Table of Contents

Volume 4, Issue 2

  April/May/June 2012

  Pages 81 - 224

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Vitamin D: Its role in disease prevention

William B. Grant and Vin Tangpricha
Pages 81 - 83
http://dx.doi.org/10.4161/derm.20435
Abstract | Full Text | PDF

Evidence that vitamin D reduces the risk of many types of disease is increasing exponentially. In 2011, 3,100 publications with “vitamin D” in the title or abstract were published, up from 2,606 in 2010, 1,303 in 2005, and 796 in 2000. A committee operating under the auspices of the Institute of Medicine (IOM) of the US National Academies reviewed the evidence for beneficial effects of vitamin D. Their report, issued at the end of 2010,¹ found what they considered to be strong evidence for only one health outcome: skeletal health. They considered beneficial evidence only from published randomized controlled trials (RCTs) focused mainly on skeletal health. In contrast, to justify concern about higher vitamin D intake and serum 25(OH)D concentrations, they used data from nested case-control studies reporting U-shaped outcomes of prediagnostic serum 25-hydroxyvitamin D [25(OH)D] for cancer and all-cause mortality rates. They set the daily recommended intake of vitamin D at 600–800 IU for most children and adults and defined vitamin D sufficiency as a serum 25(OH)D level above 20 ng/ml (50 nmol/l). They also set a daily upper intake of 4,000 IU of vitamin D₃ and called for more RCTs to determine nonskeletal health effects. As of this writing, more than 130 journal publications have criticized the IOM report as being too conservative. One summarized the problems succinctly: “The IOM recommendations for vitamin D fail in a major way on logic, on science, and on effective public health guidance. Moreover, by failing to use a physiological referent, the IOM approach constitutes precisely the wrong model for development of nutritional policy.”²

Open Access Article

Youssef et al. make a strong case for addressing 25(OH)D concentration (vitamin D status) in hospitalized patients with infections

David McCarthy
Page 84
http://dx.doi.org/10.4161/derm.20272
Abstract | Full Text | PDF

Correcting vitamin D deficiency in the outpatient setting has become commonplace and is a routine in many primary care practices. This extension into the inpatient setting is timely and logical. The benefits of vitamin D testing continue to be demonstrated.




REVIEWS

Open Access Article

Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and white Americans

William B. Grant and Alan N. Peiris
Pages 85 - 94
http://dx.doi.org/10.4161/derm.19667
Abstract | Full Text | PDF

Considerable disparities in cancer survival rates exist between African Americans (AAs) and white Americans (WAs). Various factors such as differences in socioeconomic status (SES), cancer stage at time of diagnosis, and treatment—which this analysis considers primary explanatory factors—have accounted for many of these differences. An additional factor not usually considered is vitamin D. Previous studies have inversely correlated higher solar ultraviolet-B (UVB) doses and serum 25-hydroxyvitamin D (25(OH)D) concentrations with incidence and/or mortality rates for about 20 types of cancer and improved survival rates for eight types of cancer. Because of darker skin pigmentation, AAs have 40% lower serum 25(OH)D concentrations than WAs. This study reviews the literature on disparities in cancer survival between AAs and WAs. The journal literature indicates that there are disparities for 13 types of cancer after consideration of SES, stage at diagnosis and treatment: bladder, breast, colon, endometrial, lung, ovarian, pancreatic, prostate, rectal, testicular, and vaginal cancer; Hodgkin lymphoma and melanoma. Solar UVB doses and/or serum 25(OH)D concentrations have been reported inversely correlated with incidence and/or mortality rates for all of these cancers. This finding suggests that future studies should consider serum 25(OH)D concentrations in addressing cancer survival disparities through both measurements of serum 25(OH)D concentrations and increasing serum 25(OH)D concentrations of those diagnosed with cancer, leading to improved survival rates and reduced disparities.

