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Calcitriol(1,25 di-OH Vit D) Blood Test

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Calcitriol(1,25 di-OH Vit D)


Introduction:
Calcitriol(1,25 di-OH Vit D) is also known as: 25-hydroxy-vitamin D (Calcidiol, Calcifidiol) and 1,25 dihydroxy-vitamin D (Calcitriol).
25 OH Vitamin D Blood Tests are used to determine if bone weakness, bone malformation, or abnormal metabolism of calcium (reflected by abnormal calcium, phosphorus or PTH tests) is occurring as a result of a deficiency or excess of vitamin D.
Since vitamin D is a fat-soluble vitamin and is absorbed from the intestine like a fat, vitamin D tests are sometimes used to monitor individuals with diseases that interfere with fat absorption, such as cystic fibrosis and Crohn's disease, to assure that they have adequate amounts of vitamin D.
Vitamin D tests are sometimes used to determine effectiveness of treatment when vitamin D, calcium, phosphorus, and/or magnesium supplementation.

Calcitriol(1,25 di-OH Vit D) Blood Test

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Calcitriol(1,25 di-OH Vit D)

Introduction:
Calcitriol(1,25 di-OH Vit D) is also known as: 25-hydroxy-vitamin D (Calcidiol, Calcifidiol) and 1,25 dihydroxy-vitamin D (Calcitriol).
25 OH Vitamin D Blood Tests are used to determine if bone weakness, bone malformation, or abnormal metabolism of calcium (reflected by abnormal calcium, phosphorus or PTH tests) is occurring as a result of a deficiency or excess of vitamin D.
Since vitamin D is a fat-soluble vitamin and is absorbed from the intestine like a fat, vitamin D tests are sometimes used to monitor individuals with diseases that interfere with fat absorption, such as cystic fibrosis and Crohn's disease, to assure that they have adequate amounts of vitamin D.
Vitamin D tests are sometimes used to determine effectiveness of treatment when vitamin D, calcium, phosphorus, and/or magnesium supplementation.

Its concentration is measured by means of analysis of a blood sample drawn from the vein in the arm.
Calcitriol, also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups (abbreviated 1,25-(OH)2D3 or simply 1,25(OH)2D), which was identified by Michael F. Holick. It increases the level of calcium (Ca2+) in the blood by increasing the uptake of calcium from the gut into the blood, and possibly increasing the release of calcium into the blood from bone.
Calcitriol usually refers specifically to 1,25-dihydroxycholecalciferol, but may also sometimes include 24,25-dihydroxycholecalciferol .
Because cholecalciferol already has one hydroxyl group, only two are further specified in the nomenclature.
We all know about vitamin D. It is the vitamin that prevents rickets, preserves bone density in postmenopausal women and is not produced in patients with chronic renal failure. In this final situation renal osteodystrophy is the result.
However, there is increasing recognition that the effects of vitamin D are multifaceted and involve many aspects of health that may affect on the care of patients with or at risk for cancer.
Vitamin D is really a hormone. It is synthesized in the body as a class of molecules. Sunlight strikes the skin and causes a reaction that converts 7 dehydrocholesterol to cholecalciferol (vitamin D3). Vitamin D3 is hydroxylated in the liver to form 25-OH D3 and in the kidney to form the most active vitamin D molecule, 1,25 di(OH)D3 or calcitriol.
1,25 di(OH)D3 is further catabolized by CYP24 (24 hydroxylase), which produces 1,24,25 D3 and limits the activity of calcitriol; 1,24,25D3 is a poor VDR ligand. 25(OH)D3 is the chemical that is readily measurable by commercial assays and is the best reflection of adequate vitamin D stores.
The normal serum concentration of 25(OH)D3 is 32 ng/mL to 100 ng/mL, and normal is defined as the concentration that is associated with no further decrement in parathyroid hormone or improvement in BMD. These are the measures that have been taken as indicative of optimal vitamin D nutrition.
There are limited data regarding the relationship of parathyroid hormone with BMD and how it modulates the effect of vitamin D on tissues other than bone. As there is uncertainty regarding the optimal level of 25(OH)D3, there is controversy about the optimal daily requirement of dietary vitamin D. The recommended daily allowance established by the USDA is 400 IU of D3 per day. This is the amount of D3 necessary to avoid rickets in children. Some have argued that this allowance is too low by a factor of between three to six or more.
Vitamin D is found in blood in two forms: 25 hydroxy Vitamin D and 1,25 dihydroxy Vitamin D. 25 hydroxy Vitamin D (25 OH Vitamin D) is the major form of the hormone found in the blood and is the inactive precursor to the active hormone 1,25 dihyroxy Vitamin D. Because of its long half-life and higher concentration, 25 OH Vitamin D is commonly measured to assess and monitor Vitamin D status in individuals.
Vitamin D is produced in the skin (vitamin D3, also called cholecalciferol) on exposure to sunlight and also is ingested in foods and supplements (vitamin D2, also called ergocalciferol).
The main role of Vitamin D is to help regulate the absorption of calcium, phosphorus, magnesium. Vitamin D is vital for the growth and health of bone.

