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What Is All This Commotion about Vitamin D?

2010; Elsevier BV; Volume: 130; Issue: 2 Linguagem: Inglês

10.1038/jid.2009.353

1523-1747

Kavitha K. Reddy, Barbara A. Gilchrest,

Vitamin C and Antioxidants Research

Vitamin D levels and unprotected sun exposure as a means of increasing these levels in the general population have become hot-button issues, polarizing many in the medical community and lay public. Here, we review some of the relevant research findings, discuss prevalent recommendations based on these data, and offer our own recommendations for patient management that reflect our evaluation of the literature. Vitamin D, long known for its essential role in calcium absorption and bone health, has more recently been implicated in other aspects of health, including prevention of cancer, autoimmune disease, cardiovascular disease, and other chronic diseases (Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar). A wide range of potential functions is suggested by the discovery that at least 60 human cell types express the vitamin D receptor and more than 200 genes have been identified as directly or indirectly responsive to vitamin D (Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar). These discoveries have led to understandable speculation that suboptimal vitamin D levels may predispose individuals to many diseases. It is unfortunate for lifelong maintenance of healthy skin that the increased interest in vitamin D has also led some to advocate unprotected sun exposure or sun bed use to attain "sufficient" or optimal levels (Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar; Schoenmakers et al., 2008Schoenmakers I. Goldberg G.R. Prentice A. Abundant sunshine and vitamin D deficiency.British J Nutr. 2008; 99: 1171-1173Google Scholar). Because of space constraints, we have assumed the reader has a basic knowledge of the rationale for photoprotection, which includes prevention of photocarcinogenesis and photoaging. We discuss instead often poorly articulated issues that fuel the "vitamin D controversy" and appear to lead otherwise well-informed health-care providers to recommend unprotected UV exposure to their patients. Vitamin D level commonly refers to the serum concentration of the inactive storage form, 25-hydroxyvitamin D (25(OH)D), understood to reflect total body stores. The active form of the vitamin, 1,25-dihydroxyvitamin D (1,25(OH)2D), is more correctly viewed as a hormone, because it can be made by the body and is transported in the bloodstream to the target tissues possessing its nuclear receptor, a member of the steroid hormone superfamily (Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar). In contrast to 1,25(OH)2D levels, which are tightly regulated and virtually constant, serum 25(OH)D levels vary widely among apparently healthy individuals and over time in a single individual (Dawson-Hughes et al., 1997Dawson-Hughes B. Harris S.S. Dallal G.E. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women.Am J Clin Nutr. 1997; 65: 67-71Google Scholar; Nesby-O'Dell et al., 2002Nesby-O'Dell S. Scanlon K.S. Cogswell M.E. et al.Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994.Am J Clin Nutr. 2002; 76: 187-192Google Scholar; Tangpricha et al., 2002Tangpricha V. Pearce E.N. Chen T.C. et al.Vitamin D insufficiency among free-living healthy young adults.Am J Med. 2002; 112: 659-662Google Scholar). Irradiation of animal skin with UVB (290–315 nm), the same wavelengths primarily responsible for photocarcinogenesis (Wolpowitz and Gilchrest, 2006Wolpowitz D. Gilchrest B.A. The vitamin D questions: how much do you need and how should you get it?.J Am Acad Dermatol. 2006; 54: 301-317Google Scholar), converts 7-dehydrocholesterol in cell membranes to pre–vitamin D3, which then thermally isomerizes to vitamin D3 (cholecalciferol) and enters the bloodstream. In an analogous process in plants and fungi, UV irradiation converts ergosterol in cell walls to vitamin D2 (ergocalciferol or calciferol), which upon oral ingestion also enters the bloodstream. Ingestion of certain fish or other animal products, as well as either vitamin D2 or D3 supplements, also results in entry of vitamin D into the bloodstream. Both forms of the vitamin, D2 and D3, are measured in standard vitamin D serum assays after hydroxylation in the liver, and both are further hydroxylated to biologically active 1,25(OH)2D (Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar). Classically, there are three categories for vitamin D levels. The first level is deficient, a level causing bone disease (rickets in children or osteomalacia in adults), usually defined as 150 ng/ml or 375 nmol/l. Signs and symptoms of vitamin D toxicity, also termed intoxication, are rapidly abolished by decreasing vitamin D intake. (Because UV exposure in excess of approximately one-third a minimal erythema dose promotes conversion of pre–vitamin D3 to inactive photoproducts rather than to vitamin D, UV exposure alone cannot lead to toxic levels (Holick et al., 1980Holick M.F. MacLaughlin J.A. Clark M.B. et al.Photosynthesis of previtamin D3 in human skin and the physiologic consequences.Science. 