In Focus August 2010 - Why Vitamin D Is Not Enough - 3 Articles

NutriCology In Focus Newsletter

Why Vitamin D is Not Enough

A Trio of Articles by Stephen Levine, PhD

A Bold New Approach to Supplementation

Though vitamin D deserves to be nominated nutrient of the decade for its amazing properties, the current recommendations and approach to this pro-hormone may be seriously misguided and at times even harmful.

This may be one of the most controversial positions we have ever taken in this timely and important edition of the Focus newsletter, and it’s certainly one of our most intensively researched; we’ve spent months interviewing experts and comparing many hundreds of peer-reviewed studies. Our subject is vitamin D—the nutrient du jour, that mystic molecule that recently has graced the cover of the British Medical Journal and the pages of the New York Times, as well as grabbed the attention of most medical professionals and the entire American public.

But this is not just another vitamin D article. We’re offering you a bold and distinctly different perspective, with surprising findings that may radically shift the way you look at this astounding nutrient. In a nutshell: though vitamin D deserves to be nominated nutrient of the decade for its amazing properties, the current recommendations and approach to this pro-hormone may be seriously misguided and at times even harmful. The current approach to vitamin D too often dismisses extremely important fat soluble co-factors, ignores receptor “cross talk” that is crucial for optimal health, and misses the potential for the development of serious deficiencies and toxicities if the hugely important variations in lifestyle, genetics and diet are not taken into account.

Vitamin D may be one of the most important nutrients in our nutritional armamentarium—and currently, one of the most misunderstood. If not given safely with the correct ratios of other fat soluble nutrients, vitamin D is a tool that turns into a weapon, one that can inadvertently harm. As a tool, vitamin D can help us fight infections and slash the risk of multiple sclerosis, diabetes, heart disease, cancer (colon, breast, skin and prostate), osteoporosis, dental caries, lupus and rheumatoid arthritis, and depression.1-14 There over 47,000 peer review studies on vitamin D, stretching all the way back to 1922, with the most recent entries on its powerful role in lupus, fractures and breast cancer.15-18 And yet, despite vitamin D’s promise, scientists still don’t know what optimal levels may truly be.19-21

We are, as a society, in the midst of what might be called a vitamin D renaissance—Quest Diagnostics, for instance, reports that orders for vitamin D tests surged more than 50% in 2009, as compared to 2008;22 innumerable peer-review journals as well as newspapers and magazines have covered what may be a nearly pandemic vitamin D deficiency in our society; and in 2008 consumers bought $235 million worth of vitamin D supplements, compared to $40 million in 2001.22

Vitamin D is light transformed. As I write this, on a gloomy afternoon, the lovely phrase of nutritionist and vitamin D specialist Krispin Sullivan, interviewed in this issue, keeps singing in my mind: ”There is a band of light, a very narrow band known as ultraviolet-B, upon which all life depends. That band of light—and its capture and storage in our bodies as vitamin D—is one of the great stories of our time.”23

This newsletter is about the vitamin D story, but we offer what we believe is a more complete story—the story of vitamin D and its irreducible helpers, which evolution wove together in an inseparable braid long ago. This newsletter is also about vitamin A, new findings on carotenes, and new research on vitamin K.

The research is stunningly clear: Vitamin D is part of an ancient complex molecular script. In fact, A, D, K and E work together, and the newest research shows that these lipid-based molecules are all powerful antioxidant nutrients which are intricately bound through shared receptors. They balance and enhance each other, and as a group, profoundly influence genes, immunity, inflammation and the healthy balance of lipids in our body.24

Safely Supplement Vitamins D and A
– Key Concepts of this SPECIAL ISSUE –

• Modest, regular doses of vitamin D can slowly and safely bring us to optimal levels—even in northern latitudes. However, regular monitoring with blood tests is crucial, due to genetic variation.25-28
• Higher doses of vitamin D being recommended today have never been proven safe, especially longterm, and toxicity can show up overnight when fat stores become saturated and excess vitamin D spills into the blood; this can take many months to reverse.23, 29-32
• High dose vitamin D may increase fracture risk in elderly women. Women age 70 years or older who received a single annual high dose of vitamin D had a higher rate of falls and fractures compared to women who received placebo, according to a study in the May 2010 issue of JAMA.33
• Vitamin A deficiency is more common than we realize, because vitamin A-rich foods are rarely eaten and vitamin A toxicity has been overblown, to our profound immunological detriment.34, 43
• Vitamin A is necessary for optimal mucosal immunity—and is a key nutrient in balancing the newly discovered pro-inflammatory cytokine, IL-17.35-44
• Carotenes are not an adequate or safe substitute for vitamin A in supplements, even though they’ve long been recommended as a substitute. New research shows they are not efficiently converted to vitamin A in as many as 50% of individuals, and they can create cleavage products that form free radicals, interrupt vitamin A’s protective function, and thereby potentially raise the risk of cancer.45-47
• Most important, vitamins D and A are an ancient and inseparable team that evolution has honed through time. They must be supplemented together in order to not create a “functional” deficiency of either one. Excess D will create a “relative” deficiency of A, even when dietary levels are adequate. And vice versa.24, 48-49
• A good marriage is complementary—and the good marriage of vitamin A and vitamin D allows these two nutrients to balance, enhance, and contain each other, through an ancient (steroid) receptor called RXR. The all-important result, which cannot be achieved with either nutrient alone, is a beautifully functioning immune system that does not veer into autoimmune disease, or have trouble handling pathogens. And as we know, a healthy immune system is tightly linked to a healthy nervous system.
• Vitamin D is the only molecule that we create ourselves from light and turn into a hormone (OH25D). An astounding feat when you think about it. Similarly, vitamin A, obtained through the diet, is the other dietary lipid-based nutrient that we turn into a hormone (retinoic acid).
• Vitamin K brings up the rear, like a good third teamplayer, and enhances vitamin D’s impact on bone, and protects against kidney damage from excess D. The top vitamin K expert in this country, Sarah Booth, PhD of Tufts University, speculates that K may also work through the ancient RXR receptor, just like D and A. But that has not been studied yet.50
• Finally, vitamin E seems to play a role as well, working together with vitamins A and D.
• Fat-soluble vitamins are likely to be best absorbed when accompanied by a fatty meal, or in a fish oil base. What we take these vitamins with is as important as the vitamins themselves.23
• Thus, safe and balanced doses of A, D, K and E in an oil base, is likeliest to lead to optimal health.