 

25 OH Vitamin D tests are precribed to check bone weakness, bone malformation, or abnormal metabolism of calcium.
Since vitamin D is a fat-soluble this test is sometimes used to monitor individuals with diseases that interfere with fat absorption, such as cystic fibrosis and Crohn's disease.
Its concentration is measured by means of analysis of a blood sample drawn from the vein in the arm.
Vitamin D is an important immune system regulator. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to inhibit the development of autoimmune diseases, including inflammatory bowel disease (IBD). Paradoxically, other immune system-mediated diseases (experimental asthma) and immunity to infectious organisms were unaffected by 1,25(OH)2D3 treatment. There are similar paradoxical effects of vitamin D deficiency on various immune system functions. Vitamin D and vitamin D receptor (VDR) deficiency resulted in accelerated IBD. Experimental asthma was unaffected by 1,25(OH)2D3 treatment and was less severe among VDR-deficient mice. Vitamin D is a selective regulator of the immune system, and the outcome of 1,25(OH)2D3 treatment, vitamin D deficiency, or VDR deficiency depends on the nature of the immune response (eg, infectious disease, asthma, or autoimmune disease). An additional factor that determines the effect of vitamin D status on immune function is dietary calcium. Dietary calcium has independent effects on IBD severity. Vitamin D-deficient mice on low-calcium diets developed the most severe IBD, and 1,25(OH)2D3 treatment of mice on low-calcium diets improved IBD symptoms. However, the best results for IBD were observed when the calcium concentration was high and 1,25(OH)2D3 was administered. Both the type of immune response and the calcium status of the host determine the effects of vitamin D status and 1,25(OH)2D3 on immunity.
Populations at risk:
There are many studies that indicate there is an inverse relationship between environmental light exposure, estimated and measured blood vitamin D and cancer frequency and mortality rate. Prostate, breast, lung, colorectal, pancreatic cancer and lymphoma have all been shown to be more frequent among populations estimated to have low vitamin D levels.
There is considerable evidence that cancer cells exposed in vitro or in vivo to calcitriol undergo differentiation, cell cycle arrest and apoptosis, depending on the model and the dose of calcitriol. In addition, increasing evidence indicates that vitamin D is an important factor in angiogenesis, and in certain settings high dose vitamin D may inhibit tumor growth through disruption of angiogenesis. Finally, many investigators have shown that calcitriol potentiates the antitumor activity, in vivo and in vitro, of a number of cytotoxic agents: taxanes, anthracyclines, alkylating agents and antimetabolites.
These data have led several groups to evaluate combinations of high-dose calcitriol and a variety of antitumor agents. No additive toxicity has been seen in a number of studies. The limitation of these trials has been that the commercially available preparations of calcitriol are unsuitable for high-dose therapy. Apparent absorption and exposure are unpredictable and saturable as doses of commercially available calcitriol are escalated. This has led a new company, Novocea, to develop an improved, high-dose calcitriol formulation. Based on encouraging phase-2 data from Thomas Beer and colleagues in androgen independent prostate cancer, this company conducted a phase-3 randomized trial of docetaxel (Taxotere, Sanofi Aventis) at 32 mg/m2 on day two with or without calcitriol at 0.5 mcg/kg at day one along with weekly X4 every six weeks.
The endpoint for this trial was improved prostate specific antigen response. While this endpoint was not achieved, survival appeared to be improved and toxicity reduced in the calcitriol arm. This has led to a 1,000-patient trial to attempt to confirm this intriguing observation.
Our own research group has noted in murine and canine models that calcitriol in high dose potentiates the in vivo antitumor effect of cisplatin, paclitaxel, gemcitabine (Gemzar, Eli Lilly) and mitoxantrone. Accrual of patients is ongoing.
While considerable work remains, these data suggest that calcitriol in high doses may be a useful adjunct to standard cancer chemotherapy. A pressing issue that requires delineation is the appropriate dose of high-dose calcitriol.
It is clear that high-dose intermittent therapy is safe and nontoxic. We have given up to 100 mcg per week by IV without toxicity, and we are conducting a phase-2 trial in prostate cancer with 77 mcg IV weekly, with no appreciable toxicity. Therefore, determination of the optimal or maximally tolerated dose of calcitriol is a critical step in evaluating this agent as a drug for use in cancer therapy.
Beyond calcitriol:
In addition to the potential for high-dose calcitriol as a cancer therapy, there are increasing data that vitamin D deficiency or insufficiency is common in the population in general and in cancer patients in particular.
There are broad health consequences of low vitamin D levels. Among the clues to the systemic consequences of vitamin D deficiency are the findings in the vitamin D receptor knockout mouse. There are at least two forms of this mouse, and in this model vitamin D signaling is markedly diminished.
In addition to the expected disorders of bone and mineral metabolism these mice show abnormalities in hair, cardiac muscle, skeletal muscle, blood vessel development and susceptibility to infection and thrombogenesis. These data are intriguing in view of clinical data that suggest that infection, immune function, motor function, thrombogenesis and blood pressure control are dysregulated in individuals with low serum vitamin D levels.
Finally, it is sobering to recognize how common low serum 25(OH)D3 levels are. Beer and colleagues were among the first to point out the frequency of vitamin D deficiency among hospitalized patients. They found that more than 250 patients admitted to the Massachusetts General Hospital, 57% had levels of 25(OH)D3 less than 15 ng/mL.
We have recently examined 25(OH)D3 levels among ambulatory patients with prostate and colorectal cancer. Among more than 400 individuals, 70% of patients had 25(OH)D3 levels less than 32 ng/mL, the currently recognized lower limit of normal. In our studies, and those of many others, risk factors for vitamin D insufficiency are black race, season of the year of assessment and level of activity/sun exposure.
Whether certain kinds of patients with cancer are more likely to have low vitamin D levels is unclear. In our studies, family members and acquaintances who accompanied our patients to their ambulatory visits had a similar frequency of low 25(OH)D3 levels.
There is little information about the effect of cholecalciferol replacement on cancer risk or the risk for other ills associated with low 25(OH)D3 levels. There are randomized trials among nursing home residents showing that D3 replacement reduces the risk for falls. A recent study suggested that D3 of 1,100 IU per day plus calcium replacement reduces cancer risk.
We have begun careful studies of replacement in cancer patients that we hope will clarify how often replacement is needed, factors predictive of the need for larger doses and the optimal replacement dose.
