The Research on Vitamin D: A Very Important Vitamin

Vitamin D is a fat-soluble vitamin produced from cholesterol in the skin in a process triggered by exposure to the sun’s ultraviolet B light. Getting sufficient sunlight is the primary source of vitamin D.  Vitamin D has been getting more attention in the past several years although milk in the U.S. has long been supplemented with vitamin D.  Very few foods contain vitamin D: milk in required by law to be supplemented with 100 International Units (IU) per cup and some is present in fish and fish oil.  

During the winter, sun exposure is considerably less for the average person. Thus, vitamin D blood levels are usually lowest from October to April.  Also, many individuals don't spend much time outdoors, even during the summer.  In addition, individuals with darker skin make less vitamin D after the same level of sun exposure as a person with lighter skin.  Sunscreens block vitamin D manufacture and decrease natural production even more.

In fact, the lighter skin shades of people living far away from the equator have been attributed to the life advantages of having higher levels of vitamin D.  In the days before birth control and modern medicine, because of less sunshine far away from the equator, people with lighter skin would produce more vitamin D and have a health and reproductive advantage, but close to the equator, everyone would get enough vitamin D.  In contrast, the darker skin shades of people living near the equator have a life advantage due to having higher levels of folic acid, a vitamin destroyed by too much sunshine.  These skin color differences evolved in as little as 15 generations in the days before modern medicine thanks to survival advantages by darker skin near the equator and lighter skin away from the equator.

Vitamin D supplements are good for everyone.  Supplements have been found to cause a sizable decrease in heart disease deaths in a large, prospective epidemiologic study of elderly women.  Six double-blind studies have found decreases in falls in the elderly.  Supplements have also been found to decrease osteoporosis and fractures.  There are additional recent studies documenting that vitamin D helps prevent and/or treat a variety of cancers, depression, diabetes, hypertension,  muscle pain and weakness, multiple sclerosis, osteoarthritis, overactive bladder, periodontal disease, rheumatoid arthritis, sarcopenia, schizophrenia, stroke, and tooth loss (Click on Benefits A-L and Benefits M-Z pages here or above).  It may also help a number of other conditions in which low levels have been associated with higher levels of disease.

The current official recommended intake of vitamin D is 400 IU per day.  Most studies with supplements use at least twice this amount.  I recommend at least 1000 I.U. of vitamin D each day for everyone.  Still higher levels, 3,000 IU per day for 2 months, are recommended for those with low levels until supplies are replenished.  Adults over age 70, darker skinned individuals, and, during the winter months, people living north of a line between Los Angeles and Atlanta may need 2000 IU on a routine basis.  Breast-fed infants should receive vitamin D 1000-2000 units daily, although if their mothers are on my higher recommended dose, this may not be as important.

Vitamin D is very inexpensive and toxicity occurs very rarely.  Indeed, there has never been a single, well-documented toxicity case ever reported in an adult taking 1000 IU/day (25 mcg).  Toxicity occurs only at over 10,000 IU/day.  Thus, in my opinion, it seems more sensible and less expensive for everyone to take a daily 1000 IU supplement at an annual cost of $10.50 ( www.iHerb.com 2/04) rather than for everyone to get annual physician-ordered vitamin D blood levels ($127) as recommended by one author (Am J Clin Nutr. 2004 Mar;79(3):362-71) and an annual calcium blood level as recommended by another (CME Resource 10/01/03).  Getting adequate sunshine is an excellent substitute, but most people don't get it and during the winter it is next to impossible in northern areas.  

Since hepatitis B vaccination, at least in adults, considerably increases the risk of autoimmune disease and since vitamin D lowers the risk of many autoimmune diseases, this is yet another reason to follow my recommendations.