The Marriage of Vitamin D and
Vitamin A: A Match Made on Earth

By Stephen Levine, PhD

With the best of intentions, we have spurred a widespread deficiency in both vitamin A and vitamin D, a necessary team for optimal health and immune function. How has this twin deficiency contributed to the many immune disorders we see today?

Fact: Vitamin D reaches deep and far. Since 1979, we have identified over fifty different target tissues in the body that carry vitamin D receptors, from the bone to the kidneys, liver and intestines. Vitamin D helps regulate growth, reproduction, immunity, cardiovascular function, mood, and the neuroendocrine system. At least 200 genes are primary targets of its active, hormone form, and it indirectly regulates even more genes.23, 51-53

Fact: There is a vitamin D deficiency pandemic—50% of Americans may be lacking optimal amounts, which have been set at about 80 nmol/L (or 32 ng/ml)—what vitamin D expert Robert Heaney calls the “canonical” number, based on optimal intestinal calcium absorption. (Calcium is only one marker of vitamin D’s many functions, and according to Krispin Sullivan, CN, has been overemphasized as a solitary marker of utility and toxicity. Nonetheless, it is universally used). Vitamin D levels have dropped from an average of 30 ng/ml between 1988-1994 to 24 ng/ml between 2001-2004.23, 54-55

Fact: There is also a widespread vitamin A deficiency, since 50% of individuals may not be able to effectively convert carotenes to vitamin A, and the richest dietary sources of vitamin A (full fat milk, butter, eggs and liver) are often avoided by many individuals worried about weight or cholesterol.34, 46 As an important aside, there is also a vitamin K deficiency—not severe enough to impair clotting, for which tiny amounts are required, but a subtle deficiency that impacts vitamin D’s functions.56-58 Rich amounts of vitamin K are present in butter from grassfed cows. But cows today are fed mostly grain, and not pasture-fed.

Fact: We’re seriously sun-deprived. As noted in a 2007 study from the University of Wisconsin, “lack of sun exposure is widely accepted as the primary cause of epidemic low vitamin D status worldwide.”59-61 Even in sun-drenched climes, most of us work indoors by day and cover our skin with clothing when outside, liberally applying sunscreen to lower our risk of UV-linked damage and skin cancer. We’ve created the virtual equivalent of a cave—and cut off nature’s fine-honed mechanism for crafting a much-needed nutrient from light.62

Fact: Though Vitamin D does increase immune function and stimulate antimicrobial peptides, Vitamin A is essential for the immune function of the very mucosal tissues that are the greater part of our immune system (the gut lining). If you are deficient in Vitamin A you will not be able to migrate secretory IgA efficiently in order to wash away microbes.34, 63-64 As Michael Ash, D.O, N.D., writes in his piece on Vitamin A in this issue, “Tolerance in immunity defines health. An intolerant immune system will lead to an unhealthy person and the gut is where many people lose tolerance. Vitamin A is a missing piece of the puzzle of mucosal immunology.”

Fact: The scientific literature on both vitamins A and D can be bewilderingly inconsistent. Studies present a confusing picture on the role of sunlight, optimal levels of vitamin D and how to treat deficiency. We know that those with diabetes or kidney disease, dark skin, and infrequent sun exposure are at risk for vitamin D deficiency.25, 65-68 We know anecdotally, for instance, that the huge Somali population in Minneapolis suffers from severe vitamin D deficiency, having fled from the hot equator to a northern latitude.69 We have studies showing that higher levels of Vitamin A increase fracture risk—and studies that do not show the same risk.70-75 We have a study of young women living in Maine who were given 800 IU of vitamin D along with calcium in the winter months, and 80% reached a healthy vitamin D level over time.76 This study is unusual, because the women’s response was so good, and we do not know what other factors contributed, such as hormone status, youth, lifestyle, or diet.77

Fact: Sunlight exposure may not always be enough. Half of healthy individuals in eternally sunny Honolulu, Hawaii, who got a self-reported whopping average of 28.9 hours of golden rays a week, had low vitamin D status.78 Is there such genetic variability in the ability to convert sun to Vitamin D, that an astounding half of us simply need to supplement no matter what? Possibly. Some of us come from equatorial Africa, others from northern Scandinavia, where our ancestors adapted to plentiful or scant sunlight accordingly.

Fact: Nobody agrees on the optimal levels for supplementation of vitamin D or vitamin A.79 The Institute of Medicine’s Food and Nutrition Board is expected to soon raise the recommended dietary intake of 400 IU of vitamin D daily for the first time since 1997.80 According to vitamin D expert Robert P. Heaney, PhD, a daily oral intake of 2200 IU of vitamin D may be necessary to achieve optimal levels of vitamin D.54 His recommendation is echoed by Heike Bischoff-Ferrari, Ph.D., whose review of vitamin D studies concludes that 1,000 IU a day will bring 50% of the population to optimal levels.81-83 And yet, a study of healthy young women in Maine from September 2005 through February 2006—during the “vitamin D winter” where high latitude and lack of UV light mean we can’t manufacture the vitamin at all—found that supplementing with 800 IU of vitamin D and calcium brought 80% to optimal levels.76 800? 1000? 2200? What’s the right dose?