Vitamin D likely has much broader health effects than simply those associated with bone and mineral metabolism.
Vitamin D deficiency, often defined as a serum 25(OH)D3 level of 15 ng/mL or less, is frequent and insufficiency, defined as 25(OH)D3 level of 32 ng/mL, is common. Low 25(OH)D3 levels are common because of low dietary intake, limited sun exposure and infrequent use of sufficient supplements.
I have begun to recommend that all cancer patients ask their doctors to measure their 25(OH)D3 levels and oversee supplementation to assure blood levels are at least in the normal range. I think this is a reasonable for all adults, though the health benefits of this approach or a more aggressive replacement strategy have not been evaluated.
Vitamin D supplementation merits continued study as a potential cancer preventive approach. In addition, we will find that the use of calcitriol in combination with standard chemotherapy will improve therapy and reduce toxicity in some situations. Exactly what situations and what schedule, dose and formulation of calcitriol will be the focus of considerable study during the next few years.
Role of vitamin D in vascular calcification:
The role of vitamin D and its derivatives in vascular calcification is complex. It has long been known that in humans, hypervitaminosis D may be associated with extensive arterial calcium phosphate deposits, mostly in the form of apatite crystals. In experimental animals, the administration of pharmacological doses of vitamin D sterols can lead to widespread arterial calcification, especially in association with favourable conditions such as atherosclerosis, diabetes and chronic kidney disease (CKD).
The mechanisms by which high doses of vitamin D or its derivatives induce vascular calcification include an increase in serum calcium and phosphate, the formation of fetuin-A mineral complexes in association with a decrease in free serum levels of fetuin-A and the local induction of osteochondrogenic programmes with transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells.
In adult patients with CKD, both before and after the initiation of dialysis therapy, the severity and progression of vascular calcification have been found by two groups to correlate with circulating 25-hydroxyvitamin D [25(OH)D] levels. However, another group failed to identify an independent association of arterial calcification with serum 25(OH)D and 1,25-dihydroxyvitamin D [1,25(diOH)D] concentrations although both of them were negatively correlated with aortic pulse wave velocity and positively with brachial artery distensibility and flow-mediated dilatation. Our group also did not find an association between serum 25(OH)D levels and aortic calcification or stiffness in patients with different stages of CKD.
The long-term administration of vitamin D sterols to children and young adults with CKD was found to induce vascular calcification. The prevalence of calcinosis was higher in the children treated with calcitriol than in those treated with vitamin D2 or vitamin D3. Differences between studies may be explained by different doses, types of vitamin D sterols used and treatment duration. Of note, different types of active vitamin D derivatives, when given in high amounts to animals with CKD, are not endowed with the same calcification-inducing capacity. Thus, paricalcitol has been shown to be less pro-calcifying in uraemic rats than calcitriol or doxercalciferol . Whether this also holds true for human patients with CKD remains a matter of debate. No prospective trials are available in such patients comparing the effects of calcitriol with those of the newer active vitamin D derivatives.
Physiological versus pharmacological effects of vitamin D sterols:
The effects of vitamin D overload on the vessel wall need to be distinguished from the role of vitamin D under physiological conditions. It is well known that vitamin D exerts pleiotropic actions in multiple organs and tissues, ranging from regulation of the immune system to that of mineral metabolism. It is generally assumed that most of the vitamin's action occurs through the binding of its active metabolite, 1,25(diOH)D (calcitriol) to the vitamin D receptor (VDR), although effects mediated by other metabolites such as 25(OH)D and 24,25-dihydroxyvitamin D are also possible. In addition to the endocrine effects of VDR activation by circulating calcitriol, local 1,25(diOH)D production can also activate VDRs expressed in many tissues via an autocrine mechanism, including endothelial cells and VSMCs. Calcitriol can increase the expression of the VDR and decrease the proliferation of VSMCs. At high doses, it also can promote VSMC migration, transition into an osteoblast-like phenotype and calcification, together with up-regulation of proteins regulating mineralization and calcium transport. Thus, it is likely that autocrine, paracrine and endocrine functions of vitamin D can influence vascular structure, function and remodelling. However, Wang et al. recently challenged the concept of direct VDR activation in the blood vessel wall, based on results obtained in an original mouse model. They claim that VDRs are not expressed in arterial endothelial or smooth muscle cells, arguing that previous positive results were an artefact owing to technical problems. This issue needs to be clarified by future studies.
It is not always easy to distinguish physiological from pharmacological actions. On the one hand, low doses of both calcitriol and paricalcitol have been shown to be protective against aortic calcification in uraemic mice with low-density lipoprotein (LDL)-receptor deletion, possibly via stimulation of skeletal osteoblast surfaces and bone formation rates. In contrast, high doses of these active vitamin D sterols induced vascular mineralization, possibly in association with enhanced bone resorption. On the other hand, the observation by another group is noteworthy; the group found that non-hypercalcaemic doses of calcitriol-induced diffuse aortic calcification involving the intima and media layer only in uraemic rats but not in non-uraemic rats. These data would indicate a permissive effect of the uraemic state for cardiovascular damage, which could be induced even by relatively low doses of calcitriol.
This problem may be solved by the possibility of a U-curve relationship between vitamin D sterols and vascular calcification, as postulated by Zittermann (Figure 1). In keeping with this, Shroff et al. reported a U-shaped bimodal distribution across serum 1,25(diOH)D levels in paediatric dialysis patients. Both calcification scores and carotid intima-media thickness were significantly greater in the patients with either low or high calcitriol levels than in those with normal levels. In contrast, serum 25(OH)D levels did not correlate with any vascular measure. Of interest, low 1,25(diOH)D levels were associated with higher high-sensitivity C-reactive protein (CRP) concentrations. Calcification was most frequently observed in patients with the lowest calcitriol and the highest CRP levels. In another recent study in children with CKD, serum fetuin-A levels were inversely correlated with serum CRP but positively with the cumulative intake of 25(OH)D and calcitriol.

