Vitamin D in preventive medicine: are we ignoring the evidence?
TL;DR: Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity.
Abstract: Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.
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TL;DR: It has been more than 3 decades since the first assay assessing circulating 25-hydroxyvitamin D in human subjects was performed and led to the definition of "normal" nutritional vitamin D status, i.e., vitamin D sufficiency, and current dietary recommendations for adults are not sufficient to maintain circulating 25(OH)D levels at or above this level, especially in pregnancy and lactation.
Abstract: It has been more than 3 decades since the first assay assessing circulating 25-hydroxyvitamin D [25(OH)D] in human subjects was performed and led to the definition of "normal" nutritional vitamin D status, i.e., vitamin D sufficiency. Sampling human subjects, who appear to be free from disease, and assessing "normal" circulating 25(OH)D levels based on a Gaussian distribution of these values is now considered to be a grossly inaccurate method of identifying the normal range. Several factors contribute to the inaccuracy of this approach, including race, lifestyle habits, sunscreen usage, age, latitude, and inappropriately low dietary intake recommendations for vitamin D. The current adult recommendations for vitamin D, 200-600 IU/d, are very inadequate when one considers that a 10-15 min whole-body exposure to peak summer sun will generate and release up to 20,000 IU vitamin D-3 into the circulation. We are now able to better identify sufficient circulating 25(OH)D levels through the use of specific biomarkers that appropriately increase or decrease with changes in 25(OH)D levels; these include intact parathyroid hormone, calcium absorption, and bone mineral density. Using these functional indicators, several studies have more accurately defined vitamin D deficiency as circulating levels of 25(OH)D < or = 80 nmol or 32 microg/L. Recent studies reveal that current dietary recommendations for adults are not sufficient to maintain circulating 25(OH)D levels at or above this level, especially in pregnancy and lactation.
1,170 citations
TL;DR: Vitamin D, or lack of it, may be Hope-Simpson's ‘seasonal stimulus’ and dramatically stimulates the expression of potent anti-microbial peptides, which exist in neutrophils, monocytes, natural killer cells, and in epithelial cells lining the respiratory tract where they play a major role in protecting the lung from infection.
Abstract: In 1981, R. Edgar Hope-Simpson proposed that a 'seasonal stimulus' intimately associated with solar radiation explained the remarkable seasonality of epidemic influenza. Solar radiation triggers robust seasonal vitamin D production in the skin; vitamin D deficiency is common in the winter, and activated vitamin D, 1,25(OH)2D, a steroid hormone, has profound effects on human immunity. 1,25(OH)2D acts as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the 'oxidative burst' potential of macrophages. Perhaps most importantly, it dramatically stimulates the expression of potent anti-microbial peptides, which exist in neutrophils, monocytes, natural killer cells, and in epithelial cells lining the respiratory tract where they play a major role in protecting the lung from infection. Volunteers inoculated with live attenuated influenza virus are more likely to develop fever and serological evidence of an immune response in the winter. Vitamin D deficiency predisposes children to respiratory infections. Ultraviolet radiation (either from artificial sources or from sunlight) reduces the incidence of viral respiratory infections, as does cod liver oil (which contains vitamin D). An interventional study showed that vitamin D reduces the incidence of respiratory infections in children. We conclude that vitamin D, or lack of it, may be Hope-Simpson's 'seasonal stimulus'.
958 citations
TL;DR: An inverse association between vitamin D status and diabetes, possibly involving insulin resistance, in non-Hispanic whites and Mexican Americans is shown and may reflect decreased sensitivity to vitamin D and/or related hormones such as the parathyroid hormone.
Abstract: OBJECTIVE —To determine the association between serum 25-hydroxyvitamin D (25OHD) and diabetes risk and whether it varies by ethnicity. RESEARCH DESIGN AND METHODS —We performed an analysis of data from participants who attended the morning examination of the Third National Health and Nutrition Examination Survey (1988–1994), a cross-sectional survey of a nationally representative sample of the U.S. population. Serum levels of 25OHD, which reflect vitamin D status, were available from 6,228 people (2,766 non-Hispanic whites, 1,736 non-Hispanic blacks, and 1,726 Mexican Americans) aged ≥20 years with fasting and/or 2-h plasma glucose and serum insulin measurements. RESULTS —Adjusting for sex, age, BMI, leisure activity, and quarter of year, ethnicity-specific odds ratios (ORs) for diabetes (fasting glucose ≥7.0 mmol/l) varied inversely across quartiles of 25OHD in a dose-dependent pattern (OR 0.25 [95% CI 0.11–0.60] for non-Hispanic whites and 0.17 [0.08–0.37] for Mexican Americans) in the highest vitamin D quartile (25OHD ≥81.0 nmol/l) compared with the lowest 25OHD (≤43.9 nmol/l). This inverse association was not observed in non-Hispanic blacks. Homeostasis model assessment of insulin resistance (log e ) was inversely associated with serum 25OHD in Mexican Americans ( P = 0.0024) and non-Hispanic whites ( P = 0.058) but not non-Hispanic blacks ( P = 0.93), adjusting for confounders. CONCLUSIONS —These results show an inverse association between vitamin D status and diabetes, possibly involving insulin resistance, in non-Hispanic whites and Mexican Americans. The lack of an inverse association in non-Hispanic blacks may reflect decreased sensitivity to vitamin D and/or related hormones such as the parathyroid hormone.
