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Position of health organizations and agencies in Australia, Canada, New Zealand, the United Kingdom, and the United States, and the World Health Organization, on UV radiation and vitamin D

A brief introduction to the role of vitamin D in reducing the risk of chronic disease*

William B. Grant, Ph.D.

SUNARC

Abstract

Evidence continues to mount at an accelerating rate that vitamin D is a very important risk reduction factor for a variety of diseases, not only those associated with bone health, but also those associated with internal organs, brain development while still in the womb or in infancy, and the autoimmune diseases, and even for defense against tuberculosis. A search of PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) was used to find the evidence relating to the beneficial role of vitamin D in maintaining optimal health. This essay briefly summarizes the types of evidence that researchers examine in trying to reach a determination regarding the possible role of vitamin D for any given disease. The accompanying table indicates which types of evidence have been found for each chronic disease, other than the common bone diseases, for which it is accepted that vitamin D plays an important role. Since ultraviolet-B (UVB) radiation (290-315 nm) is the most important source of vitamin D for most Americans, much of the work has been done with respect to solar UVB irradiance. The status of the role of UVB and vitamin D with respect to individual diseases will be presented in separate essays.

Method and materials

The approach employed is a literature search starting with PubMed. Diseases for which vitamin D may be beneficial were obtained from the recent reviews on the role of vitamin D in health [1-13]. Lines of evidence employed were based on a review of the literature. The importance of each line is discussed in this section. The references included in this review are generally limited to 1-3 of the most recent works for each disease/evidence category and, in some cases, the pioneering paper in the field.

Latitudinal gradient of disease outcome
One of the earliest hints that vitamin D sufficiency may be a risk reduction factor for a disease is that there be an increase in disease outcome with increasing latitude. Solar ultraviolet B (UVB) radiation (290-315 nm) is an important source of vitamin D for many people, and it generally increases with decreasing latitude [12].

Solar exposure
Related to latitudinal gradient is evidence that exposure to solar UVB radiation is related inversely to severity or outcome of the disease in a dose-response manner. Various measures of solar UVB exposure can be used, anywhere from controlled clinical studies, geographical location or occupational exposure, to correlations with non-melanoma skin cancer (NMSC).

Vitamin D receptor
Many organs have a vitamin D receptor (VDR) that binds to 1 a,25-dihydroxyvitamin D3 (1,25(OH)D3) with high affinity [14]. There are polymorphisms of the VDR, and if it can be shown that the different polymorphisms are associated with different risk of disease, this provides evidence for a role of vitamin D.

Mechanisms
The identification of mechanisms whereby vitamin D sufficiency reduces the risk of a particular disease is an important but not necessary condition for causality [15]. Since some of the vitamin D-disease links are quite recent, not all of the mechanisms have been identified and confirmed.

Serum 25(OH)D studies
The finding of inverse correlations between serum 25-hydroxyvitamin D (25(OH)D) and disease status or outcome are important for demonstrating that vitamin D plays a role in the disease. The most useful studies are those of prediagnostic serum 25(OH)D levels, since many vitamin D-deficiency diseases such as rickets, osteomalacia and osteoporosis take years to reach detectable stages [10]. Studies of sera 25(OH)D levels concurrent with disease status are less reliable, not only because of the time lag between initiation and detection of disease, but also because the disease condition may affect the vitamin D stores by lack of UVB exposure due to staying indoors [16] or diet due to limited ability to absorb dietary vitamin D, e.g., Crohn's disease and cystic fibrosis [17].

Clinical studies
Clinical studies are, by nature, generally short-term studies, designed to determine whether application of various agents or lifestyle changes result in changes in disease state or biological markers of disease state. Since many of the vitamin D-deficiency diseases take years to develop, clinical studies are more likely to be used to search for changes in biological indicators related to vitamin D application.

Animal and laboratory studies
Since animals used in disease studies generally have much shorter lifetimes than humans, animal models are sometimes used to determine the efficacy of various substances in causing or treating disease. In addition, cells derived from humans, such as cancer cell lines, can also be used for in vitro studies.

Vitamin D intake studies
Humans obtain vitamin D from three primary sources: solar or artificial UVB radiation, diet, supplements or a pharmaceutical drug [12,18]. The relative and absolute contributions to serum 25(OH)D from each source vary for individuals according to a number of factors. Studies that rely solely on vitamin D intake are likely to be inconclusive due to the often greater contributions from solar UVB radiation [19]. It is also difficult to determine the long-term average amounts from each source. There is also concern about whether dietary vitamin D amounts can be properly assessed due to the presence of several forms of vitamin D in animal products [20]. Thus, studies relating disease outcome to vitamin D intake should be considered cautiously.