Open Access Article

Why randomized controlled trials of calcium and vitamin D sometimes fail

Joan M. Lappe and Robert P. Heaney
Pages 95 - 100
http://dx.doi.org/10.4161/derm.19833
Abstract | Full Text | PDF

The importance of nutrients for promotion of health and prevention of disease has long been recognized. Nonetheless, scientists are still trying to delineate the optimal intakes of various nutrients and their potential benefits for different populations. To that end, evidence-based medicine (EBM) has been applied to the study of nutrition. EBM methods basically call for the use of randomized controlled trials (RCTs) to establish causal connection between the intervention and any particular endpoint.

This paper focuses on problems that arise in the use of RCTS to establish a causal link between nutrients and various clinical endpoints. While many RCTS of calcium and vitamin D have been positive, many others have been null. In this paper, we discuss the reasons why effective nutrient agents may be found to be ineffective in particular studies, giving examples of such null results, and focusing on the nearly universal failure to consider biological criteria in designing RCTs. Our purpose is (1) to inform future study design so as to ensure that relevant biological facts are considered and (2) to aid in the interpretation of the abundant, but often inconsistent literature on this topic.

Open Access Article

Vitamin D and sepsis: An emerging relationship

Jordan A. Kempker, Jenny E. Han, Vin Tangpricha, Thomas R. Ziegler and Greg S. Martin
Pages 101 - 108
http://dx.doi.org/10.4161/derm.19859
Abstract | Full Text | PDF

Vitamin D insufficiency and sepsis are both highly prevalent worldwide problems and this article reviews the emerging science that is defining the intersections of these conditions. The importance of vitamin D’s role in skeletal health has long been understood but recent evidence is beginning to highlight its role in the functioning of other physiologic systems of the body. Basic science data reveal its integral role in local immune responses to pathogens and the systemic inflammatory pathways of sepsis. Furthermore, clinical scientists have found associations with respiratory infections, critical illness and sepsis but the causal relationship and its clinical impact have yet to be clearly defined. The article ends with speculations on the connections between racial disparities and seasonal differences in sepsis and vitamin D insufficiency.

Open Access Article

Beneficial effects of UV radiation other than via vitamin D production

Asta Juzeniene and Johan Moan
Pages 109 - 117
http://dx.doi.org/10.4161/derm.20013
Abstract | Full Text | PDF

Most of the positive effects of solar radiation are mediated via ultraviolet-B (UVB) induced production of vitamin D in skin. However, several other pathways may exist for the action of ultraviolet (UV) radiation on humans as focused on in this review. One is induction of cosmetic tanning (immediate pigment darkening, persistent pigment darkening and delayed tanning). UVB-induced, delayed tanning (increases melanin in skin after several days), acts as a sunscreen. Several human skin diseases, like psoriasis, vitiligo, atopic dermatitis and localized scleroderma, can be treated with solar radiation (heliotherapy) or artificial UV radiation (phototherapy). UV exposure can suppress the clinical symptoms of multiple sclerosis independently of vitamin D synthesis. Furthermore, UV generates nitric oxide (NO), which may reduce blood pressure and generally improve cardiovascular health. UVA-induced NO may also have antimicrobial effects and furthermore, act as a neurotransmitter. Finally, UV exposure may improve mood through the release of endorphins.

Open Access Article

Vitamin D supplementation in pre-dialysis chronic kidney disease: A systematic review

Jessica A. Alvarez, Haimanot Wasse and Vin Tangpricha
Pages 118 - 127
http://dx.doi.org/10.4161/derm.20014
Abstract | Full Text | PDF

Vitamin D deficiency is associated with a variety of skeletal, cardiometabolic, and immunologic co-morbidities that are present in chronic kidney disease (CKD). We performed a systematic review to investigate the effects of vitamin D supplementation, in the form of ergocalciferol or cholecalciferol, on various health outcomes in early CKD. Seventeen clinical trials were identified, only two of which were randomized, placebo controlled trials. The majority of studies supplementing with > 2,000 IU/day of cholecalciferol achieved optimal vitamin D status, whereas studies supplementing with ergocalciferol were less consistent. Studies varied widely in their effects on lowering serum parathyroid hormone concentrations. Few studies investigated effects of vitamin D treatment on other clinical health indicators in early CKD. Rigorous studies are necessary to investigate optimal vitamin D dosing strategies in early CKD for the maintenance of adequate vitamin D status, management of secondary hyperparathyroidism and improvement of non-skeletal related clinical outcomes.