Meanwhile, virtually all supplements include carotenoids as pro-vitamin A, out of fear of toxicity for retinol itself. A close look at the research shows that fear to be questionable.47, 84-86

Rather than a pharmacological model (one nutrient isolated from others), we need a nutritional model that takes into account the diet and lifestyle with which we originally evolved, and the way our receptors respond to tightly linked nutrients.

And finally, a hypothesis: Rather than a pharmacological model (one nutrient isolated from others), we need a nutritional model that takes into account the diet and lifestyle with which we originally evolved, and the way our receptors respond to these nutrients. Studies can be inconsistent if they isolate a single factor, without taking into account the tight synergy among nutrients. For instance, research shows a positive impact on bone mineral density when both vitamin D and calcium are supplemented together—and none with vitamin D alone.87-91 One could wrongly conclude that vitamin D did not impact bone.

We now turn to the robust and largely unknown scientific literature showing how closely intertwined Vitamin D is with Vitamin A. If we understand how these two pro-hormones—as well as the two other fat soluble vitamins, K and E—aid each other, then a clear picture emerges of the healthiest, safest route to supplementation and optimal levels of these nutrients.

Crosstalk: A Key Concept For Correct Supplementation

Crosstalk. It might sound like two married couples bickering at each other without listening. But in fact it’s a fundamental mechanism hardwired into our biology, by which molecules dock at the same receptor and initiate a cascade of responses in the body. Crosstalk between vitamin A and vitamin D is writ into our biology, and if we look at studies on these two fat soluble nutrients with crosstalk in mind, we begin to understand how synergy has been misinterpreted as interference.

Receptors for vitamin A and vitamin D are found in every cell.92 They were even found in human sperm in 2006.93 Even more important, vitamins A and D share an ancient receptor in the nucleus of the cell known as retinoid X receptor (RXR). RXR regulates lipid balance and it also crosstalks with other hugely important steroid receptors—such as thyroid, glucocorticoid, estrogen, progesterone, and testosterone. Though vitamin A binds to its own retinoic acid receptor (RAR) and vitamin D binds to its own vitamin D receptor (VDR), they then bind to RXR. A point that cannot be overemphasized: Because they share a receptor, if we supplement either vitamin D or vitamin A in an unbalanced fashion, we create a functional deficiency of the one not supplemented. In other words, even if our levels at baseline are adequate, adding just one to the exclusion of the other may create the equivalent of a deficiency.

The crosstalk between vitamins A and D has a profound impact on our health.

Key crosstalk effects include:

Liver reserves: Animal research shows that high levels of vitamin D lower vitamin A reserves in the liver.94-96

Cancer: Retinoic acid can help leukemia cells turn non-cancerous, and this effect is enhanced by the hormone form of vitamin D (calcitriol). And a synthetic vitamin D derivative along with a retinoid inhibits prostate cancer cells in vitro.97-103

The Heart: Low blood levels of vitamin D, vitamin A and carotenoids are all correlated with greater risk of heart disease.104-108

Bone: This is a key area of confusion and contention. Does Vitamin A increase risk of fracture? A 2009 study from the American Journal of Clinical Nutrition, reviewing 75,747 women from the Women’s Health Initiative, found no association between vitamin A intake and the risk of fracture in postmenopausal women. However, a modest increase was found with high vitamin A intake and low vitamin D.72 Our hypothesis: Given the fact that Vitamin D was already low in some individuals, and that high vitamin A will create a further “functional” deficiency, this makes sense. That may be why the highest rate of osteoporosis is found in northern Europe, where sunlight (vitamin D) is limited and vitamin A intake is high (through oily fish).109

Other recent research suggests balance is key. A study of 3,113 postmenopausal women living at higher latitudes in England found that vitamin A from cod liver oil supplements (which also contain vitamin D) did not impair bone health. Yet high vitamin A from food led to increased resorption of bone. The conclusion? “Retinol from supplements and food have different effects,” write the researchers, “which may in part be due to whether the source of retinol also provides vitamin D.”110

This argues for a balance of both nutrients, not a fear of either one. In fact, osteoblasts (which build bone) and osteoclasts (which break down bone) have receptors for both vitamins. Strong bone requires constant remodeling, and thus vitamin D and vitamin A must be in balance to optimize this process.111-113

Crosstalk is a fundamental mechanism hardwired into our biology, by which molecules dock at the same receptor and initiate a cascade of responses in the body. Crosstalk between vitamin A and vitamin D is writ into our biology, and if we look at studies on these two fat soluble nutrients with crosstalk in mind, we begin to understand how synergy between the two has been misinterpreted as interference.

Diabetes: In adults as well as children, vitamin A and vitamin D have been found to be deficient in type 1 diabetes.114 Fish oil supplements, which contain both vitamins, have been correlated with lower rates of Type 1 diabetes. In fact, the January 2009 issue of Diabetes asks if “a combination of vitamins A and D, in safe pharmacologically formulated doses…might be of benefit in the treatment of those at increased risk for type 1 diabetes.”115

The Immune System: Vitamin D helps dampen autoimmune responses and decrease pro-inflammatory T cell cytokines. Similarly, vitamin A increases regulatory T-cells that help dampen hypersensitivity reactions.1-4, 12, 13, 35-44, 116-121

