Table of Contents
Ch. I Is calcidiol an active hormone? 1
Ch. II Vitamin D as a neurosteroid hormone : from neurobiological effects to behavior 29
Ch. III Inhibitors of vitamin D hydroxylases : mechanistic tools and therapeutic aspects 67
Ch. IV Vitamin D analogues as anti-cancer therapies 145
Ch. V Paricalcitol : a vitamin D2 analog with anticancer effects with low calcemic activity 169
Ch. VI Vitamin D use among older adults in U.S. : results form national surveys 1997 to 2002 181
Ch VII Vitamin D deficiency in migrants 199
Vitamin D is a fat-soluble steroid hormone precursor that contributes to the maintenance of normal levels of calcium and phosphorus in the bloodstream. Strictly speaking, it is not a vitamin since human skin can manufacture it, but it is referred to as one for historical reasons. It is often known as calciferol. The major biologic function of vitamin D is to maintain normal blood levels of calcium and phosphorus. Vitamin D aids in the absorption of calcium, helping to form and maintain strong bones. It promotes bone mineralisation in concert with a number of other vitamins, minerals and hormones. Without vitamin D, bones can become thin, brittle, soft or misshapen. Vitamin D prevents rickets in children and osteomalacia in adults -- skeletal diseases that result in defects that weaken bones. This book gathers international research on the leading-edge of the scientific front.
"Retinol-induced Intestinal Tumorigenesis in Min/+ Mice and Importance of Vitamin D Status.
Hetland RB, Alexander J, Berg JP, Svendsen C, Paulsen JE.
Anticancer Res. 2009 Nov;29(11):4353-60.
PMID: 20032378
The effects of life-long dietary exposure, starting in utero, to high retinol, low vitamin D, or high retinol in combination with low vitamin D on intestinal tumorigenesis in Min/+ mice were investigated. In males, high retinol alone significantly increased the number (2.6-fold) and size (1.3-fold) of small intestinal tumours; in females no significant increase in tumour number or size was seen. In both genders, low vitamin D intake alone did not affect intestinal tumorigenesis. In males, intake of the combined high retinol/low vitamin D diet did not further increase the effects caused by high retinol alone. In females, however, the high retinol/low vitamin D-induced increase in tumour number (3.1-fold) and tumour size (1.5-fold) exceeded that of high retinol alone. In conclusion, a high dietary intake of retinol stimulated intestinal tumorigenesis in Min/+ mice. Furthermore, the results indicate a combined effect of high retinol and low vitamin D on tumorigenesis in females"
"From 1955 to 1990, all infants in East Germany received 600,000 IU of Vitamin D every three months for a total of 3,600,000 IU at age 18 months.
With the 400 IU/day recommendation of the American Pediatric Association in mind, I ran across this amazing paper while surfing Medline for Vitamin D. According to this paper, all infants in the German Democratic Republic (East Germany) received dangerously high doses of Vitamin D every three months in their doctors office. The policy was in place for 35 years. The first 600,000 IU dose was given at three months and then every three months until the child was 18 months of age. This works out to an average of 6,000 IU per day (actually, for several technical reasons it is not equivalent) for 18 months. The authors collected blood before the dose and then 2 weeks after the quarterly dose to obtain 25(OH)D, 1,25(OH)D, and calcium levels on a total of 43 infants.
Before the first dose, at 3 months of age, the average infant was extremely deficient (median 25(OH)D of 7 ng/ml). Two weeks after the first dose the average 25(OH)D level was 120 ng/ml, the second dose 170 ng/ml, the third dose, 180 ng/ml, the fourth dose, 144 ng/ml, the fifth dose, 110 ng/ml and after the sixth and final dose, 3.6 million total units, at age 18 months, the children had mean levels of 100 ng/ml. That is, by the 15 and 18 month doses, the children were beginning to effectively handle these massive doses.
The highest level recorded in any of the 43 infants was 408 ng/ml at age 9 months, two weeks after the third 600,000 IU dose. Thirty-four percent of the infants had at least one episode of hypercalcemia but only 3 had an elevated serum 1,25(OH)D. The authors reported that all the infants appeared healthy, even the infant with a level of 408 ng/ml, that is, no clinical toxicity was noted in any of these infants."
Factors that influence the cutaneous synthesis and dietary sources of vitamin D.
Chen TC, Chimeh F, Lu Z, Mathieu J, Person KS, Zhang A, Kohn N, Martinello S, Berkowitz R, Holick MF.
Arch Biochem Biophys. 2007 Apr 15;460(2):213-7. Epub 2007 Jan 8.
PMID: 17254541
doi: 10.1016/j.abb.2006.12.017
Vitamin D is rare in food. Among the vitamin D-rich food, oily fish are considered to be one of the best sources. Therefore, we analyzed the vitamin D content in several commonly consumed oily and non-oily fish. The data showed that farmed salmon had a mean content of vitamin D that was ~25% of the mean content found in wild caught salmon from Alaska, and that vitamin D2 was found in farmed salmon, but not in wild caught salmon. The results provide useful global guidelines for obtaining sufficient vitamin D3 by cutaneous synthesis and from dietary intake to prevent vitamin D deficiency and its health consequences.ensuing illness, especially, bone fractures in the elderly.