Vitamin D, inflammation and vascular calcification:
Inflammation is another important mechanism in the pathogenesis of vascular calcification. Associations of circulating levels of pro-inflammatory factors such as tumour necrosis factor-alpha (TNF-α), interleukin-1β and interleukin-6 with arterial calcification have been observed in general population and in patients with CKD. Circulating cytokines have also been shown to be inversely related to serum fetuin-A, an inhibitor of extraskeletal calcification. LDL receptor-deficient mice with Type 2 diabetes, which become obese upon a high-fat diet, develop aortic calcification in association with an increase in serum TNF-α and an up-regulation of the Msx2-Wnt signalling pathway. The latter favours the elaboration of osteogenic and chondrogenic programmes in the vessel wall. By dosing with TNF-α neutralizing antibody infliximab, it was possible to decrease the activity of this pathway and thereby reduce aortic calcium accumulation. Furthermore, vascular overexpression of a TNF-α transgene in mice induced aortic calcification, together with an up-regulation of the inflammation marker haptoglobin and the osteo chondrogenic transcription factors Msx2, Wnt3a and Wnt7a.
In this issue of the Journal, Aoshima et al. further examined the role of vitamin D sterols in inflammation-dependent vascular calcification (ref. to be inserted by Publisher). They used an in vitro system of human VSMCs maintained in culture for 9 days. First of all, the authors confirmed the observation that TNF-α enhances the vascular calcification process induced by a high phosphate concentration in the incubation medium. TNF-α actually increased the deposition of calcium phosphate in the VSMC cultures by nearly 100%. When adding the most active natural vitamin D sterol calcitriol or the synthetic active vitamin D derivative maxacalcitol to the incubation medium, the phosphate- and TNF-α- induced stimulation of VSMC mineralization was drastically reduced. In contrast, the two sterols failed to reduce VSMC mineralization induced by exposure to high phosphate alone.
One of the mechanisms of the vitamin D sterol effects was downregulation of the expression of Cbfa1/Runx2 and osteocalcin, that is genes that are involved in the osteochondrogenic process, with transformation of VSMCs to osteoblast-like cells. This action involved binding to the VDR and its activation; however, there was no increase in VDR expression.
The authors demonstrated the involvement of yet another remarkable mechanism of action of active vitamin D sterols. Both calcitriol and maxacalcitol reduced the expression of matrix metalloproteinase-2 (MMP-2) in their VSMC culture system, which was greatly increased in response to high phosphate and TNF-α concentrations, both at the messenger RNA and the protein level. MMP-2, which is a major elastase, degrades elastin in the vessel wall and elsewhere. It has been shown to be activated by the uraemic state , and elastin degradation by elastases activated in inflammatory states has been shown to be a major contributor to vascular calcification. Of interest, in the study by Aoshima et al., the inhibitory effect of maxacalcitol on MMP-2 expression was significantly more pronounced than that of calcitriol.
It must be pointed out that the authors examined the effects of pharmacological, not physiological, concentrations of calcitriol and comparable concentrations of maxacalcitol. This could mean that even high doses of vitamin D sterols might be beneficial in inflammation-linked vascular calcification and in the concomitant presence of a high phosphate environment. However, the studies were performed in a non-uraemic environment. Therefore, any extrapolation from these in vitro findings to the uraemic state in vivo must be done with extreme caution. That being said, the findings are in agreement with observations of beneficial effects of various active vitamin D derivatives made in some models of uraemic animals  although not in other experimental models or with other vitamin D derivatives, as mentioned above.
Figure 2 illustrates in a schematic way how low doses of vitamin D or its derivatives, i.e. doses in the physiological range, might exert protective actions against vascular calcification in the condition of CKD whereas high pharmacological doses might promote the vascular mineralization process. The existence of such apparently opposite actions is supported by the central and right part of the above mentioned U-shaped curve of the vitamin D–calcification relationship.

