Over the past decades, researchers have gathered data demonstrating that vitamin D and its metabolites possess activities far beyond the classic regulation of calcium–phosphate homeostasis. It is now ...well established that vitamin D is essential for the proper functioning of the musculoskeletal, cardiovascular, nervous, and immune systems. Furthermore, vitamin D and its analogs were shown to regulate proliferation and differentiation of keratinocyte, immune cells, and numerous cancer-derived cells, both in vivo and in vitro. On the other hand, population base studies have provided evidence that global vitamin D deficiency is correlated with the occurrence and aggravation of symptoms of skeletal, cardiovascular autoimmune, and skin disease; infections; metabolic and cognitive disorders; multiple types of cancers; as well as overall mortality. This Special Issue of International Journal of Molecular Sciences, entitled “Vitamin D and Human Health”, summarizes recent advances in our understanding of pleiotropic activity of vitamin D with a focus on its protective role against cancer, hypertension, viral infections, and neurological diseases, as well as its impact on the immune system and mitochondria. Furthermore, eight research papers provide new insight into vitamin D research and highlight new directions and targets in the prevention and treatment of human diseases.
Why should we measure free 25(OH) vitamin D? Tsuprykov, Oleg; Chen, Xin; Hocher, Carl-Friedrich ...
The Journal of steroid biochemistry and molecular biology,
June 2018, 2018-06-00, 20180601, Volume:
180
Journal Article
Peer reviewed
•Free 25(OH)D is superior over total 25(OH)D in liver and kidney pathologies, and in pregnancy.•In other health conditions the literature does not clear provide evidences of such benefits.•However, ...measuring both free and total 25(OH)D is an ideal choice to assess real vitamin D status.
Vitamin D, either in its D2 or D3 form, is essential for normal human development during intrauterine life, kidney function and bone health. Vitamin D deficiency has also been linked to cancer development and some autoimmune diseases. Given this huge impact of vitamin D on human health, it is important for daily clinical practice and clinical research to have reliable tools to judge on the vitamin D status. The major circulating form of vitamin D is 25-hydroxyvitamin D (25(OH)D), although it is not the most active metabolite, the concentrations of total 25-hydroxyvitamin D in the serum are currently routinely used in clinical practice to assess vitamin D status. In the circulation, vitamin D – like other steroid hormones – is bound tightly to a special carrier – vitamin D-binding protein (DBP). Smaller amounts are bound to blood proteins – albumin and lipoproteins. Only very tiny amounts of the total vitamin D are free and potentially biologically active. Currently used vitamin D assays do not distinguish between the three forms of vitamin D – DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D. Diseases or conditions that affect the synthesis of DBP or albumin thus have a huge impact on the amount of circulating total vitamin D. DBP and albumin are synthesized in the liver, hence all patients with an impairment of liver function have alterations in their total vitamin D blood concentrations, while free vitamin D levels remain mostly constant. Sex steroids, in particular estrogens, stimulate the synthesis of DBP. This explains why total vitamin D concentrations are higher during pregnancy as compared to non-pregnant women, while the concentrations of free vitamin D remain similar in both groups of women. The vitamin D-DBP as well as vitamin D-albumin complexes are filtered through the glomeruli and re-uptaken by megalin in the proximal tubule. Therefore, all acute and chronic kidney diseases that are characterized by a tubular damage, are associated with a loss of vitamin D-DBP complexes in the urine. Finally, the gene encoding DBP protein is highly polymorphic in different human racial groups. In the current review, we will discuss how liver function, estrogens, kidney function and the genetic background might influence total circulating vitamin D levels and will discuss what vitamin D metabolite is more appropriate to measure under these conditions: free vitamin D or total vitamin D.
Vitamin D deficiency and insufficiency is a global health issue that afflicts more than one billion children and adults worldwide. The consequences of vitamin D deficiency cannot be under estimated. ...There has been an association of vitamin D deficiency with a myriad of acute and chronic illnesses including preeclampsia, childhood dental caries, periodontitis, autoimmune disorders, infectious diseases, cardiovascular disease, deadly cancers, type 2 diabetes and neurological disorders. This review is to put into perspective the controversy surrounding the definition for vitamin D deficiency and insufficiency as well as providing guidance for how to treat and prevent vitamin D deficiency.
Modest and even severe vitamin D deficiency is widely prevalent around the world. There is consensus that a good vitamin D status is necessary for bone and general health. Similarly, a better vitamin ...D status is essential for optimal efficacy of antiresorptive treatments. Supplementation of food with vitamin D or using vitamin D supplements is the most widely used strategy to improve the vitamin status. Cholecalciferol (vitamin D
3
) and ergocalciferol (vitamin D
2
) are the most widely used compounds and the relative use of both products depends on historical or practical reasons. Oral intake of calcifediol (25OHD
3
) rather than vitamin D itself should also be considered for oral supplementation. We reviewed all publications dealing with a comparison of oral cholecalciferol with oral calcifediol as to define the relative efficacy of both compounds for improving the vitamin D status. First, oral calcifediol results in a more rapid increase in serum 25OHD compared to oral cholecalciferol. Second, oral calcifediol is more potent than cholecalciferol, so that lower dosages are needed. Based on the results of nine RCTs comparing physiologic doses of oral cholecalciferol with oral calcifediol, calcifediol was 3.2-fold more potent than oral cholecalciferol. Indeed, when using dosages ≤ 25 μg/day, serum 25OHD increased by 1.5 ± 0.9 nmol/l for each 1 μg cholecalciferol, whereas this was 4.8 ± 1.2 nmol/l for oral calcifediol
.