A New Zealand study has found that South Asian women with insulin resistance improved markedly after taking vitamin D supplements
Nutrition researcher Pamela von Hurst of the Institute of Food, Nutrition and Human Health at Albany, said while diet and exercise played a major part in the onset of type-2 diabetes, her findings reinforced the importance of vitamin D from the sun and supplements to prevent type-2 diabetes.
Initial screening of 235 Auckland women from India, Pakistan and Sri Lanka aged 20 and older, revealed 47 per cent were insulin deficient and 84 per cent were vitamin D deficient. The 81 recruited for the study were split into two groups for a randomised controlled trial and given a vitamin D supplement or placebo. As well as an improvement in insulin resistance among those who took vitamin D for six months, Ms Von Hurst said post-menopausal women in the study also showed a reduced rate of bone breakdown.
Low vitamin D serum level is related to severe fibrosis and low responsiveness to IFN-based therapy in genotype 1 chronic hepatitis C
Salvatore Petta et al.
Hepatology, Volume 9999 Issue 999A, Page NA. Published Online: 4 Dec 2009
DOI: 10.1002/hep.23489
Conclusions:
G1 CHC patients had low 25(OH)D serum levels, possibly due to reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on IFN-based therapy. (HEPATOLOGY 2010.)
Vitamin D, aging, and cancer.
Tuohimaa P.
Nutr Rev. 2008 Oct;66(10 Suppl 2):S147-52. Review.
PMID: 18844842
DOI: 10.1111/j.1753-4887.2008.00095.x
Deficiency of the prohormone calcidiol (25OH vitamin D3) seems to be associated with several aging-related chronic diseases including cancer. Our results suggest that calcidiol is mainly responsible for differentiation homeostasis, whereas calcitriol might be more involved in calcium homeostasis. Therefore, an imbalance of calcidiol rather than calcitriol is a risk factor for cancer and chronic diseases. Calcidiol insufficiency, as well as insufficient solar exposure, is associated with increased risk of several solid cancers. Both a vitamin D3 deficiency and a high concentration of calcidiol may increase cancer risk. Similarly, aging phenomena show a U-shaped association with vitamin D bioactivity. Therefore, the chronic diseases and cancers related to aging might be prevented by an optimal concentration of serum calcidiol, which remains to be determined.
The vitamin D-antimicrobial peptide pathway and its role in protection against infection.
Gombart AF.
Future Microbiol. 2009 Nov;4:1151-65.
PMID: 19895218
Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications
"I discussed in my last post how Dr Vieth has a model of tissue 1,25(OH)2D synthesis and degradation in which the level of active substance is pretty well independent of blood vitamin D level, provided the level is either rising or stable. I think it is also worth pointing out that he is talking, hypothetically, about tissue 1,25(OH)2D, not plasma level... As we know, almost nothing is known about tissue 1,25(OH)2D control.
By Vieth's hypothesis tissue 1,25(OH)2D is OK so long as there is at least SOME vitamin D present in plasma and the level dose not vary too much. Obviously there is a level below which you can have as much of the enzyme for converting vitamin D to the active form as you like, if there is no vitamin D in your blood you can't make any 1,25(OH)2D in your tissues, or in your kidneys for export to your blood to control calcium levels. At the lower extremes we have rickets and osteomalacia. These are clear cut, unarguable markers of vitamin D deficiency, in the absence of confounding factors (there are a few)."
Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk.
Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E.
Prostate. 2007 Jun 15;67(9):911-23.
PMID: 17440943
DOI: 10.1002/pros.20570
RESULTS
No association was found between these SNPs or their associated haplotypes and all PC subtypes except that haplotype 2 (A-f-b) with Cdx2 A, Fok1 f, and Bsm1 b alleles and haplotype 3 (A-F-B) with Cdx2 A, Fok1 F and Bsm1 B alleles compared to the most common haplotype (A-F-b), were associated with reduced risk of aggressive PC (high stage or Gleason sum 7; P = 0.02), both with two alleles suspected of being low risk. Carriers of the variant Cdx2 A allele who were deficient in plasma 25-hydroxyvitamin D (15 ng/ml) compared to non-carriers with normal 25-hydroxyvitamin D, had a lower risk of total and poorly differentiated PCs (Gleason sum 7) (P for interaction = 0.02 and 0.04, respectively). Plasma 1,25-dihydroxyvitamin D deficiency (26 pg/ml) was associated with a threefold risk of poorly differentiated PC (P for interaction = 0.01) when comparing carriers of the Cdx2 A allele to non-carriers with normal 1,25-dihydroxyvitamin D.
CONCLUSION
In this population of men, none of the VDR polymorphisms studied was associated with susceptibility to PC.
Carriers of the variant Cdx2 A allele with low plasma 25-hydroxyvitamin D may experience a reduction in risk of total and poorly differentiated prostate cancers compared to non-carriers with adequate 25-hydroxyvitamin D.
