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1.
Role of vitamin D supplementation in modifying outcomes after surgery: a systematic review of randomised controlled trials.
Patel, A, Caruana, EJ, Hodson, J, Morrison, R, Khor, B, Gysling, S, Trevis, J, Mangel, T, Benson, R, Zakeri, R, et al
BMJ open. 2024;(1):e073431
Abstract
BACKGROUND There is increasing evidence to suggest vitamin D plays a role in immune and vascular function; hence, it may be of biological and clinical relevance for patients undergoing major surgery. With a greater number of randomised studies being conducted evaluating the impact of vitamin D supplementation on surgical patients, it is an opportune time to conduct further analysis of the impact of vitamin D on surgical outcomes. METHODS MEDLINE, EMBASE and the Cochrane Trials Register were interrogated up to December 2023 to identify randomised controlled trials of vitamin D supplementation in surgery. The risk of bias in the included studies was assessed using the Cochrane Risk of Bias tool. A narrative synthesis was conducted for all studies. The primary outcome assessed was overall postoperative survival. RESULTS We screened 4883 unique studies, assessed 236 full-text articles and included 14 articles in the qualitative synthesis, comprising 1982 patients. The included studies were highly heterogeneous with respect to patient conditions, ranging from open heart surgery to cancer operations to orthopaedic conditions, and also with respect to the timing and equivalent daily dose of vitamin D supplementation (range: 0.5-7500 mcg; 20-300 000 IU). No studies reported significant differences in overall survival or postoperative mortality with vitamin D supplementation. There was also no clear evidence of benefit with respect to overall or intensive care unit length of stay. DISCUSSION Numerous studies have reported the benefits of vitamin D supplementation in different surgical settings without any consistency. However, this systematic review found no clear evidence of benefit, which warrants the supposition that a single biological effect of vitamin D supplementation does not exist. The observed improvement in outcomes in low vitamin D groups has not been convincingly proven beyond chance findings. TRIAL REGISTRATION NUMBER CRD42021232067.
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2.
Prevalence of vitamin D deficiency and modifiable risk factors in patients with Crohn's disease: A prospective observational study.
Fletcher, J, Brown, M, Hewison, M, Swift, A, Cooper, SC
Journal of advanced nursing. 2023;(1):205-214
Abstract
AIMS: To determine the prevalence of vitamin D deficiency in adults with Crohn's Disease (CD) in Birmingham, UK (latitude 52.4°N, -1.9°E) and identify modifiable risk factors. DESIGN/METHOD A nurse-led, single-centre, prospective study was conducted over 5 months in 2019 and 2020 in outpatients with CD, at a tertiary referral hospital in Birmingham UK. Vitamin D (25OHD) levels were measured at a single timepoint by a dried blood spot sample. Modifiable risk factor data were collected including intake of vitamin D-containing foods, use of vitamin D supplements, sun exposure and current smoking. RESULTS Total 150 participants (53.3% male, 79.3% white British). Vitamin D deficiency (25OHD <50 nmol/L) was found in 53.3%. 32.7% of participants took over-the-counter vitamin D supplements and 20.7% used prescribed supplements. We found that diets were generally poor in relation to vitamin D-rich foods. In terms of sun exposure, few (18%) had visited a sunny country recently, and few (6%) covered their whole body with clothing. Most used High Sun Protection Factor (80%) with a median grade of SPF 45. CONCLUSION Patients with CD are at high risk of vitamin D deficiency as defined by 25OHD < 50 nmol/L, with the prevalence of deficiency being highest during the winter months. Patients with CD in the UK are unlikely to maintain vitamin D levels from sunlight exposure, dietary sources or over-the-counter supplements. IMPACT Patients with Crohn's Disease are at high risk of developing vitamin D deficiency but there is little data from the UK at this latitude. We demonstrate the prevalence and severity of vitamin D deficiency in people with Crohn's Disease in the UK. The prevalence of vitamin D deficiency in this group is high and warrants monitoring by nurses and clinical teams. Nurses and clinical teams should consider strategies for vitamin D supplementation in patients with Crohn's Disease.
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3.
The impact of vitamin D on cancer: A mini review.