The Brain: Here’s an amazing study that is probably just the tip of the iceberg, showing how both vitamin A and vitamin D can impact neurotransmitters in the developing brain—for life. Newborn male rats were treated with a single dose of 3 mg vitamin A or .05 mg of vitamin D, and three months later five brain regions were studied for tissue levels of dopamine, serotonin and other metabolites. The single dose of vitamins A and D functioned as a kind of hormonal imprinting in specific brain regions, and significantly altered levels of these molecules. The researchers conclude: “The profound and lifelong effect of neonatal hormonal imprinting on neurotransmitter production of the adult brain seems to be well established…the imprinting effect of vitamin A and vitamin D must be taken into consideration.”122

What can we conclude from all this? Both vitamin A and vitamin D are far more than vitamins, with profound effects on every tissue in the body, and they dance together. Through the RXR receptor, they are linked to our most potent steroid hormones. They are involved in regulation of everything from bone to the brain, the kidney to the immune system, the heart to the pancreas.49, 123-124 Adequate levels are crucial to health, and many of us are not getting enough of either, given our modern lifestyles and diet. With that in mind, we now proceed to the recommendations and insights of key experts on Vitamin A and Vitamin D.

Back to top


  1. Amor S. Vitamin D links genetic and environmental risk factors in multiple sclerosis. Commentary. CNS Neurol Disord Drug Targets. 2010 Nov 1;9(5):524. PMID: 21058462
  2. Weinstock-Guttman B, Zivadinov R, Qu J, Cookfair D, Duan X, Bang E, Bergsland N, Hussein S, Cherneva M, Willis L, Heininen-Brown M, Ramanathan M. Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients. J Neurol Neurosurg Psychiatry. 2010 Nov 3. PMID: 21047880
  3. Disanto G, Ramagopalan SV, Para AE, Handunnetthi L. The emerging role of vitamin D binding protein in multiple sclerosis. J Neurol. 2010 Nov 2. PMID: 21042807
  4. Schwartz GG. Multiple sclerosis and prostate cancer: what do their similar geographies suggest? Neuroepidemiology. 1992;11(4-6):244-54. PMID: 1291888
  5. Palacios C, Joshipura K, Willett W. Nutrition and health: guidelines for dental practitioners. Oral Dis. 2009 Sep;15(6):369-81. PMID: 19467151
  6. Delong LK, Wetherington S, Hill N, Kumari M, Gammon B, Dunbar S, Tangpricha V, Chen SC. Vitamin d levels, dietary intake, and photoprotective behaviors among patients with skin cancer. Semin Cutan Med Surg. 2010 Sep;29(3):185-9.PMID: 21051012
  7. Shahriari M, Kerr PE, Slade K, Grant-Kels JE. Vitamin D and the skin. Clin Dermatol. 2010 Nov-Dec;28(6):663-8.PMID: 21034990
  8. Jacobs ET, Thomson CA, Flatt SW, Al-Delaimy WK, Hibler EA, Jones LA, Leroy EC, Newman VA, Parker BA, Rock CL, Pierce JP. Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study. Am J Clin Nutr. 2010 Oct 27. PMID: 20980485
  9. Rendina D, De Filippo G, Strazzullo P. Should vitamin D status be assessed in patients with congestive heart failure? Nutr Metab Cardiovasc Dis. 2010 Nov;20(9):627-32. PMID: 20947319
  10. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappé DL, Muhlestein JB; Intermountain Heart Collaborative (IHC) Study Group. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010 Oct 1;106(7):963-8. PMID: 20854958
  11. Meems LM, van der Harst P, van Gilst WH, de Boer RA. Vitamin D Biology in Heart Failure: Molecular Mechanisms and Systematic Review. Curr Drug Targets. 2010 Aug 27.PMID: 20795939
  12. Guillot X, Semerano L, Saidenberg-Kermanac'h N, Falgarone G, Boissier MC. Vitamin D and inflammation. Joint Bone Spine. 2010 Nov 8. PMID: 21067953
  13. Kriegel MA, Manson JE, Costenbader KH. Does Vitamin D Affect Risk of Developing Autoimmune Disease?: A Systematic Review. Semin Arthritis Rheum. 2010 Nov 1.PMID: 21047669
  14. Di Monaco M, Vallero F, Castiglioni C, Di Monaco R, Tappero R. Low levels of 25-hydroxyvitamin D are associated with the occurrence of concomitant upper limb fractures in older women who sustain a fall-related fracture of the hip. Maturitas. 2010 Sep 29. PMID: 20888157
  15. Napoli N, Vattikuti S, Ma C, Rastelli A, Rayani A, Donepudi R, Asadfard M, Yarramaneni J, Ellis M, Armamento-Villareal R. High prevalence of low vitamin d and musculoskeletal complaints in women with breast cancer. Breast J. 2010 Nov;16(6):609-16. PMID: 21070438
  16. Szodoray P, Tarr T, Bazso A, Poor G, Szegedi G, Kiss E. The immunopathological role of vitamin D in patients with SLE: data from a single centre registry in Hungary. Scand J Rheumatol. 2010 Oct 26. PMID: 20977384
  17. Kamen DL. Vitamin D in lupus - new kid on the block? Bull NYU Hosp Jt Dis. 2010;68(3):218-22. PMID: 20969555
  18. Rabenda V, Bruyère O, Reginster JY. Relationship between bone mineral density changes and risk of fractures among patients receiving calcium with or without vitamin D supplementation: a meta-regression. Osteoporos Int. 2010 PMID: 21060990