Open Access Article

Does vitamin D deficiency contribute to erectile dysfunction?

Marc B. Sorenson and William B. Grant
Pages 128 - 136
http://dx.doi.org/10.4161/derm.20361
Abstract | Full Text | PDF

Erectile dysfunction (ED) is a multifactorial disease, and its causes can be neurogenic, psychogenic, hormonal and vascular. ED is often an important indicator of cardiovascular disease (CVD) and a powerful early marker for asymptomatic CVD. Erection is a vascular event, and ED is often a vascular disease caused by endothelial damage and subsequent inhibition of vasodilation. We show here that risk factors associated with a higher CVD risk also associate with a higher ED risk. Such factors include diabetes mellitus, hypertension, arterial calcification and Inflammation in the vascular endothelium. Vitamin D deficiency is one of several dynamics that associates with increased CVD risk, but to our knowledge, it has not been studied as a possible contributor to ED. Here we examine research linking ED and CVD and discuss how vitamin D influences CVD and its classic risk factors—factors that also associate to increased ED risk. We also summarize research indicating that vitamin D associates with reduced risk of several nonvascular contributing factors for ED. We conclude that VDD contributes to ED. This hypothesis should be tested through observational and intervention studies.

Open Access Article

Vitamin D and asthma

Sheena D. Brown, H. Hardie Calvert and Anne M. Fitzpatrick
Pages 137 - 145
http://dx.doi.org/10.4161/derm.20434
Abstract | Full Text | PDF

Asthma, one of the most prevalent diseases affecting people worldwide, is a chronic respiratory disease characterized by heightened airway inflammation, airway hyperresponsiveness and airflow obstruction in response to specific triggers. While the specific mechanisms responsible for asthma are not well understood, changing environmental factors associated with urban lifestyles may underlie the increased prevalence of the disorder. Vitamin D is of particular interest in asthma since vitamin D concentrations decrease with increased time spent indoors, decreased exposure to sunlight, less exercise, obesity, and inadequate calcium intake. Additionally, a growing body of literature suggests that there is a relationship between vitamin D status and respiratory symptoms, presumably through immunomodulatory effects of vitamin D. This review discusses vitamin D as it relates to asthma across the age spectrum, with a focus on human studies.

Open Access Article

Potential benefits of vitamin D for patients with systemic lupus erythematosus

Abha Singh and Diane L. Kamen
Pages 146 - 151
http://dx.doi.org/10.4161/derm.20443
Abstract | Full Text | PDF

Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease. Vitamin D deficiency has been proposed as an environmental trigger of disease onset and as a contributor to increased SLE activity. SLE patients are prone to develop vitamin D deficiency because of photosensitivity leading to sun avoidance and other sun protective measures. The impact of vitamin D on immune function previously seen in vitro and in cross-sectional studies has now been shown in prospective human studies, strengthening the evidence that there is a connection between SLE and vitamin D status. This review describes the role of vitamin D on immune function, prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency in SLE patients, and review current vitamin D recommendations for patients with SLE.

Open Access Article

Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria?

