute to the dilemma. Due to the danger of having skin cancer that follow sun damage to the skin, the health authorities suggest that children who are younger than one year of age should prevent direct sunlight and also utilise sunscreens (Harris & Dawson-Hughes, 1998), both of which have the impact of reducing the production of vitamin D in the skin. Hence, vitamin D supplementation is the only viable approach of achieving optimal vitamin D level. The high percentage of insufficiency and deficiency of vitamin D seen in the African-American adolescent females in the study are similar to previous researchers in African-Americans (Nesdy-O'Dell, 2002). Relatively lower serum 25(OH)D status have been presented in African-American adolescents as compared with Caucasian adults, and in recent times a number of situation of nutritional rickets were considered in African-American infants and young children in the United States (Kreiter et al, 2000: Nesdy-O'Dell, 2002).
1.5.3.2 Adolescents
Like in infants and children, deficiency of Vitamin D in adolescents was also noted to be epidemic in most developed cities in various countries like in Northern Europe and the United States by the end of the 19th century. The significance of the role of vitamin D as well as sunlight in the prevention and cure of some diseases like rickets has made major implications eradicating diseases like rickets as a main health concern for adolescents. What is not-well acceptable is that the deficiency of vitamin D is usual in otherwise healthy, adolescents (Outila et al., 2001), young-adult, and elderly people (Chapuy et al., 1997; Lips, 2001). For instance, 52% of Hispanic and black adolescents in a research conducted in Boston (Gordon et al, 2004) and 48% of white pre-adolescents females in a study conducted in Maine (Sullivan et al, 2005) had 25-hydroxyvitamin D status below 20 ng/ml. On one hand, some studies has also been conducted at the end of, 42% of 15- to 49-year-old black girls and women throughout the United States had found out to have 25-hydroxyvitamin D status below 20 ng/ml 25 and 32% of healthy adolescents, residents and physicians, at a Boston hospital were noted to be vitamin D-deficient, in spite of drinking a glass of milk and having a multivitamin each day and eating salmon at least once a week (Tangpricha et al, 2002). In some regions like Europe, where very few foods are Vitamin D fortified, adolescents would appear to be at specifically high risk (Gordon et al, 2004). Those people who are living close to the equator who are exposed to the light of the sun without sun protection have robust status of 25- hydroxyvitamin D above 30 ng/ml (Vieth, 2004). But, even in the sunniest regions, the deficiency of vitamin D is common when most of the skin is protected from the sun.
1.5.3.3 Elderly
As mentioned, vitamin D deficiency not only gives risks to infants and adolescents but also to elderly people. The prevalence of the deficiency of Vitamin D is considered to be high among elderly, especially among nursing home residents (Gloth & Tobin, 1995). In previous studies of medical inpatients in Massachusetts, the prevalence of deficiency was 57% (Gascon-Barre, 2005). The principal causes of the deficiency among elder people in Canada and US are said to be either the reduction or complete abstinence of consumption of vitamin D fortified foods, supplements and lack of sunlight exposure (Trivedi, Doll & Khaw, 2003).
1.5.3.4 Pregnant and lactating women
Pregnant and lactating women vitamin D deficiency is noted to be typical in northern regions (Weiler et al, 2007; Lips 2006) and is a main risk aspect for the deficiency of vitamin D in infancy (Munns, Zacharin & Rodda, 2006). Prompt enhancement of the fetus in the latter period of pregnancy tends to reduce maternal vitamin D as integration of calcium within the skeleton in the final trimester of the pregnancy increases. Herein, the deficiency of pregnant and lactating women may be connected not only with rickets and newborn hypocalcemia, but also with smaller quantity, dental malformations and decreased vitamin D in breast milk (Munns, Zacharin & Rodda, 2006). It is a fact that fetus and newborn are completely dependent on the mother for supplying them with vitamin D that crosses the placenta and is represented both in infant stores and in the quantity of vitamin D accessible in breast milk. Herein, it is very essential that mothers have status of vitamin D sufficient to provide their Vitamin D needs and those of their infants.
Studies which have been conducted from Denmark with veiled Moslem women have shown that in a relative absence of exposure to sunlight a dietary intake of 600 IU vitamin D daily is still insufficient to sustain the adequate level vitamin D. With this, the researchers have recommended that 1,000 IU per day should be more appropriate for these women (Glerup et al, 2000).