  19. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010 Aug;85(8):752-7;PMID: 20675513
  20. Goodwin, Pamela J. MD, MSc. Vitamin D in Breast Cancer -- the Debate Continues: An Expert Interview With Dr. Pamela J. Goodwin Medscape Hematology-Oncology Expert Interview 2009 Jun 06.
  21. Hanse, Karen E. Optimal Vitamin D Status. Journal of Bone and Mineral Research,Volume 24, Issue 4, 2009 Aug; 756.
  22. Parker-Pope, Tara. The Miracle of Vitamin D: Sound Science or Hype? The New York Times, 2010 Feb 1;
  23. Personal Interview with Krispin Sullivan.
  24. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001 Nov 30;294(5548):1866-70. PMID: 11729302
  25. Gutiérrez OM, Farwell WR, Kermah D, Taylor EN. Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey. Osteoporos Int. 2010 Sep 17. PMID: 20848081
  26. Holt SK, Kwon EM, Koopmeiners JS, Lin DW, Feng Z, Ostrander EA, Peters U, Stanford JL.Vitamin D pathway gene variants and prostate cancer prognosis. Prostate. 2010 Sep 15;70(13):1448-60.PMID: 20687218
  27. Ozaydin E, Dayangac-Erden D, Erdem-Yurter H, Derman O, Coşkun T. The relationship between vitamin D receptor gene polymorphisms and bone density, osteocalcin level and growth in adolescents. J Pediatr Endocrinol Metab. 2010 May;23(5):491-6.PMID: 20662348
  28. Nelson ML, Blum JM, Hollis BW, Rosen C, Sullivan SS. Supplements of 20 microg/d cholecalciferol optimized serum 25-hydroxyvitamin D concentrations in 80% of premenopausal women in winter. J Nutr. 2009 Mar;139(3):540-6. PMID: 19158226
  29. Peters S, Adams A. Vitamin d supplementation to reduce the risk of falls and fractures: the dosing dilemma.Orthopedics. 2010 Oct 1;33(10):748-51. PMID: 20954621
  30. Stumpf WE. The dose makes the medicine. Drug Discov Today. 2006 Jun;11(11-12):550-5. PMID: 16713907
  31. Dawson-Hughes B, Harris SS. High-dose vitamin D supplementation: too much of a good thing? JAMA. 2010 May 12;303(18):1861-2. PMID: 20460627
  32. Muskiet FA, Dijck-Brouwer DA, van der Veer E, Schaafsma A. Do we really need> or = 100 microg vitamin D/d, and is it safe for all of us? Am J Clin Nutr. 2001 Dec;74(6):862-4. PMID: 11722970
  33. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010 May 12;303(18):1815-22. PMID: 20460620
  34. Personal conversation with Michael Ash, N.D.
  35. Zhou X, Kong N, Wang J, Fan H, Zou H, Horwitz D, Brand D, Liu Z, Zheng SG.Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J Immunol. 2010 Sep 1;185(5):2675-9. 2010 Aug 2.PMID: 20679534
  36. Wang C, Kang SG, HogenEsch H, Love PE, Kim CH Retinoic acid determines the precise tissue tropism of inflammatory Th17 cells in the intestine. J Immunol. 2010 May 15;184(10):5519-26. Epub 2010 Apr 16.PMID: 20400707
  37. Bai A, Lu N, Guo Y, Liu Z, Chen J, Peng Z.All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis.J Leukoc Biol. 2009 Oct;86(4):959-69. Epub 2009 May 28.PMID: 19477911
  38. Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, Skapenko A.Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010 Oct;62(10):2876-85.PMID: 20583102
  39. Peron JP, Yang K, Chen ML, Brandao WN, Basso AS, Commodaro AG, Weiner HL, Rizzo LV.Oral tolerance reduces Th17 cells as well as the overall inflammation in the central nervous system of EAE mice.J Neuroimmunol. 2010 Oct 8;227(1-2):10-7. Epub 2010 Jul 2.PMID: 20580440
  40. Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, Melendez AJ, McInnes IB.Mast cells express IL-17A in rheumatoid arthritis synovium.J Immunol. 2010 Apr 1;184(7):3336-40. Epub 2010 Mar 3.PMID: 20200272
  41. Klemann C, Raveney BJ, Oki S, Yamamura T. Retinoid signals and TH17-mediated pathology. Nihon Rinsh Meneki Gakkai Kasihi, 2009 Feb; 32(1):20-8. PMID: 19252374
  42. Klemann C, Raveney BJ, Klemann AK, Ozawa T, von Horsten S, Shudo K, Oki S, Yamamura T. Synthetic retinoid AM80 inhibits TH17 clels and ameliorates experimental autoimmune encephalomyelitis. Am J Pathol, 2009, Jun; 174(6):2234-45. PMID: 19389933
  43. Ahmad SM, Haskell MJ, Raqib R, Stephensen CB.Markers of innate immune function are associated with vitamin a stores in men. J Nutr. 2009 Feb;139(2):377-85. Epub 2008 Dec 17.PMID: 19091796
  44. Mucida D, Park Y, Cheroutre H. From the diet to the nucleus: vitamin A and TGF-beta join efforts at the mucosal interface of the intestine. Semin Immunol. 2009 Feb;21(1):14-21. Epub 2008 Sep 21. Review.PMID: 18809338
  45. Weeks B. Vitamin A and Beta-Carotene. Journal of Orthomolecular Medicine, Vol. 18 Nos. 3 & 4, 2003, p. 131-145.
  46. Leung WC, Hessel S, Meplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G. Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15 '-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB Journal 2009, 23(4), 1041-1053. PMID: 19103647
  47. Russell R. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Ntr 2000; 71: 878-84. PMID: 10731492
  48. Pizzorno, J. What have we learned about vitamin D dosing? Integrative Medicine. Vol 9, No. 1, Feb/Mar 2010. p. 8-12
  49. Carlberg C. Lipid soluble vitamins in gene regulation. Biofactors. 1999;10(2-3):91-7. PMID: 10609868