Sharif B. Mohr, Edward D. Gorham, John E. Alcaraz, Christopher I. Kane, Caroline A. Macera, J. Kellogg Parsons, Deborah L. Wingard and Cedric F. Garland
Pages 152 - 157
http://dx.doi.org/10.4161/derm.20449
Abstract | Full Text | PDF

A wide range of epidemiologic and laboratory studies combined provide compelling evidence of a protective role of vitamin D on risk of breast cancer. This review evaluates the scientific evidence for such a role in the context of the A.B. Hill criteria for causality, in order to assess the presence of a causal, inverse relationship, between vitamin D status and breast cancer risk. After evaluation of this evidence in the context of Hill’s criteria, it was found that the criteria for a causal relationship were largely satisfied. Studies in human populations and the laboratory have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer. Vitamin D supplementation is an urgently needed, low cost, effective, and safe intervention strategy for breast cancer prevention that should be implemented without delay. In the meantime, randomized controlled trials of high doses of vitamin D₃ for prevention of breast cancer should be undertaken to provide the necessary evidence to guide national health policy.

Open Access Article

Influence of drugs on vitamin D and calcium metabolism

Uwe Gröber and Klaus Kisters
Pages 158 - 166
http://dx.doi.org/10.4161/derm.20731
Abstract | Full Text | PDF

In the past, interactions between drugs and vitamin D have received only little or no attention in the health care practices. However, since more and more drugs are used for the treatment of patients, this topic is increasingly relevant. Several drugs can interfere with the vitamin D and bone metabolism. Drugs that activate the pregnane X receptor can disrupt vitamin D metabolism and vitamin D function. Beside this, the medication oriented supplementation of vitamin D can ameliorate the pharmacologic action of some drugs, such as bisphosphonates, cytostatics and statins.

Open Access Article

Vitamin D's potential to reduce the risk of hospital-acquired infections

Dima A. Youssef, Tamra Ranasinghe, William B. Grant and Alan N. Peiris
Pages 167 - 175
http://dx.doi.org/10.4161/derm.20789
Abstract | Full Text | PDF

Health care–associated and hospital-acquired infections are two entities associated with increased morbidity and mortality. They are highly costly and constitute a great burden to the health care system. Vitamin D deficiency (< 20 ng/ml) is prevalent and may be a key contributor to both acute and chronic ill health. Vitamin D deficiency is associated with decreased innate immunity and increased risk for infections. Vitamin D can positively influence a wide variety of microbial infections.

Herein we discuss hospital-acquired infections, such as pneumonia, bacteremias, urinary tract and surgical site infections, and the potential role vitamin D may play in ameliorating them. We also discuss how vitamin D might positively influence these infections and help contain health care costs. Pending further studies, we think it is prudent to check vitamin D status at hospital admission and to take immediate steps to address existing insufficient 25-hydroxyvitamin D levels.




REPORTS

Open Access Article

An ecological study of cancer mortality rates in California, 1950–64, with respect to solar UVB and smoking indices

William B. Grant
Pages 176 - 182
http://dx.doi.org/10.4161/derm.19834
Abstract | Full Text | PDF

Purpose: This paper addresses whether nonmelanoma skin cancer (NMSC) mortality rates can serve as a useful index of population ultraviolet-B (UVB) irradiance and vitamin D production in a manner that affects the risk of internal cancers
Methods: This analysis uses the ecological study approach with cancer mortality rate data from 19 state economic areas in California. This paper uses age-adjusted data for those aged 40 y or older. Two additional indices for solar UVB doses were also used: latitude and surface UVB doses for July 1992 from the total ozone mapping spectrometer. Lung cancer mortality rates served as the index of the health effects of smoking
Results: Significant inverse correlations with NMSC mortality rate in multiple linear regression analyses were found during the period 1950–64 for eight types of cancer for males: bladder, brain, colon, gastric, prostate, and rectal cancer; multiple myeloma; and non-Hodgkin lymphoma. No similar results emerged for females with respect to all three UVB indices. Their NMSC mortality rates averaged 60% lower than those for males. Lung cancer mortality rates were directly correlated with three types of cancer for males: laryngeal, oral, and renal. No significant correlations with NMSC mortality rates appeared for later periods
Conclusions: NMSC mortality rates were found inversely correlated with internal cancers for males in the period 1950–64. After that period, no further such correlations were found. The reasons may hypothetically include reduced NMSC mortality rates, high immigration rates, movement from rural to urban locations and reduced solar UVB irradiance.