Frequency of Deficiency Studies

Afro-Americans Lower Vitamin D Levels: 42% of 1,546 Afro-Americans had low 25(OH)D levels vs. 4.2% of 1426 European-American. Amer J Clin Nutr 7/02. Scanlon, the author, recommends 4 times current recommended amount. Ed: Afro-American ancestors evolved near the equator in Africa with plenty of sunshine. Research suggests that dark skin pigment protects against the destruction of folic acid under the skin by excessive sunlight. Thus, dark skin protects vital folic acid levels while enough vitamin D was being made. Light skinned people living away from the equator didn't have to worry about the sun destroying folic acid, but those with lighter skin survived better because their lighter skin allowed more vitamin D to be produced.  Hence, dark-skinned people living far away from the equator aggravated by the modern life style which leads to lots of time indoors, results in even lower levels of vitamin D than that found in light-skinned people who are also often deficient.

Americans: Vitamin D Deficiency Common Nationwide Even in People on Multivitamins: Using data from the third National Health and Nutrition Examination Survey for 15,390 adults, vitamin supplements caused a higher serum level of 25 (OH) D3 (79.47 vs 74.38 nmol/L) and a lower prevalence of vitamin D deficiency (39% vs 48%). Vitamin D deficiency was higher among women, elderly, and minorities. The current dose of vitamin D in routine vitamin supplements is still insufficient. The impact of routine vitamin supplementation on serum levels of 25 (OH) D3 among the general adult population and patients with chronic kidney disease. Tareen N, et al. Charles R Drew University, Los Angeles. Ethn Dis 2005 Autumn;15(4 Suppl 5):S5-102-6. Ed: The government's guidelines of 400 units per day is clearly insufficient. A daily 1000 units with 2000 for the elderly, during the winter, and in individuals with darker skin would be better.

Americans: 42% US Teens Vitamin D Insufficient: In a study of 307 U.S. teens, 24% patients were vitamin D deficient (serum 25OHD level, </=15 ng/mL [</=37.5 nmol/L]). By using a broader definition (25OHD level, </=20 ng/mL [</=50 nmol/L]), 42% patients were vitamin D insufficient. Serum 25OHD levels were inversely correlated with parathyroid hormone levels (r = -0.29), and were 24% lower during winter compared with summer. In a final multivariate model, season, ethnicity, milk and juice consumption, body mass index, and physical activity were significant independent predictors of hypovitaminosis D. Prevalence of vitamin D deficiency among healthy adolescents. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ.  Harvard Medical. Arch Pediatr Adolesc Med. 2004 Jun;158(6):531-7. Children 4-8 in one study from the southern states found better vitamin D levels. Vitamin D insufficiency may be common among children and adolescents at the beginning of spring. The risk may be highest among older children because vitamin D intake does not adequately rise in proportion with increases in body mass. In any case, I recommend a vitamin D supplement for people of all ages.

Americans: Girls in Maine Low in Vitamin D: At the 2003 Meeting of the American Society for Bone and Mineral Research, Susan Sullivan of the University of Maine presented data showing that almost half of the Bangor area girls in her study had insufficient levels of vitamin D in their blood in March, a time of the year when the nutrient usually falls to its lowest level over the course of the year. In September, when the nutrient is usually at its highest level, 17 percent also fell below the standard, currently 20 nanograms per milliliter of blood.

Americans: Vitamin D Deficiency Very Common; Even Worse Over Age 50: The government recommends dietary and supplemental vitamin D of 200 IU per day for people under 50, 400 IU per day for ages 51 to 70, and 600 IU per day over 70. The diets of 27,000 people in the Third National Health and Nutrition Examination Survey and 19,000 people in the Continuing Survey of Food Intakes by Individuals found that less than 10% of adults 50 to 70 years old, and only about 2% of people over 70, were found to be getting the recommended amounts of vitamin D from food and only 30% of people ages 50-70 and 10% of those over 70 when counting supplements as well. Among people 14 to 50 years old, 50% of females and 65% of males were getting recommended amounts vs. 53 -63% of all children. A previous study found 42% of hospitalized patients under age 65 were vitamin D deficient, and 37% of people consuming recommended amounts of vitamin D were still deficient. J Amer Dietetic Assn 2004;104:980–3. 