1980; 210: 203-205Google Scholar).) All three categories are strongly influenced by dietary calcium ingestion and absorption because the functions of vitamin D that determine these signs and symptoms require calcium (Wolpowitz and Gilchrest, 2006Wolpowitz D. Gilchrest B.A. The vitamin D questions: how much do you need and how should you get it?.J Am Acad Dermatol. 2006; 54: 301-317Google Scholar). The definition of vitamin D deficiency sometimes also includes an elevated level of parathyroid hormone (PTH), a molecule that stimulates intestinal absorption and renal tubular reabsorption of calcium as well as renal production of 1,25(OH)2D (Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar). More recently, two new terms have been introduced: "insufficient" is a level above deficient, as defined here, but below a variously defined "sufficient" level. Conceptually, an insufficient level is statistically associated in one or more epidemiologic studies with a higher incidence or prevalence of a disease of interest such as cancer, cardiovascular disease, or diabetes. It is hypothesized on the basis of indirect evidence that a very high serum 25(OH)D level drives the inactive vitamin into cells that express 1-hydroxylase, where it is then converted to active 1,25(OH)2D and exerts healthful effects such as differentiation, thus decreasing cancer risk, for example (Autier and Gandini, 2007Autier P. Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.Arch Intern Med. 2007; 167: 1730-1737Google Scholar; Bischoff-Ferrari et al., 2006Bischoff-Ferrari H.A. Giovannucci E. Willett W.C. et al.Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.Am J Clin Nutr. 2006; 84: 18-28Google Scholar; Holick, 2008Holick M.F. Vitamin D and sunlight: strategies for cancer prevention and other health benefits.Clin J Am Soc Nephrol. 2008; 3: 1548-1554Google Scholar). Typically, to determine a sufficient level, studied populations have been divided into quartiles or quintiles based on 25(OH)D levels and the disease of interest found to be increased 1.5- to 2-fold among subjects in the lowest group relative to the highest group (Giovannucci, 2005Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States.Cancer Causes Control. 2005; 16: 83-95Google Scholar; Melamed et al., 2008Melamed M.L. Michos E.D. Post W. et al.25-hydroxyvitamin D levels and the risk of mortality in the general population.Arch Intern Med. 2008; 168: 1629-1637Google Scholar). The proportion of affected individuals is low in all subject groups, typically 0.5–2% (Freedman et al., 2008Freedman D.M. Chang S.C. Falk R.T. et al.Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.Cancer Epidemiol Biomarkers Prev. 2008; 17: 889-894Google Scholar; Wactawski-Wende et al., 2006Wactawski-Wende J. Kotchen J.M. Anderson G.L. et al.Calcium plus vitamin D supplementation and the risk of colorectal cancer.N Engl J Med. 2006; 354: 684-696Google Scholar), and thus the overwhelming majority of "insufficient" subjects do not have the disease of interest. Because each study selects somewhat different 25(OH)D levels as cutoffs within the population, numerous values have been suggested as the lower limit of "sufficient." A recent consensus conference of five investigators interested in this issue recommended 30–40 ng/ml (75–100 nmol/l) (Bischoff-Ferrari et al., 2006Bischoff-Ferrari H.A. Giovannucci E. Willett W.C. et al.Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.Am J Clin Nutr. 2006; 84: 18-28Google Scholar), but some publications and many Internet blogs recommend cutoffs up to twice this level (Hollis et al., 2007Hollis B.W. Wagner C.L. Drezner M.K. et al.Circulating vitamin D3 and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status.J Steroid Biochem Mol Biol. 2007; 103: 631-634Google Scholar; GrassrootsHealth, 2008GrassrootsHealth Vitamin D Scientists' Call to Action Statement.http://www.grassrootshealth.net/media/download/scientists_letter_072208.pdfDate: 2008Google Scholar; Looking, 2008Looking Fit Top 10 Myths About Vitamin D.http://www.lookingfit.com/hotnews/top-10-myths-about-vitamin-d.htmlDate: 2008Google Scholar). Some definitions of "sufficient" include the criterion that PTH levels be maximally suppressed—i.e., not lowered further by increasing 25(OH)D levels (Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar)—but PTH levels are rarely measured in clinical practice and even more rarely before and after vitamin D challenge. In any case, the desirability of keeping PTH levels at their nadir, incapable of reduction by further elevation of 25(OH)D levels, is philosophical: no study has demonstrated a health benefit of minimizing PTH levels in normal individuals. Of note, by definition, an individual need not have any past, present, or future health problem to be classified as vitamin D insufficient. Equally, there need be no detectable benefit of increasing an individual's 25(OH)D level, even for a period of years; and individuals classified as sufficient are still at risk for all the studied diseases. As a fat-soluble molecule, 25(OH)D dissolves in fat, and thus serum measurements of vitamin D tend to decrease with increasing body mass index (Giovannucci, 2005Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States.Cancer Causes Control. 