Remaining problems and perspective:
There are no prospective randomized intervention trials in CKD patients comparing the effect of native vitamin D or active vitamin D derivatives on vascular calcification with that of placebo. Although the results obtained in experimental studies done in vitro and in vivo are encouraging, it remains to be seen whether in patients with CKD, the increasingly prescribed correction of vitamin D insufficiency or deficiency with pharmacological doses of vitamin D3 or vitamin D2 have positive or negative effects with respect to arterial calcification. The same question needs to be answered with respect to the pharmacological doses of active vitamin D sterols administered for the treatment of secondary hyperparathyroidism. The negative results of the PRIMO study [38] that failed to show a beneficial effect of long-term paricalcitol administration on cardiac structure and function in chronic haemodialysis patients with left ventricular hypertrophy confirms the need for intervention studies with firm outcomes.

Function:
Calcitriol increases blood calcium levels ( [Ca2+] ) by promoting absorption of dietary calcium from the gastrointestinal tract and increasing renal tubular reabsorption of calcium thus reducing the loss of calcium in the urine. Calcitriol also stimulates release of calcium from bone by its action on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL, which in turn activates osteoclasts.
Calcitriol acts in concert with parathyroid hormone (PTH) in all three of these roles. For instance, PTH also stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete inorganic phosphate (Pi), the counterion of Ca2+. The resulting decrease in serum phosphate causes Ca5(PO4)3OH to dissolve out of bone thus increasing serum calcium. PTH also stimulates the production of calcitriol (see below).
Many of the effects of calcitriol are mediated by its interaction with the calcitriol receptor, also called the vitamin D receptor or VDR. For instance, the unbound inactive form of the calcitriol receptor in intestinal epithelial cells resides in the cytoplasm. When calcitriol binds to the receptor, the ligand-receptor complex translocates to the cell nucleus, where it acts as a transcription factor promoting the expression of a gene encoding a calcium binding protein. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium (Ca2+) from the intestine across the intestinal mucosa into the blood.
The maintenance of electroneutrality requires that the transport of Ca2+ ions catalyzed by the intestinal epithelial cells be accompanied by counterions, primarily inorganic phosphate. Thus calcitriol also stimulates the intestinal absorption of phosphate.
The observation that calcitriol stimulates the release of calcium from bone seems contradictory, given that sufficient levels of serum calcitriol generally prevent overall loss of calcium from bone. It is believed that the increased levels of serum calcium resulting from calcitriol-stimulated intestinal uptake causes bone to take up more calcium than it loses by hormonal stimulation of osteoclasts. Only when there are conditions, such as dietary calcium deficiency or defects in intestinal transport, which result in a reduction of serum calcium does an overall loss of calcium from bone occur.
Calcitriol also inhibits the release of calcitonin,[citation needed] a hormone which reduces blood calcium primarily by inhibiting calcium release from bone. (The effect of calcitonin on renal excretion is disputed.)
Vitamin D and its active metabolite, 1,25-di(OH)-vitamin D or calcitriol, have long been recognized as important regulators of serum calcium and bone health. Production of calcitriol is dependent on adequate vitamin D. Following constitutive conversion of vitamin D to 25(OH)-vitamin D by the liver, most circulating calcitriol (hormonal calcitriol) is made by the highly regulated 1alpha-hydroxylase (CYP27B1) present in the kidneys. Numerous other tissues also possess 1alpha-hydroxylase and appear to produce calcitriol locally at high concentrations. The receptor for calcitriol, the vitamin D receptor (VDR), is expressed in virtually all tissues. Thus, this latter form of calcitriol production constitutes a classic paracrine-autocrine system. Local production of calcitriol may even be important in the classic calcitriol target tissues of bone and the parathyroid gland because investigators have demonstrated the presence of 1alpha-hydroxylase in bone and parathyroid cells.
Activation of the VDR by hormonal or locally produced calcitriol generally promotes differentiation of tissues and inhibits proliferation. Some regulatory actions of VDR are even independent of calcitriol. Scientists have investigated the relationship of vitamin D deficiency to cancer, cardiovascular disease, neuromuscular function, and autoimmune diseases.