Seraphin, G, Rieger, S, Hewison, M, Capobianco, E, Lisse, TS
The Journal of steroid biochemistry and molecular biology. 2023;:106308
Abstract
In this review, we summarize the most recent advances in vitamin D cancer research to provide molecular clarity, as well as its translational trajectory across the cancer landscape. Vitamin D is well known for its role in regulating mineral homeostasis; however, vitamin D deficiency has also been linked to the development and progression of a number of cancer types. Recent epigenomic, transcriptomic, and proteomic studies have revealed novel vitamin D-mediated biological mechanisms that regulate cancer cell self-renewal, differentiation, proliferation, transformation, and death. Tumor microenvironmental studies have also revealed dynamic relationships between the immune system and vitamin D's anti-neoplastic properties. These findings help to explain the large number of population-based studies that show clinicopathological correlations between circulating vitamin D levels and risk of cancer development and death. The majority of evidence suggests that low circulating vitamin D levels are associated with an increased risk of cancers, whereas supplementation alone or in combination with other chemo/immunotherapeutic drugs may improve clinical outcomes even further. These promising results still necessitate further research and development into novel approaches that target vitamin D signaling and metabolic systems to improve cancer outcomes.
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Does maternal vitamin D status influence placental weight or vascular and inflammatory pathology? Secondary analysis from the Kellogg Pregnancy Study.
Mead, MJ, McWhorter, CA, Rodgers, MD, Ebeling, MD, Shary, JR, Gregoski, MJ, Hollis, BW, Hewison, M, Johnson, D, Caplan, MJ, et al
The Journal of steroid biochemistry and molecular biology. 2023;:106358
Abstract
INTRODUCTION Positive effects of vitamin D (vitD) supplementation on comorbidities of pregnancy (COP) have been explored; however, few studies have elucidated the pathophysiology behind the development of these COP and the potential relationship with derangements in placental development and morphology. Additionally, it is known that placentas weighing 10th-90th % for gestational age are associated with better outcomes. Therefore, the objective of this study was to assess the impact of resulting circulating serum 25(OH)D concentrations associated with intake of high or low doses of supplementary vitD on placental development and morphology in women who participated in a randomized double blind, placebo-controlled trial of vitD supplementation. We hypothesized that if maternal serum 25(OH)D concentration (vitD status marker) is insufficient/deficient, then placental weight and % for gestational age (GA) will be smaller and will correlate with increased vascular and inflammatory placental pathologic findings. METHODS The findings of the present study are a secondary analysis of data generated from a previously reported randomized controlled trial (RCT), the Kellogg Vitamin D Pregnancy Study. Pregnant women (n = 297) in this RCT (January 2013 - April 2018) were randomly assigned to 400 IU vs. 4400 IU vitD/day (10-14 weeks' gestational age) and followed to delivery. 132 placentas were analyzed by pathologists blinded to treatment, and the 2016 Amsterdam Consensus Criteria were used to categorize grouping/grading of placental pathology and weight. Total [25(OH)D] was measured using radioimmunoassay (ng/mL). Chi-square and Student's t-test were used to show the difference in maternal characteristics by treatment group and by placental weight. Chi-square analysis was used to determine differences between the percent pathology findings by treatment group. Students t-test was used to determine the differences in vitD status and the frequency of placental lesions. Association between [25(OH)D] area under the curve (AUC) and placental morphology were determined in a regression model that included maternal BMI ≥ 30 kg/m2, race/ethnicity, and vitD treatment group allocation. Data were analyzed using SAS v9.4 (Cary, NC) and statistical significance was indicated by p < 0.05. RESULTS The percent pathology findings by treatment group were not significantly different for each of the placental pathology categories as defined by the 2016 Amsterdam Consensus Criteria including placental weight. However, when using 25(OH)D as a biomarker for vitD status, linear regression model showed maternal serum [25(OH)D] AUC was significantly associated with greater placental weight (p = 0.023). Logistic regression models showed mothers with BMI ≥ 30 kg/m2 had larger placental weight (p = 0.046), and Hispanic and white/Caucasian mothers had greater placental weights than Black American mothers (p = 0.025). When placentas ≥ 90th % for GA, n = 7, were removed from the placental pool, Pearson correlation still showed a positive association between maternal serum 25(OH)D AUC and placental weight (p = 0.011). In a second linear regression model of placentas ≥ 90th % for GA (n = 7) vs. placentas < 90th % (n = 108), maternal serum 25(OH)D AUC was significantly greater in those placentas ≥ 90th % (p = 0.03); however, this was not associated with increased perinatal mortality. CONCLUSION FINDINGS suggest increasing maternal serum [25(OH)D] via vitamin D supplementation during pregnancy did not adversely affect placental morphology; trends showed those in the treatment group had fewer placental lesions. Placental weight was found to be significantly associated with [25(OH)D] AUC, which represents maternal vitamin D status over the course of pregnancy; 7 placentas ≥ 90th % for GA were not associated with perinatal mortality.