Argentina Elderly Usually Vitamin D Deficient: A study of 336 Argentina over 65 found a high prevalence (52%-87%) of subjects with 25OHD levels in the deficiency-insufficiency range (25OHD levels <20 ng/ml). The lower levels with in northern Argentina, closer to the equator. Eur J Clin Nutr. 2004 Feb;58(2):337-42

Depression, Schizophrenia, and Alcoholism Patients Lower Levels: In a small University of Frankfurt study of 120 adults, the quarters with depression, schizophrenia, and alcoholism all showed lower vitamin D blood levels but no differences between diagnostic groups. Vitamin D in schizophrenia, major depression and alcoholism. Schneider B, Weber B, Frensch A, Stein J, Fritz J. J Neural Transm. 2000;107(7):839-42.

Elderly: Centenarians 95% Found Deficient: 99 out of 104 elderly overage 98 had undetectable levels of vitamin D and other abnormalities characterizing a pathophysiological sequence of events linking vitamin D deficiency, low serum calcium, and secondary hyperparathyroidism with an increase in bone resorption and severe osteopenia. Recommend vitamin D and calcium. Low vitamin D status, high bone turnover, and bone fractures in centenarians. Passeri G, Pini G, et al. J Clin Endocrinol Metab. 2003 Nov;88(11):5109-15. Ed: Although vitamin D has many great benefits for the elderly, I have found very few nursing home patients in central Illinois receiving it in 2004.

Hungarians 74% Deficient, Tunisians 47%: The prevalence of hypovitaminosis D among healthy Hungarian women during spring, summer, autumn and winter was 71%, 46.3%, 49.4% and 56.7%, respectively. Osteoporos Int. 2004 Jun;15(6):447-51. The Tunisian study found deficiency was still higher in females, in older individuals, in women wearing the veil, after menopause, and in those with low oral intake of vitamin D. Osteoporos Int. 2004 Jun 10 

Iranian Adults: 80% Deficient in Vitamin D: 1,210 Tehran adults 20-64 years old were randomly selected. 25 (OH) D serum levels were measured. Prevalence of severe, moderate and mild Vitamin D deficiency was 9.5%, 57.6% and 14.2%. Vitamin D serum levels had no significant statistical relation with the duration of exposure to sunlight, kind of clothing and BMI. Calcium intake in the normal vitamin D group was significantly higher than the other groups (714 mg/day vs. 503, 577, and 595). Vitamin D serum levels in young and middle aged females were significantly lower than the older group.  In order to avoid complications of vitamin D deficiency, supplemental dietary intake seems essential. Vitamin D deficiency and causative factors in the population of Tehran. Hashemipour S, Larijani B, Pajouhi M, Javadi E, Sedaghat M, Soltani A, Adibi H, Shafaei AR, Hamidi Z, Khalili-Fard AR, Hossein-Nezhad A, Booya F. BMC Public Health. 2004 Aug 25;4(1):38

Israel Study Find 26% Inpatients Very Deficient: Despite being a very sunny country, a study of hospital inpatients found a high rate of hypovitaminosis D (serum 25-HO-D < 15 ng/ml) in 77 of 280 inpatients (26%). The amount of sunlight exposure, serum albumin concentration, being housebound or resident of a nursing home, vitamin D intake, ethnic group, cerebrovascular accident and glucocorticoid therapy were all significantly associated with hypovitaminosis D. Hypovitaminosis D among inpatients in a sunny country. Hochwald O, Harman-Boehm I, Castel H. Isr Med Assoc J. 2004 Feb;6(2):82-7

Tanning Beds Double Vitamin D and Strengthen Bones: In a study of 50 adults who used tanning beds at least weekly and 106 controls, the tanners had 90% more vitamin D (serum 25(OH)D 115.5 vs. 60.3; P <0.001), parathyroid hormone concentrations 18% lower than those of controls, and higher bone mineral density at the hip. Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density. Tangpricha V, Turner A, et al. Boston University. Am J Clin Nutr. 2004 Dec;80(6):1645-9. 