  50. Personal conversation with Sarah Booth, Ph.D.
  51. Stumpf WE, The main role of vitamin D: seasonal regulation of vital functions. Eur J Drug Metab Pharmacokinet. 2007 Jan-Mar;32(1):1-6. PMID: 17479537
  52. Koike N, Stumpf WE. Sweat gland epithelial and myoepithelial cells are vitamin D targets. Exp Dermatol. 2007 Feb;16(2):94-7.PMID: 17222221
  53. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton S, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC. A ChIP-seq-defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Res, 2010. 20: 1352-1360. PMID: 20736230
  54. Heaney RP. The Vitamin D requirement in health and disease. J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):13-9. Epub 2005 Jul 18. PMID: 16026981
  55. Ginde AA, Liu MC, Camargo CA Jr. Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004. Arch Intern Med. 2009 Mar 23;169(6):626-32. PMID: 19307527
  56. Jatoi A, Lennon C, O'Brien M, Booth SL, Sadowski J, Mason JB. Protein-calorie malnutrition does not predict subtle vitamin K depletion in hospitalized patients. Eur J Clin Nutr. 1998 Dec;52(12):934-7. PMID: 9881890
  57. Strople J, Lovell G, Heubi J. Prevalence of subclinical vitamin K deficiency in cholestatic liver disease. J Pediatr Gastroenterol Nutr. 2009 Jul;49(1):78-84. PMID: 19502999
  58. Duggan P, Cashman KD, Flynn A, Bolton-Smith C, Kiely M. Phylloquinone (vitamin K1) intakes and food sources in 18-64-year-old Irish adults. Br J Nutr. 2004 Jul;92(1):151-8. PMID: 15230998
  59. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, Hollis BW, Drezner MK. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007 Jun;92(6):2130-5. Epub 2007 Apr 10. PMID: 17426097
  60. Binkley N, Krueger D, Drezner MK. Low vitamin D status: Time to recognize and correct a Wisconsin epidemic. WMJ. 2007 Dec;106(8):466-72. PMID: 18237070
  61. Webb AR, Kift R, Durkin MT, O'Brien SJ, Vail A, Berry JL, Rhodes LE. The role of sunlight exposure in determining the vitamin D status of the U.K. white adult population. Br J Dermatol. 2010 Nov;163(5):1050-5. PMID: 20716215
  62. Grant WB. In defense of the sun: An estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermatoendocrinol. 2009 Jul;1(4):207-14.PMID: 20592792
  63. Sarkar J, Gangopadhyay NN, Moldoveanu Z, Mestecky J, Stephensen CB.Vitamin A is required for regulation of polymeric immunoglobulin receptor (pIgR) expression by interleukin-4 and interferon-gamma in a human intestinal epithelial cell line. J Nutr. 1998 Jul;128(7):1063-9.PMID: 9649586
  64. Chandra RK, Wadhwa M. Nutritional modulation of intestinal mucosal immunity. Immunol Invest. 1989 Jan-May;18(1-4):119-26. PMID: 2659508
  65. Mehrotra R, Norris K.Hypovitaminosis D, neighborhood poverty, and progression of chronic kidney disease in disadvantaged populations. Clin Nephrol. 2010 Sup;74(S1):95-98.PMID: 20979972
  66. Stefíková K, Spustová V, Krivošíková Z, Okša A, Gazdíková K, Fedelešová V, Dzúrik R. Insulin resistance and vitamin D deficiency in patients with chronic kidney disease stage 2-3. Physiol Res. 2010 Oct 15PMID: 20945958
  67. Vilarrasa N, Vendrell J, Maravall J, Elío I, Solano E, San José P, García I, Virgili N, Soler J, Gómez JM. Is plasma 25(OH) D related to adipokines, inflammatory cytokines and insulin resistance in both a healthy and morbidly obese population? Endocrine. 2010 Oct;38(2):235-42. PMID: 21046484
  68. Janner M, Ballinari P, Mullis PE, Flück CE. High prevalence of vitamin D deficiency in children and adolescents with type 1 diabetes.Swiss Med Wkly. 2010 Sep 3;140:w13091. PMID: 20853194
  69. Kirby, David. Minneapolis and the Somali autism riddle. Huffington Post. 2008 Nov 14.
  70. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47-54. PMID: 11754708
  71. Michaëlsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and risk of fracture. N Engl J Med 2003;348;287-94. PMID: 12540641
  72. Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women's Health Initiative Observational Study. Am J Clin Nutr. 2009 Jan;89(1):323-30. PMID: 19056568
  73. Forsmo S, Fjeldbo SK, Langhammer A. Childhood cod liver oil consumption and bone mineral density in a population-based cohort of peri- and postmenopausal women: the Nord-Trondelag Health Study. Am J Epidemiol. 2008 Feb 15;167(4):406-11. Epub 2007 Nov 21.PMID: 18033763
  74. Ribaya-Mercado JD, Blumberg JB. Vitamin A: is it a risk factor for osteoporosis and bone fracture? Nutr Rev. 2007 Oct;65(10):425-38. Review.PMID: 17972437
  75. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47-54. PMID: 11754708
  76. Nelson J, Blum J, Hollis B, Rosen C, Sullivan S. Supplements of 20 ug/d cholecalciferol optimized serum 25-hydroxyvitamin D concentrations in 80% of premenopausal women in winter. Journal of Nutrition, 2009 Jan: 540-546.
  77. Email commentary by Joseph Pizzorno, N.D.
  78. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, Hollis BW, Drezner MK. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007 Jun;92(6):2130-5. PMID: 1742609