Open Access Article

Evidence-based D-bate on health benefits of vitamin D revisited

Michael F. Holick
Pages 183 - 190
http://dx.doi.org/10.4161/derm.20015
Abstract | Full Text | PDF

Vitamin D has received worldwide attention not only for its importance for bone health in children and adults but also for reducing risk for many chronic diseases including autoimmune diseases, type 2 diabetes, heart disease, many cancers and infectious diseases. Vitamin D deficiency is pandemic due to the fact that most humans have depended on sun for their vitamin D requirement which they now either avoid or wear sun protection for fear of skin cancer. There are few foods that naturally contain vitamin D. Some countries permit vitamin D fortification especially dairy products, some cereals and juice products. The Institute of Medicine made its recommendations based on a population-based model; the Endocrine Society's Practice Guidelines on Vitamin D was for the prevention and treatment of vitamin D deficiency, which helps explain the differences in the recommendations. The Guidelines defined vitamin D deficiency as a 25-hydroxyvitamin D < 20 ng/mL, insufficiency as 21–29 ng/mL and sufficiency as 30–100 ng/mL. To prevent vitamin D deficiency The Guidelines recommended vitamin D intake should be: children < 1 y 400–1,000 IU/d, children 1–18 y 600–1,000 IU/d and adults 1,500–2,000 IU/d.

Open Access Article

Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: A randomized, controlled trial

Ruth E. Grossmann, Susu M. Zughaier, Meena Kumari, Shabnam Seydafkan, Robert H. Lyles, Shuling Liu, Viranuj Sueblinvong, Michael S. Schechter, Arlene A. Stecenko, Thomas R. Ziegler and Vin Tangpricha
Pages 191 - 197
http://dx.doi.org/10.4161/derm.20332
Abstract | Full Text | PDF

Background: Vitamin D insufficiency is common in cystic fibrosis (CF) and vitamin D repletion may have an important role in improving clinical outcomes in CF. This randomized, placebo-controlled, pilot study examined the feasibility and impact of a single, large dose of cholecalciferol on vitamin D status and clinical outcomes in subjects with CF.
Methods: Thirty adults with were randomized in a double-blinded, pilot study to receive 250,000 IU cholecalciferol or placebo within 48 h of hospital admission for a pulmonary exacerbation. Concentrations of 25-hydroxyvitamin D (25(OH)D), clinical outcomes and potential adverse events were assessed up to one year after randomization. Mixed effects linear regression models were used to evaluate the difference in mean serum concentrations and log-rank analyses were used to evaluate survival.
Results: Data from all subjects was analyzed. Serum 25(OH)D concentrations increased from a mean of 30.6 ± 3.2 ng/mL to 58.1 ± 3.5 ng/mL (p < 0.001) at one week and 36.7 ± 2.6 ng/mL by 12 weeks (p = 0.06) in the vitamin D group; in contrast, serum 25(OH)D concentrations remained unchanged in the placebo group. Unadjusted, one-year survival and hospital-free days were increased in the vitamin D group (p = 0.029, p = 0.036; respectively). There was also a trend toward increased IV antibiotic therapy-free days in the vitamin D group (p = 0.073). There were no signs of hypervitaminosis D or adverse events. Serum PTH and calcium concentrations were similar across both groups.
Conclusions: In this pilot study, a single, oral bolus of cholecalciferol increased serum 25(OH)D concentrations and was associated with a trend toward improved clinical outcomes in CF subjects hospitalized for a pulmonary exacerbation. Further investigation is needed into the clinical impact of improved vitamin D status in patients with CF.