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5.
The impact of genetic variation within the vitamin D pathway upon skeletal muscle function: A systematic review.
Bollen, SE, Bass, JJ, Wilkinson, DJ, Hewison, M, Atherton, PJ
The Journal of steroid biochemistry and molecular biology. 2023;:106266
Abstract
Studies in vitro have demonstrated a key molecular role for 1,25-dihydroxyvitamin D (1,25D) in skeletal muscle function, with vitamin D-deficiency (low serum 25-hydroxyvitamin D, 25D) being associated with muscle pain and weakness. Despite this, an understanding of the overall role of vitamin D in muscle health (particularly the impact of vitamin D-related genetic variants) has yet to be fully resolved, relative to more well-studied targets such as the skeleton. Thus, we aimed to review existing studies that have investigated relationships between skeletal muscle function and single nucleotide polymorphisms (SNPs) within vitamin D-related genes. A systematic review of papers published between January 2000 and June 2022 on PubMed, EMBASE and Web of Science pertaining to association between functionally relevant vitamin D receptor genetic variants and variants within genes of the vitamin D pathway and skeletal muscle function/outcomes was performed. 21 articles were included in the review for final analysis, of which 20 only studied genetic variation of the VDR gene. Of the included articles, 81 % solely included participants aged ≥ 50 years and of the 9 studies that did not only include White individuals, only 2 included Black participants. Within the vitamin D system, the VDR gene is the primary gene of which associations between polymorphisms and muscle function have been investigated. VDR polymorphisms have been significantly associated with muscle phenotypes in two or more studies. Of note A1012G was significantly associated with higher handgrip strength, but the results for other SNPs were notably variable between studies. While the lack of definitive evidence and study heterogeneity makes it difficult to draw conclusions, the findings of this review highlight a need for improvements with regards to the use of more diverse study populations, i.e., inclusion of Black individuals and other people of colour, and expanding research scope beyond the VDR gene.
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6.
Predicting comorbidities of pregnancy: A comparison between total and free 25(OH)D and their associations with parathyroid hormone.
McWhorter, CA, Mead, MJ, Rodgers, MD, Ebeling, MD, Shary, JR, Gregoski, MJ, Newton, DA, Baatz, JE, Hollis, BW, Hewison, M, et al
The Journal of steroid biochemistry and molecular biology. 2023;:106420
Abstract
Pregnancy is a unique time when amplified sex steroid concentrations promote an escalation in vitamin D binding protein (DBP) synthesis, associated with increased total vitamin D and metabolites, including 25-hydroxyvitamin D (25(OH)D). Free 25(OH)D concentration increases disproportionately to total 25(OH)D during pregnancy, likely an adaptation to supply the woman and fetus with readily available 25(OH)D. Highlighting the importance of the calcium metabolic stress during pregnancy, the interactional relationship between serum 25(OH)D and PTH has been evaluated. Maternal total 25(OH)D and total 25(OH)D/iPTH are measures of vitamin D status and biomarkers for potential pregnancy complications. It has been proposed that free 25(OH)D and free 25(OH)D/iPTH could be better indicators of vitamin D status and predictors of pregnancy complications such as gestational diabetes (GDM), hypertensive disorders of pregnancy, and preterm delivery. This study aims to determine if free 25(OH)D and its association with PTH are more accurate predictors of comorbidities of pregnancy than total 25(OH)D and its association with PTH. In this post hoc analysis of the Kellogg Pregnancy Study, a double-blind randomized placebo-controlled trial, participants included 297 women with singleton pregnancies: 191 participants were randomized into a group receiving a daily prenatal (400 IU vitamin D3) while 196 received a prenatal plus extra supplementation (4400 IU vitamin D3). Blood and urine samples were collected monthly. 297 participants' serum total 25(OH)D concentrations were measured using radioimmunoassay at baseline (visit 1) and 5-7 months' gestation (visit 6-7). 93 participants' serum free 25(OH)D and PTH concentrations were measured using ELISA and immunoradiometric assay, respectively, at visit 1 and 6-7; 66 participants had paired samples and were included in this analysis. Data were analyzed using SAS 9.4, Cary, N.C. or SPSS v28, IBM Corporation, Armonk, N.Y. Results were considered significant with a p < 0.05. A significant relationship exists between the ratio of total 25(OH)D/iPTH and free 25(OH)D/iPTH grouped by total 25(OH)D ≥ 30 ng/mL and < 30 ng/mL as an indicator of maternal vitamin D status. There was a statistically significant relationship between lower mean free 25(OH)D/iPTH and the development of GDM at visit 1 (p = 0.0003) and at visit 6-7 (p = 0.001) while total 25(OH)D/iPTH and GDM were significantly related only at visit 1 (p = 0.029). In this exploratory cohort, neither free 25(OH)D/iPTH nor total 25(OH)D/iPTH were significantly associated with increased incidence of preterm delivery, hypertensive disorders, or combined comorbidities of pregnancy. An univariate logistic regression evaluating the outcome of gestational diabetes while independently controlling for independent factors showed the ratio of free 25(OH)D/iPTH was more closely associated with gestational diabetes than the ratio of total 25(OH)D/iPTH, although neither were significant. This proof-of-concept analysis suggests that the ratio of free 25(OH)D/iPTH is associated with the development of gestational diabetes throughout pregnancy while total 25(OH)D/iPTH is only associated with the outcome early in pregnancy. Further investigation is warranted to explore this relationship between calcium metabolic stress during pregnancy with a larger cohort to improve validity,reproducibility, and relevance to other pregnancy comorbidities.