  79. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC. Benefit–risk assessment of vitamin D supplementation. Osteoporos Int. 2010 Jul;21(7):1121-32. Epub 2009 Dec 3. PMID: 19957164
  80. Mitka M. More Evidence on Low Vitamin D Levels Fuels Push to Revise Recommended Intake JAMA. 2009;302(23):2527-2528. PMID: 20009047
  81. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, Bischoff-Ferrari HA, Cavalier E, Ebeling PR, Fardellone P, Gandini S, Gruson D, Guérin AP, Heickendorff L, Hollis BW, Ish-Shalom S, Jean G, von Landenberg P, Largura A, Olsson T, Pierrot-Deseilligny C, Pilz S, Tincani A, Valcour A, Zittermann A. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev. 2010 Sep;9(11):709-15 PMID: 20601202
  82. Bischoff-Ferrari HA. Vitamin D and fracture prevention. Endocrinol Metab Clin North Am. 2010 Jun;39(2):347-53, table of contents. Review.PMID: 20511056
  83. Bischoff-Ferrari H. Vitamin D: what is an adequate vitamin D level and how much supplementation is necessary? Best Pract Res Clin Rheumatol. 2009 Dec;23(6):789-95. Review.PMID: 19945690
  84. Fu X, Wang XD, Mernitz H, Wallin R, Shea MK, Booth SL. 9-Cis retinoic acid reduces 1alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice. J Nutr. 2008 Dec;138(12):2337-41. PMID: 19022954
  85. Babu TA, Sharmila V. Vitamin A supplementation in late pregnancy can decrease the incidence of bronchopulmonary dysplasia in newborns. J Matern Fetal Neonatal Med. 2010 Dec;23(12):1468-9 PMID: 20298108
  86. Ng KY, Ma MT, Leung KK, Leung PS. Vitamin D and vitamin A receptor expression and the proliferative effects of ligand activation of these receptors on the development of pancreatic progenitor cells derived from human fetal pancreas. Stem Cell Rev. 2010 Mar 31. PMID: 20354914
  87. Lips P, Bouillon R, van Schoor NM, Vanderschueren D, Verschueren S, Kuchuk N, Milisen K, Boonen S. Reducing fracture risk with calcium and vitamin D. Clin Endocrinol (Oxf). 2010 Sep;73(3):277-85.PMID: 20796001
  88. Jarjou LM, Laskey MA, Sawo Y, Goldberg GR, Cole TJ, Prentice A. Effect of calcium supplementation in pregnancy on maternal bone outcomes in women with a low calcium intake. Am J Clin Nutr. 2010 Aug;92(2):450-7. Epub 2010 Jun 16. PMID: 20554790
  89. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P. Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2007; 92:1415–23. PMID: 17264183
  90. Feskanich D, Willett WC, Stampfer MJ, Colditz GA. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am J Public Health. 1997; 87:992–97. PMID: 9224182
  91. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005; 293:2257–64. PMID: 15886381
  92. Racz A, Barsony J. Hormone-dependent translocation of vitamin D receptors Is linked to transactivation The Journal of Biological Chemistry Vol. 274, No. 27, 1999 Jul 2 pp. 19352–19360. PMID: 10383447
  93. Corbett ST, Hill O, Nangia AK. Vitamin D receptor found in human sperm. Urology. 2006 Dec;68(6):1345-9. PMID: 17169662
  94. Schmidt DR, Holmstrom SR, Fon Tacer K, Bookout AL, Kliewer SA, Mangelsdorf Regulation of bile acid synthesis by fat-soluble vitamins A and D. J Biol Chem. 2010 May 7;285(19):14486-94. PMID: 20233723
  95. Stumpf WE. Vitamin D and the digestive system. Eur J Drug Metab Pharmacokinet. 2008 Apr-Jun;33(2):85-100.PMID: 18777944
  96. Rohde CM, DeLuca HF. All-trans retinoic acid antagonizes the action of calciferol and its active metabolite, 1,25-dihydroxycholecalciferol, in rats. J Nutr, 135. 2005. pp. 1647-1652. PMID: 15987844
  97. Li RJ, Ying X, Zhang Y, Ju RJ, Wang XX, Yao HJ, Men Y, Tian W, Yu Y, Zhang L, Huang RJ, Lu WL. All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells. J Control Release. 2010 Oct 29. PMID: 20971141
  98. Duong V, Rochette-Egly C. The molecular physiology of nuclear retinoic acid receptors. From health to disease.Biochim Biophys Acta. 2010 Oct 20PMID: 20970498
  99. Kim SH, Yoo JC, Kim TS. Nargenicin enhances 1,25-dihydroxyvitamin D(3)- and all-trans retinoic acid-induced leukemia cell differentiation via PKCbetaI/MAPK pathways.Biochem Pharmacol. 2009 Jun 1;77(11):1694-701.PMID: 19428323
  100. Bastie JN, Balitrand N, Guillemot I, Chomienne C, Delva L.Cooperative action of 1alpha,25-dihydroxyvitamin D3 and retinoic acid in NB4 acute promyelocytic leukemia cell differentiation is transcriptionally controlled.Exp Cell Res. 2005. PMID: 16181625
  101. Tokar EJ, Ancrile BB, Ablin RJ, Webber MM.Cholecalciferol (vitamin D3) and the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) are synergistic for chemoprevention of prostate cancer.J Exp Ther Oncol. 2006;5(4):323-33.PMID: 17024972
  102. Sepulveda VA, Weigel NL, Falzon M.Prostate cancer cell type-specific involvement of the VDR and RXR in regulation of the human PTHrP gene via a negative VDRE.Steroids. 2006 Feb;71(2):102-15.PMID: 16243370
  103. Ikeda N, Uemura H, Ishiguro H, Hori M, Hosaka M, Kyo S, Miyamoto K, Takeda E, Kubota Y. Combination treatment with 1alpha,25-dihydroxyvitamin D3 and 9-cis-retinoic acid directly inhibits human telomerase reverse transcriptase transcription in prostate cancer cells. Mol Cancer Ther. 2003 Aug;2(8):739-46.PMID: 12939463