A large proportion of the population has low vitamin D levels, which are generally defined as a serum level of 25(OH)-vitamin D less than 20 or 30 ng/mL. Although sunlight stimulates skin production of vitamin D, many in modern society are dependent on ingestion of vitamin D in milk or supplements to maintain normal vitamin D levels, especially during the winter months. Vitamin D deficiency is particularly common in hospitalized individuals, those with chronic diseases, and African Americans. Over the past decade, the relationship of vitamin D deficiency to the risk of developing diabetes mellitus (DM) and the risk for diabetic complications has been of great interest to scientists.
Dialysis patients have an enormous burden of vitamin D abnormalities, and this burden also falls on diabetics, who constitute almost 50% of new dialysis patients. Due to the loss of renal function, dialysis patients are unable to produce adequate calcitriol. Consequently, these patients have very low hormonal calcitriol levels. Without supplementation with calcitriol or a calcitriol analog, they have profoundly diminished activation of the VDR in tissues throughout the body. Wolf and colleagues examined incident hemodialysis patients, and found that diabetics were more likely to be severely 25(OH)-vitamin D-deficient (< 10 ng/mL) than nondiabetics (22% vs 17%). Lower 25(OH)-vitamin D levels and lower calcitriol levels strongly correlated with an increased risk for death during the first 90 days in patients not given injectable calcitriol or an analog.
Vitamin D and the risk of developing DM:
Several observational studies have suggested that either low vitamin D levels or low vitamin D intake may predispose to the development of both type 1 and type 2 DM. The Nurses' Health Study found that vitamin D intake above 800 IU/day and more than 1200 mg of calcium per day were associated with a 33% reduction in the risk of developing type 2 DM compared with an intake of < 600 mg of calcium and < 400 IU of vitamin D. A meta-analysis of largely observational studies concluded that there was "a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalent type 2 DM or metabolic syndrome." Evidence from interventional trials suggests that combined vitamin D and calcium supplementation may help prevent type 2 DM in only some populations at high risk for diabetes.
Low vitamin D levels, low sun exposure, and low intake of vitamin D have each been associated with an increased risk for the development of type 1 DM. In animal models, induction of type 1 DM by streptozocin induces a marked fall in calcitriol levels, whereas 25(OH)-vitamin D levels remain normal. Treatment with insulin restores calcitriol levels to normal. Calcitriol has an immunomodulatory effect. In a nonobese diabetic mouse model, administration of calcitriol or 1alpha-(OH)-vitamin D (a precursor of calcitriol) has been shown to significantly reduce the likelihood of development of type 1 DM.
Low vitamin D levels and the presence of DM or glucose intolerance:
A report from Martins and colleagues on data from over 15,000 adults in the Third National Health and Nutrition Examination Survey is perhaps the best recent evidence on vitamin D and the general population. The 25(OH)-vitamin D levels were lower in diabetics, women, the elderly, and racial minorities, groups that are at increased risk of having chronic kidney disease (CKD). Scragg and colleagues reported in 1995 the association of low 25(OH)-vitamin D levels with the presence of DM or glucose intolerance. Consistent with these findings, low vitamin D levels are associated with obesity, as assessed by body mass index or waist circumference, and weakly with elevated glycated hemoglobin (A1C) levels.
Vitamin D and diabetic complications:
Wang and colleagues studied 1739 Framingham offspring participants without prior cardiovascular disease, and found that low 25(OH)-vitamin D levels (< 15 ng/mL) were significantly associated with an increased incidence of a first cardiovascular event during the mean 5.4 years of follow-up.  Among diabetics in this cohort, low 25(OH)-vitamin D levels were significantly more common than nondiabetics (11% vs 7%), but the association of low vitamin D levels to first cardiovascular event remained after adjustment for diabetics and other known risk factors.
Low 25(OH)-vitamin D levels have been shown to correlate with the presence of cardiovascular disease in diabetics. Similarly, hypovitaminosis D has been independently associated with carotid artery intimal-medial thickening, a harbinger of cerebrovascular and cardiovascular events. Suzuki and colleagues found that microvascular complications were more frequent when vitamin D levels were low, despite similar duration of disease and other clinical characteristics compared with control patients without complications.
These data suggest that diabetic patients are at greater risk of being vitamin D-deficient and harmed by this deficiency. The presence of CKD will compromise the production of calcitriol, and potentially further contribute to inadequate vitamin D signaling. Consistent with this, among 463 diabetics with CKD, low vitamin D levels were independently associated with the presence of cardiovascular disease.