2005; 16: 83-95Google Scholar; Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar). Whether 25(OH)D in fat is as bioavailable as it is when protein bound in the serum is debatable, but serum vitamin D levels in overweight or obese persons underestimate their total body stores (Wortsman et al., 2000Wortsman J. Matsuoka L.Y. Chen T.C. et al.Decreased bioavailability of vitamin D in obesity.Am J Clin Nutr. 2000; 72: 690-693Google Scholar) and are considerably lower than in leaner individuals in similar environments (Arunabh et al., 2003Arunabh S. Pollack S. Yeh J. et al.Body fat content and 25-hydroxyvitamin D levels in healthy women.J Clin Endocrinol Metab. 2003; 88: 157-161Google Scholar; Kumar et al., 2009Kumar J. Muntner P. Kaskel F.J. et al.Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001–2004.Pediatrics. 2009Google Scholar), placing them disproportionately in the lower quartiles and quintiles of populations stratified by 25(OH)D level. A recent study reporting an association of hypertension, diabetes, and other cardiovascular risk factors with low 25(OH)D levels in children and adolescents claims that the association persists when the data are analyzed after correcting for adiposity (Kumar et al., 2009Kumar J. Muntner P. Kaskel F.J. et al.Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001–2004.Pediatrics. 2009Google Scholar), but in fact their subanalysis omits only those above the 95% cutoff in weight for infants and those with body mass index >30 kg/m2 for older children, leaving many severely overweight participants. Thus, obesity remains a likely confounding factor for many, if not all, of the associations between low 25(OH)D levels and poor health outcomes. Of course, it is possible, if seemingly far-fetched, to argue the reverse—that obese and sedentary people are at high risk of many diseases specifically because they have low serum 25(OH)D levels (Garland et al., 2007Garland C.F. Gorham E.D. Mohr S.B. et al.Vitamin D and prevention of breast cancer: pooled analysis.J Steroid Biochem Mol Biol. 2007; 103: 708-711Google Scholar; Giovannucci, 2005Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States.Cancer Causes Control. 2005; 16: 83-95Google Scholar). Interestingly, in the context of considering how best to correct vitamin D insufficiency in the population, lean and obese subjects are reported to comparably increase serum 25(OH)D levels after a standardized oral supplement, but following a whole-body UVB exposure obese subjects appear to increase 25(OH)D levels less than half as much as lean subjects (Wortsman et al., 2000Wortsman J. Matsuoka L.Y. Chen T.C. et al.Decreased bioavailability of vitamin D in obesity.Am J Clin Nutr. 2000; 72: 690-693Google Scholar). The current official daily recommendation for adequate intake of vitamin D is 200–600 international units (IU)/day (American Academy of Dermatology, 2009American Academy of Dermatology Position Statement on Vitamin D.http://www.aad.org/forms/policies/uploads/ps/aad_ps_vitamin_d.pdfDate: 2009Google Scholar), depending on age, although this is under review and may be revised upward as early as May 2010 (Grant and Boucher, 2009Grant W.B. Boucher B.J. Current impediments to acceptance of the ultraviolet-B-vitamin D-cancer hypothesis.Anticancer Res. 2009; 29: 3597-3604Google Scholar). These amounts were calculated by committee, from assumptions about typical sun exposure and dietary intake, and are intended to ensure a serum 25(OH)D level in the presumptively adequate range (US National Institutes of Health, 2009US National Institutes of Health Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D.http://ods.od.nih.gov/factsheets/vitamind.aspDate: 2009Google Scholar). Most multivitamins accordingly contain 400 IU of vitamin D. Recommendations for higher levels of supplementation have flooded the literature and the Internet. Most appear based on intervention studies that demonstrate a statistically significant health benefit of 700–1100 IU/day of vitamin D (plus 1.0–1.5 g/day of calcium) as an oral supplement (Bischoff-Ferrari et al., 2006Bischoff-Ferrari H.A. Giovannucci E. Willett W.C. et al.Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.Am J Clin Nutr. 2006; 84: 18-28Google Scholar; Lappe et al., 2007Lappe J.M. Travers-Gustafson D. Davies K.M. et al.Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.Am J Clin Nutr. 2007; 85: 1586-1591Google Scholar). To date, such studies have involved primarily elderly women, many of whom were initially vitamin D deficient (not "insufficient"), and pertain largely to reduction in falls and fractures (Wolpowitz and Gilchrest, 2006Wolpowitz D. Gilchrest B.A. The vitamin D questions: how much do you need and how should you get it?.J Am Acad Dermatol. 2006; 54: 301-317Google Scholar). No study has documented any benefit of supplementation greater than 700–1200 IU/day. It is estimated that for every 100 IU of vitamin D2 or D3 ingested daily, serum 25(OH)D levels increase 1.0 ng/ml, or 2.5 nmol/l (Heaney et al., 2003Heaney R.P. Davies K.M. Chen T.C. et al.Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.Am J Clin Nutr. 2003; 77: 204-210Google Scholar; Holick, 2008Holick M.F. Vitamin D and sunlight: strategies for cancer prevention and other health benefits.Clin J Am Soc Nephrol. 2008; 3: 1548-1554Google Scholar), suggesting that in the complete absence of dietary vitamin D or UV exposure, a daily supplement of at least 1,000 IU is needed to avoid vitamin D deficiency, defined as <10 ng/ml, or 36,000 women (average age 62 years) followed on average for 7 years, which failed to demonstrate a reduction in incidence, morbidity, or mortality for colorectal cancer (Wactawski-Wende et al., 2006Wactawski-Wende J. Kotchen J.M. Anderson G.L. et al.Calcium plus vitamin D supplementation and the risk of colorectal cancer.N Engl J Med. 2006; 354: 684-696Google Scholar). Subsequent analysis of the same population investigating other possible benefits of vitamin D and calcium supplementation suggested by prior epidemiologic studies further revealed no significant impact on overall mortality, coronary or other cardiovascular death, cerebrovascular death, or total cancer deaths (LaCroix et al., 2009LaCroix A.Z. Kotchen J. Anderson G. et al.Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women's Health Initiative calcium–vitamin D randomized controlled trial.J Gerontol. 2009; 64: 559-567Google Scholar). There were modest and nonsignificant reductions in fractures of the hip and vertebrae (Jackson et al., 2006Jackson R.D. LaCroix A.Z. Gass M. et al.Calcium plus vitamin D supplementation and the risk of fractures.N Engl J Med. 2006; 354: 669-683Google Scholar). Although the Women's Health Initiative studies have been discounted by many in the field for using too small a supplement, they remain the largest and best controlled efforts to date to implicate vitamin D in health outcomes. Negative results were also noted in a prospective study of nearly 17,000 subjects recruited from the National Health and Nutrition Examination Survey study and followed up to 12 years; there was no effect of 25(OH)D level on mortality risk for five of six cancer types or for overall cancer mortality (Freedman et al., 2007Freedman D.M. Looker A.C. Chang S.C. et al.Prospective study of serum vitamin D and cancer mortality in the United States.J Natl Cancer Inst. 2007; 99: 1594-1602Google Scholar). Subsequently, these investigators performed numerous additional analyses of the data in response to the suggestion that they might have missed important associations detected in previous smaller studies by failing to account for race or season of the 25(OH)D determination or to separately examine only subjects with low 25(OH)D levels. All these analyses, and more, yielded no additional associations between cancer mortality and 25(OH)D levels (Freedman et al., 2009Freedman D.M. Fuhrman B. Graubard B.I. et al.Vitamin D and cancer mortality.Cancer Epidemiol Biomarkers Prev. 2009; 18 (response 359–60): 359Google Scholar). Studying a second independent large population of postmenopausal women, these investigators also found no relationship between breast cancer risk and baseline levels of either 25(OH)D or 1,25(OH)D, also suggested by some to affect multiple health outcomes (Freedman et al., 2008Freedman D.M. Chang S.C. Falk R.T. et al.Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.Cancer Epidemiol Biomarkers Prev. 2008; 17: 889-894Google Scholar). More than one-half to three-fourths of many studied populations of apparently healthy people are now classified as vitamin D insufficient (Ginde et al., 2009Ginde A.A. Liu M.C. Camargo Jr, C.A. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004.Arch Intern Med. 2009; 169: 626-632Google Scholar; Holick, 2007Holick M.F. Vitamin D deficiency.N Eng J Med. 2007; 357: 266-281Google Scholar), and it is suggested that they are at increased risk of disease or early death and require interventions whose long-term risks are unknown. From a dermatologic perspective, the major concern is the position of the Indoor Tanning Association and a small number of authors who advocate increased UV exposure as the best way to correct this situation, despite the anticipated increases in skin cancer, including melanoma, and photoaging. From a broader public health perspective, however, other problems exist. First and most critically, having the media and certain physician groups propagate alarmist health messages that later prove