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Vitamin D and miscarriage: a systematic review and meta-analysis.
Tamblyn, JA, Pilarski, NSP, Markland, AD, Marson, EJ, Devall, A, Hewison, M, Morris, RK, Coomarasamy, A
Fertility and sterility. 2022;118(1):111-122
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Plain language summary
Miscarriage causes significant physical and psychological harm. Vitamin D deficiency (low serum levels of 25- hydroxyvitamin D) is a major global health concern, with pregnant women and those planning pregnancy at increased risk. The aim of this study was to evaluate the association between vitamin D status and pregnancy loss, including spontaneous miscarriage and recurrent miscarriage. This study is a systematic review and meta-analysis of ten studies (6 where observational studies and 4 interventional studies). Results show that women who were vitamin D deficient were at significantly increased risk of miscarriage compared with those who were vitamin D replete. This association was maintained when women with insufficient levels were included, with a biologic gradient evident. Authors conclude that new evidence-based interventions are required for women at risk of miscarriage.
Abstract
OBJECTIVE To investigate whether a significant association between vitamin D status and the risk of miscarriage or recurrent miscarriage (RM) exists. DESIGN Systematic review and meta-analysis. SETTING Not applicable. PATIENT(S): Women with miscarriage and RM. INTERVENTION(S): We searched the Ovid MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials from database inception to May 2021. Randomized and observational studies investigating the association between maternal vitamin D status and miscarriage and/or vitamin D treatment and miscarriage were included. MAIN OUTCOME MEASURE(S): The primary outcome was miscarriage or RM, with vitamin D status used as the predictor of risk. Whether vitamin D treatment reduces the risk of miscarriage and RM was also assessed. RESULT(S): Of 902 studies identified, 10 (n = 7,663 women) were included: 4 randomized controlled trials (n = 666 women) and 6 observational studies (n = 6,997 women). Women diagnosed with vitamin D deficiency (<50 nmol/L) had an increased risk of miscarriage compared with women who were vitamin D replete (>75 nmol/L) (odds ratio, 1.94; 95% confidence interval, 1.25-3.02; 4 studies; n = 3,674; I2 = 18%). Combined analysis, including women who were vitamin D insufficient (50-75 nmol/L) and deficient (<50 nmol/L) compared with women who were replete (>75 nmol/L), found an association with miscarriage (odds ratio, 1.60; 95% confidence interval, 1.11-2.30; 6 studies; n = 6,338; I2 = 35%). Although 4 randomized controlled trials assessed the effect of vitamin D treatment on miscarriage, study heterogeneity, data quality, and reporting bias precluded direct comparison and meta-analysis. The overall study quality was "low" or "very low" using the Grading of Recommendations, Assessment, Development and Evaluations approach. CONCLUSION(S): Vitamin D deficiency and insufficiency are associated with miscarriage. Whether preconception treatment of vitamin D deficiency protects against pregnancy loss in women at risk of miscarriage remains unknown. REGISTRATION NUMBER CRD42021259899.
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UK Nutrition Research Partnership 'Hot Topic' workshop: Vitamin D-A multi-disciplinary approach to (1) elucidate its role in human health and (2) develop strategies to improve vitamin D status in the UK population.