 

 

Purpose of the test:
Purpose of the test is to measure the level of Vitamin D in blood in order to check for a problem related to bone metabolism or parathyroid function, possible Vitamin D deficiency or malabsorption, and to monitor some patients taking Vitamin D.
25 OH Vitamin D test is normally ordered to identify a possible deficiency in vitamin D, when calcium is low or the patient has symptoms of vitamin D deficiency, such as bone malformation in children (rickets) and bone weakness, softness, or fracture in adults (osteomalacia).
1,25 di OH Vitamin D test usually is ordered when calcium is high or the patient has a disease that might produce excess amounts of Vitamin D, such as sarcoidosis or some forms of lymphoma.
Vitamin D tests can also be used to diagnose problems with parathyroid gland functioning since parathyroid hormone is essential for vitamin D activation.
25 OH Vitamin D test
If calcium is low or the patient has symptoms of vitamin D deficiency, such as bone malformation in children (rickets) and bone weakness, softness, or fracture in adults (osteomalacia), the 25 OH Vitamin D test usually is ordered to identify a possible deficiency in vitamin D.
1,25 di OH Vitamin D test
If calcium is high or the patient has a disease that might produce excess amounts of Vitamin D, such as sarcoidosis or some forms of lymphoma, the 1,25 di OH Vitamin D test usually is ordered.
Vitamin D tests also may be used to help diagnose or monitor problems with parathyroid gland functioning since parathyroid hormone is essential for vitamin D activation.
When vitamin D, calcium, phosphorus, or magnesium supplementation is necessary, vitamin D levels are sometimes measured to monitor treatment effectiveness.
What is being tested?
There are two forms of vitamin D that can be measured in the blood, 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. 25-hydroxyvitamin D is the major form of the hormone found in the blood and is the inactive precursor to the active hormone, 1,25-dihydroxyvitamin D. Because of its long half-life and higher concentration, 25-hydroxyvitamin D is commonly measured to assess and monitor vitamin D status in individuals.
Vitamin D comes from two sources: endogenous, which is produced in the skin on exposure to sunlight, and exogenous, which is ingested in foods and supplements. The chemical structures of these types of vitamin D are slightly different, and they are named vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). The D2 form is found in foods and in most vitamin preparations and supplements. Vitamin D3 is the form produced in the body and is also used in some supplements. Vitamin D2 and D3 are equally effective.
Many tests for 25-hydroxyvitamin D do not distinguish D2 and D3 forms of the vitamin and report only a total 25-hydroxyvitamin D. Newer methods, however, may report levels of both 25-hydroxy D2 and D3 and then add them together for a total 25-hydroxyvitamin D level. Total 25-hydroxyitamin D concentration is what is used to assess vitamin D status.
Sources and Forms of Vitamin D

The main role of Vitamin D is to help regulate the absorption of calcium, phosphorus, and (to a lesser extent) magnesium. Vitamin D is vital for the growth and health of bone; without it, bones will be soft, malformed, and unable to repair themselves normally, resulting in diseases called rickets in children and osteomalacia in adults. Vitamin D has also been implicated in the regulation of autoimmunity, metabolic function, and cancer prevention.
25-hydroxyvitamin D is used to determine if bone weakness, bone malformation, or abnormal metabolism of calcium (reflected by abnormal calcium, phosphorus, PTH) is occurring as a result of a deficiency or excess of vitamin D.
Since vitamin D is a fat-soluble vitamin and is absorbed from the intestine like a fat, vitamin D is sometimes used to monitor individuals with diseases that interfere with fat absorption, such as cystic fibrosis and Crohn's disease, and in patients who have had gastric bypass surgery and may not be able to absorb enough Vitamin D. Vitamin D is sometimes used to determine effectiveness of treatment when vitamin D, calcium, phosphorus, and/or magnesium supplementation is prescribed.

 

When is it ordered?
25-hydroxyvitamin D
If calcium is low or the patient has symptoms of vitamin D deficiency, such as bone malformation in children (rickets) and bone weakness, softness, or fracture in adults (osteomalacia), 25-hydroxyvitamin D usually is ordered to identify a possible deficiency in vitamin D. Vitamin D deficiency is thought to be much more common than previously believed. Some studies have shown that as many of 50% of the elderly and women being treated for osteoporosis may be Vitamin D deficient. 25-hydroxyvitamin D is often ordered before an individual begins drug therapy for osteoporosis. Some osteoporosis medications now include the recommended Vitamin D dose.
1,25-dihydroxyvitamin D
If calcium is high or the patient has a disease that might produce excess amounts of vitamin D, such as sarcoidosis or some forms of lymphoma, 1,25-dihydroxyvitamin D usually is ordered. Rarely, this testing may be indicated when abnormalities of 1-alphahydroxylase are suspected.
Vitamin D levels also may be used to help diagnose or monitor problems with parathyroid gland functioning since PTH is essential for vitamin D activation. When vitamin D, calcium, phosphorus, or magnesium supplementation is necessary, vitamin D levels are sometimes measured to monitor treatment effectiveness.