Genetics and Biochemistry

Baldness Sometimes Linked to Vitamin D Gene Mutation: Alopecia is a feature of vitamin D receptor (VDR) mutations in humans and mice. This alopecia results from an inability to initiate the anagen phase of the hair cycle after follicle morphogenesis is complete. Thus, once the initial hair is shed it does not regrow. VDR expression in the epidermal component of the hair follicle, the keratinocyte, is critical for maintenance of the hair cycle. Skorija K, Cox M, et al. MGH-Harvard. Mol Endocrinol. 2004 Dec 9

Calbindin, a Calcium Binding Protein Regulated by Vitamin D: Calbindin-D(9k) (CaBP-9k) is a cytosolic calcium binding protein mainly expressed in the duodenum, placenta and uterus, and intestinal CaBP-9k is regulated by 1, 25-dyhydroxyvitamin D3. However, despite the presence of vitamin D receptors, uterine CaBP-9k is not under the control of vitamin D. Differential transcriptional and translational regulations of calbindin-D9k by steroid hormones and their receptors in the uterus of immature mice. An BS, Choi KC, Hong EJ, Jung YW, Manabe N, Jeung EB. Chungbuk National University, Korea. J Reprod Dev. 2004 Aug;50(4):445-53. Calbindin is also present in the human brain and may be involved in some way with schizophrenia.

Height Affected by Polymorphisms of Vitamin D Receptor Gene: The vitamin D receptor (VDR) gene is important to human stature, as it mediates metabolic pathways, calcium homeostasis, and phosphate homeostasis, which influence growth. In a study of 1873 European-Americans from 406 families, all four tested SNPs were linked to adult height. Within family associations with height were detected at BsmI and TaqI loci (p = 0.048 and 0.039). Analyses based on BsmI/TaqI haplotypes also revealed evidence for linkage (p = 0.05) and association (p = 0.001) with height. The bT haplotype was significantly associated with higher adult height (p = 0.033, within family association test). Vitamin D receptor gene polymorphisms are linked to and associated with adult height. Xiong DH, Xu FH, et al. Creighton University. J Med Genet. 2005 Mar;42(3):228-34.

Natural Killer Cells Boosted by Vitamin D: Vitamin D(3) upregulated protein 1 (VDUP1) is a stress-response gene that is upregulated by 1,25(OH)(2)D(3) in tumor cells.  It is a critical factor for the development and function of Natural Killer cells.  These help stop cancer. Immunity. 2005 Feb;22(2):195-208

Rickets: Vitamin D-dependent Rickets type I (VDDRI) Gene: An abnormal gene causes a rare autosomal recessive hereditary defect in vitamin D metabolism. Patients with VDDRI have mutations of chromosome 12 that affect the gene for the enzyme 1-alpha-hydroxylase, resulting in decreased levels of 1,25(OH)(2) vitamin D. Clinical features include growth failure, hypotonia, weakness, rachitic rosary, convulsions, tetany, open fontanels, and pathologic fractures. The oral and dental manifestations are markedly hypoplastic, yellowish-to-brownish enamel in all permanent teeth, malocclusion, and chronic periodontal disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003 Jun;95(6):705-9

Teeth: VDDRI Children's Teeth Protected by Vitamin D and Phosphate: A study of 32 children and 16 adults with VDDRI showed that supplementation allowed the teeth of the children to develop normally. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: prevention by early treatment with 1-hydroxyvitamin D. Chaussain-Miller C, Sinding C, Wolikow M, Lasfargues JJ, Godeau G, Garabedian M. J Pediatr. 2003 Mar;142(3):324-31