Results

The evidence that vitamin D reduces the risk of disease is summarized in Table 1. The diseases are arranged in descending order by the number of lines of evidence that were found to be supported in the health journal literature. The various types of cancer are listed together in approximate order of the strength of the evidence regarding the role of vitamin D. Most of these cancers are epithelial cancers, so vitamin D has similar risk reduction effects in each. In addition to cancer, evidence is presented for hypertension, multiple sclerosis, type 1 diabetes mellitus (DM), secondary HPT, myopathy, heart disease (coronary and congestive heart failure), schizophrenia, rheumatoid arthritis, tuberculosis, and type 2 DM.

Table 1.  A summary of evidence that vitamin D reduces the risk of specific chronic diseases, ordered by approximate strength of the evidence in terms of numbers of types of evidence presented (from Grant and Holick, A review of evidence supporting the role of vitamin D in reducing the risk of chronic diseases, submitted to American Journal of Clinical Nutrition, March 9, 2004 in conjunction with the National Institute of Health’s conference, Vitamin D in the 21st Century: Bone and Beyond held in Bethesda, MD, October 9-10, 2003).  Vitamin D is firmly accepted as a risk reduction factor for most of the skeletal disease such as rickets, osteopenia, osteoporosis, and osteomalacia, so they are not included in this tabulation.

Discussion

The results for individual diseases will be presented in separate essays by disease.

References

Note: Abstracts of these papers may be found at PubMed (http://www.ncbi.nlm.nih.gov/pubmed/)

1. Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective. Pediatrics. 2003;112:e132-5.

2. Frost HM, Schonau E. The "muscle-bone unit" in children and adolescents: a 2000 overview. J Pediatr Endocrinol Metab. 2000;13:571-90.

3. Vieth R. Vitamin D Nutrition and its Potential Health Benefits for Bone, Cancer and Other Conditions. J Nutr Env Med 2001;11:275-91.

4. Grant WB. An estimate of premature cancer mortality in the United States due to inadequate doses of solar ultraviolet-B radiation, Cancer, 2002;94:1867-75.

5. Ponsonby AL, McMichael A, van der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology. 2002;181-182:71-8.

6. Barthel HR, Scharla SH. [Benefits beyond the bones -- vitamin D against falls, cancer, hypertension and autoimmune diseases] Dtsch Med Wochenschr. 2003;128:440-6.

7. Calvo MS, Whiting SJ. Prevalence of vitamin D insufficiency in Canada and the United States: importance to health status and efficacy of current food fortification and dietary supplement use. Nutr Rev. 2003;61:107-13.

8. Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand). 2003:49:277-300.

9. Heaney RP. Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr. 2003;78:912-9.

10. Holick MF. Vitamin D: A millenium perspective. J Cell Biochem. 2003;88:296-307.

11. Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003;89:552-72.

12. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004 Mar;79(3):362-71.

13. Grant WB, Strange RC, Garland CF. Health benefits of ultraviolet-B radiation through production of vitamin D, J Cos Dermatol, in press.

14. Chen TC, Persons KS, Lu Z, Mathieu JS, Holick MF. An evaluation of the biologic activity and vitamin D receptor binding affinity of the photoisomers of vitamin D3 and previtamin D3. J Nutr Biochem. 2000;11:267-72.

15. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 58;295-300,1965.

16. Chuck A, Todd J, Diffey B. Subliminal ultraviolet-B irradiation for the prevention of vitamin D deficiency in the elderly: a feasibility study. Photodermatol Photoimmunol Photomed. 2001;17:168-71.

17. Lo CW, Paris PW, Clemens TL, Nolan J, Holick MF. Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes. Am J Clin Nutr. 1985;42:644-9.

18. Sowers MR, Wallace RB, Hollis BW, Lemke JH. Parameters related to 25-OH-D levels in a population-based study of women. Am J Clin Nutr. 1986;43:621-8.

19. Grant WB, Garland CF. A critical review of studies on vitamin D in relation to colorectal cancer. Nutr Cancer. in press.

20. Ovesen L, Brot C, Jakobsen J. Food contents and biological activity of 25-hydroxyvitamin D: a vitamin D metabolite to be reckoned with? Ann Nutr Metab. 2003;47:107-13.

*Grant WB, Holick MF. A review of evidence supporting the role of vitamin D in reducing the risk of chronic diseases. Submitted to Am J Clin Nutr (March 9, 2004).