Open Access Article

Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyvitamin D and all-cause mortality rate

William B. Grant
Pages 198 - 202
http://dx.doi.org/10.4161/derm.20514
Abstract | Full Text | PDF

Evidence continues to mount that vitamin D reduces the risk and mortality rates of many types of disease. However, evidence from prospective cohort studies is sometimes weaker than that from case–control and ecological studies. A suggested reason for this discrepancy is that, because serum levels of 25-hydroxyvitamin D [25(OH)D] change over time, a single 25(OH)D concentration measurement taken at study enrollment does not reliably indicate 25(OH)D concentration related to the health outcome. To evaluate this suggestion further, this paper plots results from 12 prospective cohort studies of all-cause mortality rate vs. follow-up time. The regression fit to the hazard ratio per 20-nmol/l increase in serum 25(OH)D concentration vs. time increased from 0.82 (95% CI, 0.67–1.02) for 6 y to 0.96 (95% CI, 0.90–1.01) for 14 y. The value extrapolated for zero follow-up time was 0.72 (95% CI, 0.50–1.03), giving a hazard ratio reduction 3.5 times higher than the standard result from the meta-analysis [0.92 (95% CI, 0.89–0.95)]. Using the example of the Vitamin D Pooling Project of Rarer Cancers, this paper also discusses follow-up time’s effect in interpreting prospective cohort studies of cancer outcome. This paper recommends that meta-analyses of prospective cohort studies account for follow-up time and, if possible, that studies measure serum 25(OH)D concentration every 2–4 y.

Open Access Article

Role of solar UVB irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries

William B. Grant
Pages 203 - 211
http://dx.doi.org/10.4161/derm.20965
Abstract | Full Text | PDF

A large body of evidence indicates that solar ultraviolet-B (UVB) irradiance and vitamin D reduce the risk of incidence and death for many types of cancer. However, most of that evidence comes from midlatitude regions, where solar UVB doses are generally high in summer. Data on cancer standardized incidence ratios (SIRs) by sex and 54 occupation categories based on 1.4 million male and 1.36 million female cancer cases for 1961–2005 in the five Nordic countries provide the basis for an ecological study of the role of solar UVB in the risk of many types of cancer at high latitudes. Lip cancer SIRs less lung cancer SIRs for men was the best index of solar UVB dose, which was weakly inversely correlated with both melanoma and nonmelanoma skin cancer (NMSC) SIRs. Lung cancer SIRs were used as the index of the effects of smoking. For men, the UVB index was significantly inversely correlated with 14 types of internal cancer—bladder, breast, colon, gallbladder, kidney, laryngeal, liver, lung, oral, pancreatic, pharyngeal, prostate, rectal and small intestine cancer. For women, the same UVB index was inversely correlated with bladder, breast and colon cancer. These results generally agree with findings from other studies. These results provide more support for the UVB-vitamin D-cancer hypothesis and suggest that widespread fear of chronic solar ultraviolet (UV) irradiance may be misplaced.




COMMENTARY

Open Access Article

Is vitamin D status relevant to metabolic syndrome?

Barbara J. Boucher
Pages 212 - 224
http://dx.doi.org/10.4161/derm.20012
Abstract | Full Text | PDF

Review of the evidence on hypovitaminosis D as a risk factor for metabolic syndrome and its sequelae, T2DM and CVD, suggests long-term vitamin D repletion could reduce these risks. There is mechanistic evidence for protective effects for MetS and the balance of evidence, (cross-sectional and prospective), supports this postulate. Much of the data so far available from randomized controlled trials is weakened by inadequate power, low vitamin D dosages, starting supplementation too late in life or after MetS disorders have developed or, most importantly, by non-inclusion of many recognizable confounders. On balance, therefore, maintenance of US 2010 recommended intakes for bone protection has the potential to prove protective for MetS. Supplementation has been shown to increase survival in patients with cardiac disorders; whether higher doses would provide useful protection for apparently healthy people in the general population awaits the outcomes of ongoing randomized-controlled trials that, it is hoped, will prove or disprove causality for hypovitaminosis D in MetS and its long-term ill-effects.