Teeth: Common Vitamin D Receptor Polymorphism Doubles Tooth Loss and Gingivitis: 125 healthy, middle-aged men with dental exams over 23 years had ApaI and TaqI polymorphisms measured by polymerase chain reaction. Genotype distributions were 33% AA, 46% Aa, 21% aa; and 42% TT, 37% Tt, 21% tt. The AA genotype showed the highest rates of progression of alveolar bone loss (5% versus 1% and 2% of teeth in Aa and aa, respectively; P = 0.03), clinical attachment loss (37% vs. 17% and 27% of teeth; P = 0.004), and tooth loss (2 versus 1 and 1 teeth; P = 0.04). Total damage was highest in the AATT and AATt genotypes. Boston Univ. Vitamin D receptor alleles, periodontal disease progression, and tooth loss in the VA dental longitudinal study. Inagaki K, Krall EA, Fleet JC, Garcia RI. J Periodontol. 2003 Feb;74(2):161-7. Ed: This disadvantageous polymorphism probably causes many more health disadvantages than just the teeth.  While it hasn't been proven, vitamin D supplements probably offsets the disadvantage. Inexpensive gene testing is not yet available, so take your vitamin D.

Teeth: Vitamin D Receptor and Estrogen Receptor Polymorphisms Contribute to Loss of Teeth and Bone Mineral: A Japanese study in 149 postmenopausal women of estrogen receptor (ER) and vitamin D receptor (VDR) gene polymorphisms found the distribution of ER PvuII and XbaI and VDR BsmI restriction fragment length polymorphisms was as follows: pp, 30.2%; Pp, 49.7%; PP, 20.1%; xx, 71.8%; Xx, 22.5%; XX, 2.7%; bb, 76.5%; Bb, 22.2%; and BB, 1.3%. Participants with pp allele had fewer teeth remaining than did those with P allele. There were no significant differences in oral bone mass and postcranial BMD among three alleles at the PvuII site. Participants with X and bb allele had less oral bone mass and lower postcranial BMD than did those with xx and B allele, respectively. Menopause. 2003 May-Jun;10(3):250-7

Solar ultraviolet B photons are absorbed by 7-dehydrocholesterol in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3. Season, latitude, time of day, skin pigmentation, aging, sunscreen use, and glass all influence the cutaneous production of vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D3.

Vitamin D(2) Calciferol Inferior to D(3) Cholecalciferol: The relative potencies of vitamins D(2) and D(3) were evaluated by administering single doses of 50,000 IU of each to 20 healthy male volunteers and following the time course of serum vitamin D and 25-hydroxyvitamin D (25OHD) over a period of 28 days.The two calciferols produced similar rises in serum concentration of the administered vitamin, indicating equivalent absorption. Both produced similar initial rises in serum 25OHD over the first 3 days, but 25OHD continued to rise in the D(3)-treated men, peaking at 14 days, whereas serum 25OHD fell rapidly in the D(2)-treated and was not different from baseline at 14 d. Area under the curve (AUC) to day 28 was 60.2 ng.d/ml for vitamin D(2) and 204.7 for vitamin D(3) (P < 0.002). Vitamin D2 is much less effective than vitamin D3 in humans. Armas LA, Hollis BW, Heaney RP. Creighton University. J Clin Endocrinol Metab. 2004 Nov;89(11):5387-91

Vitamin D3 suppresses the androgen-stimulated growth of mouse mammary carcinoma SC-3 cells by transcriptional repression of fibroblast growth factor 8. Using an oligonucleotide microarray, 220 genes were found upregulated 200%+, and 84 genes were downregulated to less than one-third, compared with the testosterone-stimulated SC-3 cells. Fgf8 was markedly repressed in response to vitamin D3. The exogenous addition of FGF8 canceled the growth suppression by vitamin D3 in SC-3 cells. All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen-related and fgf8 transcriptions. Kawata H, et al. Jichi Medical University, Tochigi, Japan. J. Cell. Physiol. Feb. 23, 2006.  Ed: This study shows the use of the amazing oligonucleotide microarrays, which I find fascinating.

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