Third, oral calcifediol has a higher rate of intestinal absorption and this may have important advantages in case of decreased intestinal absorption capacity due to a variety of diseases. A potential additional advantage of oral calcifediol is a linear dose-response curve, irrespective of baseline serum 25OHD, whereas the rise in serum 25OHD is lower after oral cholecalciferol, when baseline serum 25OHD is higher. Finally, intermittent intake of calcifediol results in fairly stable serum 25OHD compared with greater fluctuations after intermittent oral cholecalciferol.
Abstract
Context
Vitamin D is classically recognized as a regulator of calcium and phosphorus metabolism. Recent advances in the measurement of vitamin D metabolites, diagnosis of vitamin D ...deficiency, and clinical observations have led to an appreciation that along with its role in skeletal metabolism, vitamin D may well have an important role in nonclassical settings. Measurement of the circulating form of vitamin D that best describes total body stores, namely 25-hydroxyvitamin D, can be unreliable despite many sophisticated methodologies that have been proposed and implemented. Likewise, evidence from clinical studies showing a beneficial role of vitamin D in different disease states has been controversial and at times speculative. Moreover, the target concentrations of 25-hydroxyvitamin D to address a number of putative links between vitamin D inadequacy and nonskeletal diseases are further areas of uncertainty.
Setting
To address these issues, an international conference on “Controversies in Vitamin D” was held in Pisa, Italy, in June 2017. Three main topics were addressed: (i) vitamin D assays and the definition of hypovitaminosis D; (ii) skeletal and extraskeletal effects of vitamin D; (iii) therapeutics of vitamin D.
Results
This report provides a summary of the deliberations of the expert panels of the conference.
Conclusions
Despite great advances in our appreciation of vitamin D metabolism, measurements, biological actions on classical and nonclassical tissues, and therapeutics, all of which this report summarizes, much more work remains to be done so that our knowledge base can become even more secure.
This summary statement reports the deliberations and conclusions of an international conference on “Controversies in Vitamin D.”
•Free 25(OH)D can be measured directly by a two step immunoassay, ultrafiltration or dialysis. All such assays need further validation.•Free 25(OH)D can also be calculated based on measurements of ...total vitamin D metabolites, DBP, albumin, and the affinities between the metabolite and the binding proteins.•The measurement of DBP needs validation and standardization, and the affinity for the polymorphic DBP needs reassessment.•Some DBP assays are compromised by unequal affinity of the antibody employed for all known DBP isoforms, and the affinity of DBP for the vitamin D metabolites may vary under different physiologic conditions.•Assays to evaluate functional differences in DBP genetic variants may shed light on the role of DBP in regulating free 25(OH)D levels.•Free 25(OH)D (measured or calculated with the best available methodology) is closely correlated with total 25(OH)D concentrations in healthy adults.•Calculated and measured free 25(OH)D (using the best presently available methods) is lower in African Americans than in US Caucasians. Africans living in The Gambia, in contrast to African Americans, have high total and high free 25(OH)D while having the same DBP/GC genotypes, suggesting that differences in free 25(OH)D are not driven by genetic factors.•Free not total 25(OH)D or 1,25(OH)2D regulates vitamin D actions in all cells tested so far.•Whether free 25(OH)D correlates better than total 25(OH)D to serum PTH, bone mass and bone markers or extra-skeletal endpoints is not yet well established.•The relative importance of free versus total 25(OH)D or 1,25(OH)2D under different physiological and pathological conditions requires further studies.
There is general consensus that serum 25(OH)D is the best biochemical marker for nutritional vitamin D status. Whether free 25(OH)D would be a better marker than total 25(OH)D is so far unclear. Free 25(OH)D can either be calculated based on the measurement of the serum concentrations of total 25(OH)D, vitamin D-binding protein (DBP), albumin, and the affinity between 25(OH)D and its binding proteins in physiological situations. Free 25(OH)D can also be measured directly by equilibrium dialysis, ultrafitration or immunoassays. During the vitamin D workshop held in Boston in March 2016, a debate was organized about the measurements and clinical value of free 25(OH)D, and this debate is summarized in the present manuscript. Overall there is consensus that most cells apart from the renal tubular cells are exposed to free rather than to total 25(OH)D. Therefore free 25(OH)D may be highly relevant for the local production and action of 1,25(OH)2D. During the debate it became clear that there is a need for standardization of measurements of serum DBP and of direct measurements of free 25(OH)D. There seems to be very limited genetic or racial differences in DBP concentrations or (probably) in the affinity of DBP for its major ligands. Therefore, free 25(OH)D is strongly correlated to total 25(OH)D in most normal populations. Appropriate studies are needed to define the clinical implications of free rather than total 25(OH)D in normal subjects and in disease states. Special attention is needed for such studies in cases of abnormal DBP concentrations or when one could expect changes in its affinity for its ligands.
Abstract
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D ...receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D–deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
1,25-Dihydroxvitamin D3 1,25(OH)2D3 is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D ...receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.
Vitamin D and aging Gallagher, J Christopher
Endocrinology and metabolism clinics of North America,
06/2013, Volume:
42, Issue:
2
Journal Article
Peer reviewed
Open access
Age-related changes affect vitamin D metabolism and increase the requirement for vitamin D in the elderly. Also there is an age related decrease in calcium absorption and a higher calcium intake is ...needed. Increasing calcium from dietary sources may be better than supplements, and requires increasing the intake of dairy products or other and calcium-fortified foods. Evidence suggests that vitamin D and calcium nutrition can be improved in the elderly by increasing the vitamin D intake to 800 IU daily together with a total calcium intake of 1000 mg daily. This combination is a simple, inexpensive strategy that can reduce fractures in institutionalized individuals by 30%.
PDF