1.6 Disorder of Vitamin D metabolism
1.6.1 Rickets
1.6.2 Vitamin d resistance
1.6.3 Osteomalacia
1.6.4 Osteoporosis
One of the diseases that are cause by the disorder of vitamin d metabolism is osteoporosis. A skeletal disorder which is characterized by low density of the bone and micro- architectural deterioration of the bony tissue is known as osteoporosis. Osteoporosis is a bone disease in which the bones lose calcium, become more brittle, and break more easily. This is a metabolic disease involving loss of bone mineral with advancing age. It results in decreased bone strength and increased vulnerability to fractures. It particularly affects older women. Unlike syphilis, documentary sources are largely silent on this disease—in order to study the history of osteoporosis we must study bones.
The prime cause of osteoporosis in women is the hormonal changes which accompany the menopause. However, a number of factors associated with modern Western life-styles also seem to play a part in exacerbating bone loss. Osteoporosis is a health risk for the elderly due to the fractures associated with it.
Most modern Western nations it is a major and growing cause of mortality and disability. It is clearly of interest from the point of view of our present-day understanding of this disease to study its history in earlier European populations with life-styles very different from our own. I have attempted one such study (Mays 1996), using skeletons of medieval women from Wharram Percy.
Factors thought to exacerbate osteoporotic bone loss following the menopause include sedentary life-style, deficient calcium intake, cigarette smoking and perhaps vitamin D deficiency (Mays 1996).While anyone can have osteoporosis, it is most common in elderly people, particularly women. Because of osteoporosis, one in five women breaks a hip before the age of 75. Fractures of the spine, resulting in pain, decrease in height, and a forward deformity of the spine (dowager's hump) are even more common. Inactivity makes osteoporosis worse (Christodoulou and Cooper, 2003).
Although the best protection from osteoporosis is prevention, scholars now have some effective treatments. As with all kinds of arthritis and rheumatism, consistent good health practices are crucial. This starts with a lifestyle that excludes smoking and drinking too much alcohol. The discussion outlines the healthy habits that are useful in preventing and dealing with osteoporosis (Eddy et al, 1998). Study shows that there are significant discrepancies in the incidence and effect of osteoporosis in various populations all over the world (Cooper & Melton, 1996). According to studies, hip fractures are much more usual in whites than non-whites people. In addition, studies have also revealed that there is a substantial variation within individuals of a given gender and race. It has been mentioned that age adjusted hip fractures are more prevalent among residents of Scandinavia than those white people who live in Oceania or America. In European regions, hip fracture are said to vary more than sevenfold from one region to another (Johnell et al, 1992).
1.6.5 Vitamin D toxicity
One of the disorders of the Vitamin D metabolism is the toxicity Vitamin D which is commonly noticeable in patients with vitamin D intake which is ranging from 40,000 IU daily. Among the reported situation of vitamin D toxicity, nearly all who have been involved in doses which are higher than those utilized in the clinical trials reviewed: those individuals with compromised health, specifically in line with renal insufficiency, and confounding by hydrochlorothiazide treatment (Hathcock et al, 2007). The 25(OH)D highlights reported were coherently higher than those seen with a vitamin D3 daily dose of 250 _g. Hence, such study can be considered as inappropriate or helpful as the basis of a NOAEL for the public. Conversely, the situations which exhibits Vitamin D toxicity all had serum 25(OH)D intensity which is ranging from 700 to _1600 nmol/L (Jacobus et al, 1992). Such findings have been able to increase the confidence in the NOAEL of 250 _g, since the 25(OH)D absorption usually attained with that intake (220 nmol/L) (Heaney et al, 2003) are much lower. In a case study of an 85-y-old woman who is experiencing hypercalcemia and other unfavorable implications from a significantly low dose of vitamin D3 (Jansen, Janssen & de Jong, 1997). The study have found that the serum 25(OH)D absorption on admission were 62 nmol/L, which is well below that noted to be linked with Vitamin D toxicity. Such case study appears to be an unusual case which has not been simulated elsewhere in other studies.
1.7 Assay Methods for Vitamin D and its Metabolites Measurements (Historical Background)
1.7.1 Competitive Protein Binding Assay
1.7.2 Enzyme Linked Immunosorbent Assay
1.7.3 Radioimmunoassay
1.7.4 Chemiluminescence Protein Binding Assay
1.7.5 High Performance Liquid Chromatography
1.7.6 Liquid Chromatography-Tandem Mass Spectrometry
1.7.7 Limitations of Vitamin D Assays
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