What does the test result mean?
There are differences among Vitamin D methods, making a universal reference range difficult to establish. Total 25-hydroxyvitamin D (D2 + D3) is the correct measure of Vitamin D status. There is currently no consensus on the level which indicates deficiency.
25-hydroxyvitamin D
Low blood levels of 25-hydroxyvitamin D may mean that you are not getting enough exposure to sunlight or enough dietary vitamin D to meet your body’s demand or that there is a problem with its absorption from the intestines. Occasionally, drugs used to treat seizures, particularly phenytoin (Dilantin), can interfere with the production of 25-hydroxyvitamin D in the liver.
There is increasing evidence that vitamin D deficiency may increase the risk of some cancers, immune diseases, and cardiovascular disease.
High levels of 25-hydroxyvitamin D usually reflect excess supplementation from vitamin pills or other nutritional supplements.
1,25-dihydroxyvitamin D
Low levels of 1,25-dihydroxyvitamin D can be seen in kidney disease and are one of the earliest changes to occur in persons with early kidney failure.
High levels of 1,25-dihydroxyvitamin D may occur when there is excess parathryoid hormone or when there are diseases, such as sarcoidosis or some lymphomas, that can make 1,25-dihydroxyvitamin D outside of the kidneys.
High levels of vitamin D and calcium can lead to the calcification and damage to organs, particularly the kidneys and blood vessels.
If magnesium levels are low, they can cause a low calcium level that is resistant to vitamin D and parathyroid hormone regulation. It may be necessary to supplement both magnesium and calcium to regain normal function.
Reference range values: 15-75 ng/L
Abnormal findings
25 OH Vitamin D test
Low blood levels of 25 hydroxy Vitamin D may mean that patient is not getting enough exposure to sunlight or enough dietary vitamin D to meet body's demand or that there is a problem with its absorption from the intestines. Occasionally, drugs used to treat seizures, particularly phenytoin (Dilantin), can interfere with the production of 25 OH Vitamin D in the liver.
High levels of 25 hydroxy Vitamin D usually reflect excess supplementation from vitamin pills or other nutritional supplements.
1,25 di OH Vitamin D test
Low levels of 1,25 di OH Vitamin D can be seen in kidney disease and are one of the earliest changes to occur in persons with early kidney failure.
High levels of 1,25 di OH Vitamin D may occur when there is excess parathryoid hormone or when there are diseases, such as sarcoidosis or some lymphomas, that can make 1,25 di OH Vitamin D outside of the kidneys.
Things to know:
1.  Is fortifying milk and cereals with vitamin D a good practice?
Yes. The amount of vitamin D produced by the body may be insufficient, especially when there is limited exposure to sunlight (winter, places with overcast and cloudy weather). Since dietary vitamin D is found naturally only in a few foods, such as cod liver oil, dietary intake would not be sufficient for most people. However, in the United States, vitamin D is routinely added to milk, fortified cereals, and fruit juices to ensure adequate dietary availability. Fortification has been a real success story in the United States, drastically reducing the rate of juvenile rickets and making it a relatively rare occurrence.
2.  Can I get my vitamin D from yogurt and cheese?
Maybe. Although all milk is fortified, many dairy products are not. The current Recommended Dietary Allowance (RDA) for vitamin D is being revised, and some experts suggest that adults should take at least 2000 IU of vitamin D daily.
3.  Are there other uses for vitamin D?
Yes, there is a topical form of vitamin D cream that is used to treat psoriasis. Research is being done in other areas, including the potential use of vitamin D to help control autoimmune conditions.
4.  Is vitamin D a necessary component of calcium supplements?
Since absorption of calcium is dependent on vitamin D, many manufacturers of calcium supplements add vitamin D to assure optimal calcium uptake. If you have adequate amounts of vitamin D from other sources, the additional vitamin D is not necessary. The amount of vitamin D in these tablets is not likely to lead to excess vitamin D or be harmful either.

 

References:
http://www.labtestportal.com/tests/vitamin-d-19.html
http://www.healio.com/Hematology-Oncology/news/print/hematology-oncology/%7B872DC5EE-CBC1-44C7-B8C7-E4AF45CEB1C3%7D/Vitamin-D-more-than-a-bone-factor
http://labtestsonline.org/understanding/analytes/vitamin-d/tab/faq
http://en.wikipedia.org/wiki/Calcitriol
http://ndt.oxfordjournals.org/content/early/2012/03/18/ndt.gfs046.full
http://www.medscape.org/viewarticle/573383
http://www.labtestportal.com/lab-test-interpretation/all-lab-tests/Vitamin-D-25-Hydroxy.html
http://www.ncbi.nlm.nih.gov/pubmed/15585793
http://www.direct-ms.org/pdf/VitDMS/LemireImmuneProp.pdf
http://www.nlm.nih.gov/medlineplus/ency/article/003569.htm

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