  104. Wu J, Garami M, Cheng T, Gardner DG. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Invest. 1996 Apr 1;97(7):1577-88. PMID: 8601621
  105. Witte KK, Nikitin NP, Parker AC, von Haehling S, Volk HD, Anker SD, Clark AL, Cleland JG.The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure.Eur Heart J. 2005. PMID: 174260916081469
  106. Seelig MS.Letter: Ischaemic heart disease, vitamins D and A, and magnesium.Br Med J. 1975 Sep 13;3(5984):647-8. PMID: 1164649
  107. Nakao R, Nelson OL, Park JS, Mathison BD, Thompson PA, Chew BP.Effect of astaxanthin supplementation on inflammation and cardiac function in BALB/c mice.Anticancer Res. 2010 Jul;30(7):2721-5. PMID: 20683004
  108. Pennathur S, Maitra D, Byun J, Sliskovic I, Abdulhamid I, Saed GM, Diamond MP, Abu-Soud HM.Potent antioxidative activity of lycopene: A potential role in scavenging hypochlorous acid.Free Radic Biol Med. 2010 Jul 15;49(2):205-13 PMID: 20388538
  109. Rosengren BE, Ahlborg HG, Gärdsell P, Sernbo I, Daly RM, Nilsson JA, Karlsson MK. Bone mineral density and incidence of hip fracture in Swedish urban and rural women 1987-2002. Acta Orthop. 2010 Aug;81(4):453-9. PMID: 20515431
  110. Macdonald HM, Mavroeidi A, Barr RJ, Black AJ, Fraser WD, Reid DM Vitamin D status in postmenopausal women living at higher latitudes in the UK in relation to bone health, overweight, sunlight exposure and dietary vitamin D.Bone. 2008 May;42(5):996-1003 PMID: 18329355
  111. M. J. Seibel, Simon P. Robins, John P. Bilezikian. Dynamics of bone and cartilage metabolism. Elsevier. 2006. pp. 314 f.
  112. Fleet, JC. Molecular regulation of calcium and bone metabolism through the vitamin D receptor. J Musculoskelet Neuronal Interact 2006; 6(4):336-337. PMID: 17185813
  113. Bland R. Steroid hormone receptor expression and action in bone. Clin Sci (Lond). 2000 Feb;98(2):217-40. Review. PMID: 10657279
  114. Joergensen C, Gall MA, Schmedes A, Tarnow L, Parving HH, Rossing P. Vitamin D levels and mortality in type 2 diabetes. Diabetes Care October 2010 vol. 33 no. 10 2238-2243. PMID: 20606205
  115. Wasserfall C, Atkinson M. Taking a daily vitamin to prevent type 1 diabetes? Diabetes. 2009 Jan. 58:24-25. PMID: 19114727
  116. Semba RD. Vitamin A, immunity and infection. Clin Infect Dis. 1994 Sep;19(3):489-99. PMID: 10604208
  117. Ross AC. Vitamin A deficiency and retinoid repletion regulate the antibody response to bacterial antigens and the maintenance of natural killer cells. Clin Immunol Immunopathol. 1996 Sep;80(3 Pt 2):S63-72. PMID: 8811065
  118. Stephensen CB. Vitamin A, infection and immune function. Annu Rev Nutr. 2001;21:167-92. PMID: 11375434
  119. Rumore MM. Vitamin A as an immunomodulating agent. CLin Pharm. 1993 Jul;12(7):506-14. PMID: 8354037
  120. Reifen R. Vitamin A as an anti-inflammatory agent. Proc Nutr Soc. 2002 Au;61(3):397-400. PMID: 12230799
  121. Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc. 1999 Aug:58(3):719-27. PMID: 10604208
  122. Tekes K, Gyenge M, Folyovich A, Csaba G. Influence of neonatal vitamin A or vitamin D treatment on the concentration of biogenic amines and their metabolites in the adult rat brain.Horm Metab Res. 2009 Apr;41(4):277-80. PMID: 19053013.
  123. Zou A, Elgort MG, Allegretto EA. Retinoid X receptor (RXR) ligands activate the human 25-hydroxyvitamin D3-24-hydroxylase promoter via RXR heterodimer binding to two vitamin D-responsive elements and elicit additive effects with 1-25-Dihydroxyvitamin D3. Journal of Biol Chem. Vol 272, No. 30 1997 Jul 25. pp. 19025-19034. PMID: 9228086
  124. Ng KY, Ma MT, Leung KK, Leung PS. Vitamin D and Vitamin A receptor expression and the proliferative effects of ligand activation of these receptors on the development of pancreatic progenitor cells derived from human fetal pancreas. Stem Cell Rev. 2010 Mar 31. PMID: 20354914

Back to top

In Focus on NutriCology®
Editor-in-Chief: Stephen A. Levine, Ph.D.
Executive Editor: Jill Neimark
Medical Editor: Jeffrey L. Anderson, M.D.
Assistant Editors: Daniel Milosevich, CN, Diane Raile, CNC
Graphic Design & Layout: Christian Northcott
IN FOCUS publishes emerging nutritional science and scientific theories that should not be construed to be conclusive scientific proof of any specific cause, effect, or relationship. The publication is for the educational use of healthcare practitioners and physicians. The articles in the publication are the independent scientific views and theories of the authors. IN FOCUS takes no position on the views and theories expressed but offers them for candid inquiry and debate. The articles are not intended for use in support of the sale of any commercial product and should not be construed as indicative of the use or efficacy of any commercial product. Emerging science and scientific theories do not constitute scientific proof of any specific cause, effect, or relationship.
Copyright © 2010 NutriCology®.
Special permission is required to reproduce by any manner, in whole or in part, the materials herein contained.
Cutting Edge Nutritional Research