932 citations
Cites background from "Vitamin D in preventive medicine: a..."
...Initial findings from animal studies showed that insulin released from the isolated perfused pancreas of the rat is lower in vitamin D–deficient animals than control animals (1), while pancreatic receptors for 1,25-dihydroxyvitamin D3 in -cells have been identified in a number of species (2)....
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...Vitamin D deficiency results in hyperparathyroidism (2,15), through which it may influence glucose metabolism....
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...Blood levels of 25hydroxyvitamin D (25OHD), the main metabolite of vitamin D, are a marker of vitamin D status (2)....
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TL;DR: Vitamin D(3) reduces the inflammatory milieu in CHF patients and might serve as a new antiinflammatory agent for the future treatment of the disease.
890 citations
TL;DR: Currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.
Abstract: Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes. In vitro data show that, in addition to modulating innate immune cells, vitamin D also promotes a more tolerogenic immunological status. In vivo data from animals and from human vitamin D supplementation studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity. In this review, currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.
733 citations
Cites background from "Vitamin D in preventive medicine: a..."
...One important factor may be the availability of sufficient vitamin D levels [97,98] as various epidemiological studies suggest associations between vitamin D deficiency and a higher incidence of autoimmune diseases, such as T1D, MS, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD)....
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References
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TL;DR: Obese subjects had significantly lower basal 25-hydroxyvitamin D concentrations and higher parathyroid hormone concentrations than did age-matched control subjects and the incremental increase in vitamin D(3) was 57% lower in obese than in nonobese subjects.
2,980 citations
"Vitamin D in preventive medicine: a..." refers background in this paper
...The alterations in vitamin D metabolism of obese subjects in comparison with lean subjects are also associated with functional alterations such as elevated PTH levels (Bell et al. 1985; Wortsman et al. 2000)....
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...Obese subjects have an increased risk for low circulating 25(OH)D levels (Bell et al. 1985; Wortsman et al. 2000) due to the storage of vitamin D and 25(OH)D in adipose tissue (Wortsman et al. 2000)....
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...Moreover, a nested case–control study based on serum drawn from a cohort of 25 620 individuals reported that concentrations of 25(OH)D in the range of 65–100 nmol/l were associated with large reductions in the incidence of colorectal cancer compared with lower 25(OH)D levels (Garland et al. 1991)....
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TL;DR: The effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women are studied.
Abstract: Background. Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known. Methods. We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [±SD] age, 84±6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 μg (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women. Results. Among the women who completed the 18-month study, the number of hip fra...
2,714 citations
TL;DR: In men and women 65 years of age or older who are living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck, spine, and total body over the three-year study period and reduced the incidence of nonvertebral fractures.
Abstract: Background Inadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons. Methods We studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density, biochemical measures of bone metabolism, and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home. They received either 500 mg of calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. Bone mineral density was measured by dual-energy x-ray absorptiometry, blood and urine were analyzed every six months, and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records. Results The mean (±SD) changes in bone mineral density in the calcium–vitamin D and placebo groups were as follows: femoral neck, +0.50±4.80 and -0.70±5.03 percent, respectively (P = 0.02); spine, +2.12±4.06 and +1.22±4.25 percent (P = 0.04); and total body,...
2,207 citations
"Vitamin D in preventive medicine: a..." refers background in this paper
...Bone mineral loss at the femoral neck, spine, and total body could be prevented with a combined daily supplement of 17·5mg vitamin D and 500 mg Ca (Dawson-Hughes et al. 1997)....
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TL;DR: Vitamin D supplementation was associated with a decreased frequency of type 1 diabetes when adjusted for neonatal, anthropometric, and social characteristics and Ensuring adequate vitamin D supplementation for infants could help to reverse the increasing trend in the incidence ofType 1 diabetes.
1,872 citations
"Vitamin D in preventive medicine: a..." refers background in this paper
...Moreover, administration of 50mg vitamin D/d to infants can obviously markedly reduce the prevalence of type 1 diabetes in later life (Hyppönen et al. 2001)....
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...Children suspected of having rickets during the first year of life had a threefold increased prevalence of type 1 diabetes in comparison with those without such a suspicion (Hyppönen et al. 2001)....
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TL;DR: The assembled data from many vitamin D supplementation studies reveal a curve for vitamin D dose versus serum 25-hydroxyvitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10000 IU) vitamin D/d.
1,450 citations
"Vitamin D in preventive medicine: a..." refers background in this paper
...Dose–response studies with daily doses of oral vitamin D have demonstrated that 10, 25, 100 and 250mg vitamin D result in a mean increase of circulating 25(OH)D levels of 45, 48, 56, and 112 nmol/l, respectively (Vieth, 1999; Vieth et al. 2001a)....
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