The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude.
van der Mei IA, Ponsonby AL, Engelsen O, Pasco JA, McGrath JJ, Eyles DW, Blizzard L, Dwyer T, Lucas R, Jones G.
Environ Health Perspect. 2007 Aug;115(8):1132-9.
PMID: 17687438
doi: 10.1289/ehp.9937.
Conclusion
Vitamin D insufficiency is common over a wide latitude range in Australia. Season appears to be more important than latitude, but both accounted for less than one-fifth of the variation in serum 25(OH)D levels, highlighting the importance of behavioral factors. Current sun exposure guidelines do not seem to fully prevent vitamin D insufficiency, and consideration should be given to their modification or to pursuing other means to achieve vitamin D adequacy.
"Women from India, Pakistan and Sri Lanka with insulin resistance showed marked improvement after taking vitamin D supplements, says a study.
Von Hurst, nutrition lecturer at the Institute of Food, Nutrition and Human Health at Albany, conducted the study for her doctoral thesis.
Insulin resistance is largely symptom-free and sufferers are unaware of their condition. 'Once it has fully developed into type-2 diabetes, it can be treated, but not cured,' says Von Hurst.
Von Hurst says that while diet and exercise play a major part in the onset of type-2 diabetes, her findings reinforce the importance of vitamin D from the sun and supplements to prevent type-2 diabetes. She also found evidence of vitamin D increasing bone strength in older women.
"
Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients.
Romagnoli E, Caravella P, Scarnecchia L, Martinez P, Minisola S.
Br J Nutr. 1999 Feb;81(2):133-7.
PMID: 10450331
The results of the present study emphasize the importance of 25-hydroxyvitamin D measurement, and the need to increase vitamin D intake in Italy; foodstuff fortification and supplement use must be considered in order to prevent negative effects of vitamin D deficiency on skeletal integrity.
All hospitalized patients, both in summer and in winter,
are characterized by the highest prevalence of hypovitaminosis
D, especially the older patients. Medical
inpatients may be at risk for vitamin D deficiency,
Vitamin D Deficiency in the Morbidly Obese.
Buffington C, Walker B, Cowan GS Jr, Scruggs D.
Obes Surg. 1993 Nov;3(4):421-424.
PMID: 10757956
These data suggest that low vitamin D may be associated with obesity per se. Hypovitaminosis D, when it is found in post-bariatric surgery patients, may not be caused by the surgery since it may have been present to some degree pre-operatively.
Obesity and Vitamin D
One third of Americans are obese. While much of that epidemic is surely due to playing Nintendo instead of baseball, or the consumption of soft drinks instead of water, does that explain
it all? Is it a coincidence that the twin epidemics of obesity and vitamin D deficiency are occurring together?
Vitamin D deficiency is the cause of common obesity.
Foss YJ.
Med Hypotheses. 2009 Mar;72(3):314-21. Epub 2008 Dec 2.
PMID: 19054627
doi:10.1016/j.mehy.2008.10.005
Common obesity and the metabolic syndrome may therefore result from an anomalous adaptive winter response. The stimulus for the winter response is proposed to be a fall in vitamin D. The synthesis of vitamin D is dependent upon the absorption of radiation in the ultraviolet-B range of sunlight. At ground level at mid-latitudes, UV-B radiation falls in the autumn and becomes negligible in winter. It has previously been proposed that vitamin D evolved in primitive organisms as a UV-B sensitive photoreceptor with the function of signaling changes in sunlight intensity. It is here proposed that a fall in vitamin D in the form of circulating calcidiol is the stimulus for the winter response, which consists of an accumulation of fat mass (obesity) and the induction of a winter metabolism (the metabolic syndrome). Vitamin D deficiency can account for the secular trends in the prevalence of obesity and for individual differences in its onset and severity. It may be possible to reverse the increasing prevalence of obesity by improving vitamin D status.
"The major factor which stimulates weight gain in winter months is vitamin D. Human bodies get vitamin D from sunlight; as the hours of sunlight become less with the onset of fall, so our levels of vitamin D decrease.
Low levels of vitamin D affect the brain's production of the hormone leptin. Leptin plays a vital role in controlling appetite and metabolism; so as the amount of vitamin D in our bodies decreases so does the leptin, and this causes an increase in our appetite and a change in our metabolism.
Researchers at Aberdeen University found that obese people had 10% less vitamin D than people of average weight. The study also found that excess body fat absorbed vitamin D so the body couldn't use it. Scientists now believe that there is a direct correlation between obesity and low levels of vitamin D.
"Friday Oct 16, 2009 (foodconsumer.org) -- Results of a new trial presented at an international research conference in Bruges suggest that vitamin D supplementation can reduce the risk of premature births and boost the health of newborn babies, the Times reported Oct 10.
Vitamin D deficiency, which is common everywhere, has been linked in many previous studies to a variety of illnesses from heart disease, cancers, multiple sclerosis
and many others.
In the trial, Dr. Bruce Hollis and Dr. Carol Wagner of the Medical University of South Carolina, Charleston, gave one group of pregnant women 4,000 IUs per day of vitamin D at about three months of pregnancy. They gave a second group 400 IUs per day, amounts recommended by U.S. and UK"