Lanham-New, SA, Buttriss, JL, Gibson-Moore, H, Staines, KA, Webb, AR, Cashman, KD, Hewison, M, Martineau, AR, Smith, CP, Butler-Laporte, G, et al
Nutrition bulletin. 2022;(2):246-260
Abstract
Vitamin D is truly unique-not a 'vital' amine in the true sense of the word, but rather a prohormone, which is produced in the skin during exposure to sunlight (UVB radiation at 290-315 nm) and which can also be obtained from food and from supplements. A high prevalence of low vitamin D status has been reported across the world in a wide range of population groups, and this includes communities living in low latitude areas despite the abundance of sunlight. It is accepted that vitamin D status is reflected by the level of the circulating metabolite 25-hydroxyvitamin D (25[OH]D), which is produced by hepatic hydroxylation of vitamin D, derived either from the skin from UV exposure or the gut from oral intake. Vitamin D has been associated with a wide range of health outcomes, but controversies remain as to their exact nature and extent and whether associations are in the causal pathway. In order to enable wider discussions on this nutrient, a 'Hot Topic' Vitamin D Workshop achieved funding from the UK Nutrition Research Partnership Medical Research Council call. The objectives of the workshop were (1) to elucidate the role of vitamin D in human health and (2) develop strategies to improve vitamin D status in the UK population. This paper provides a detailed resume of the discussions of the workshop; of the presentations and concomitant Q&As; and of identified areas for future research.
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9.
The Vitamin D/Vitamin D receptor (VDR) axis in muscle atrophy and sarcopenia.
Bollen, SE, Bass, JJ, Fujita, S, Wilkinson, D, Hewison, M, Atherton, PJ
Cellular signalling. 2022;:110355
Abstract
Muscle atrophy and sarcopenia (the term given to the age-related decline in muscle mass and function), influence an individuals risk of falls, frailty, functional decline, and, ultimately, impaired quality of life. Vitamin D deficiency (low serum levels of 25-hydroxyvitamin D (25(OH)D3)) has been reported to impair muscle strength and increase risk of sarcopenia. The mechanisms that underpin the link between low 25(OH)D3 and sarcopenia are yet to be fully understood but several lines of evidence have highlighted the importance of both genomic and non-genomic effects of active vitamin D (1,25-dihydroxyvitamin D (1,25(OH)2D3)) and its nuclear vitamin D receptor (VDR), in skeletal muscle functioning. Studies in vitro have demonstrated a key role for the vitamin D/VDR axis in regulating biological processes central to sarcopenic muscle atrophy, such as proteolysis, mitochondrial function, cellular senescence, and adiposity. The aim of this review is to provide a mechanistic overview of the proposed mechanisms for the vitamin D/VDR axis in sarcopenic muscle atrophy.
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10.
Autoimmune disease and interconnections with vitamin D.
Fletcher, J, Bishop, EL, Harrison, SR, Swift, A, Cooper, SC, Dimeloe, SK, Raza, K, Hewison, M
Endocrine connections. 2022;(3)
Abstract
Vitamin D has well-documented effects on calcium homeostasis and bone metabolism but recent studies suggest a much broader role for this secosteroid in human health. Key components of the vitamin D system, notably the vitamin D receptor (VDR) and the vitamin D-activating enzyme (1α-hydroxylase), are present in a wide array of tissues, notably macrophages, dendritic cells and T lymphocytes (T cells) from the immune system. Thus, serum 25-hydroxyvitamin D (25D) can be converted to hormonal 1,25-dihydroxyvitamin D (1,25D) within immune cells, and then interact with VDR and promote transcriptional and epigenomic responses in the same or neighbouring cells. These intracrine and paracrine effects of 1,25D have been shown to drive antibacterial or antiviral innate responses, as well as to attenuate inflammatory T cell adaptive immunity. Beyond these mechanistic observations, association studies have reported the correlation between low serum 25D levels and the risk and severity of human immune disorders including autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. The proposed explanation for this is that decreased availability of 25D compromises immune cell synthesis of 1,25D leading to impaired innate immunity and over-exuberant inflammatory adaptive immunity. The aim of the current review is to explore the mechanistic basis for immunomodulatory effects of 25D and 1,25D in greater detail with specific emphasis on how vitamin D-deficiency (low serum levels of 25D) may lead to dysregulation of macrophage, dendritic cell and T cell function and increase the risk of inflammatory autoimmune disease.