Reviews in Endocrine and Metabolic Disorders
Many are behind a $40 paywall, but their references are free online
Table of contents
- New light on an old vitamin: The role of the sunshine vitamin D in chronic disease – editorial free
- Low serum vitamin D-status, air pollution and obesity: A dangerous liaison – free
- Sunshine vitamin and thyroid – free
- Vitamin-D concentrations, cardiovascular risk and events - a review of epidemiological evidence
- Current evidence on vitamin D deficiency and kidney transplant: What’s new?
- Low vitamin D status and obesity: Role of nutritionist
- Vitamin D and autism, what’s new? - free
- Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications - free
- The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: A review of the epidemiology, clinical trials, and mechanisms
- The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention
- Vitamin D and its role in psoriasis: An overview of the dermatologist and nutritionist – free
- Shedding new light on female fertility: The role of vitamin D
- Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept
- Vitamin D and diabetes mellitus: Causal or casual association?
- Vitamin D: Musculoskeletal health
- Adrenal disorders: Is there Any role for vitamin D?
Christian A. Koch
As a child, I always enjoyed consuming milk products and more so as I grew and became active in athletics. One of my dynamic trainers, Dieter Roth, was responsible for leading me and my fellow athletes into Bavarian championships. I was fortunate to never have suffered a fracture from excessive running or weight training. Perhaps my daily vitamin D consumption helped in addition to genetics. I became interested in the science of vitamin D after encountering some patients with hypercalcemia . During my tenure at the University of Mississippi, one of my mentees, Dr. M. Ullah, had expressed desire to explore the field of hypertension and I recommended that he review literature on the topic vitamin D and blood pressure regulation, resulting in several publications [2, 3, 4, 5].
My interest grew after I met a pregnant black African American woman that presented with nausea/vomiting, hypertension, a serum calcium of 14 mg/dl (elevated), parathyroid hormone (PTH) level of 102 pg/ml (elevated), and 25-hydroxy(OH) vitamin D level of 12 ng/ml. After hydration and a declining serum calcium to 10 mg/dl, she was prescribed oral vitamin D2 50,000 IU weekly and advised to follow-up. She had a history of noncompliance and (interestingly) took the prescribed vitamin D daily instead of weekly after discharge. She did not follow up in the antenatal or endocrine clinic as scheduled until 3 months later when she presented to the emergency room with headaches and elevated blood pressures (150–170 mm Hg systolic and 70–80 mm Hg diastolic). At this time, her serum calcium level was mildly elevated at 10.9 mg/dl, PTH was 49 pg/ml (inappropriately normal for the level of serum calcium) but the 25-OH vitamin D level was now very high (348.9 ng/ml). At 39 weeks of pregnancy, she had an elective Cesarean delivery of a healthy baby without further complications. The infant was monitored closely for 72 h for any signs of tetany, because of the mother’s primary hyperparathyroidism which created a high risk for hypocalcemia. The serum calcium of the baby was normal (10.1 mg/dl) at birth and the baby remained completely asymptomatic at the time of discharge from the hospital, suggesting that at least one parathyroid gland of the baby was not suppressed in functionality, secreting PTH .
To my knowledge, the highest reported 25-OH vitamin D level of “vitamin D intoxication” due to food products or dietary supplements is 1482 ng/ml (3700 nmol/L). This has been treated with intravenous fluid hydration, administration of glucocorticoids, sodium phosphate, and bis phosphonates, without complications on 2 year follow-up (reviewed in Araki et al., ref. ). The second highest reported 25-OH vitamin D level is 1220 ng/ml (3045 nmol/L) and occurred in a 58-year old man with a concomitant serum calcium of 15 mg/dl (3.75 nmol/L). Symptoms included fatigue, excessive thirst, polyuria, and poor cognition. Utilizing liquid chromatography, tandem mass spectroscopy detected exclusively 25OHD3 and no 25OHD2. The man took multiple supplements with one labeled to contain 1600 IU (40 mcg) of vitamin D, 99% D3, however, analysis showing that each such capsule contained 186,400 IU (4660 mcg) of vitamin D3 . As it turns out, the patient had taken 1,864,000 IU (46,600 mcg) of vitamin D3 daily for 2 months and was treated with normal saline, furosemide, calcitonin, and pamidronate over several weeks, considering that the half-life of 25OH vitamin D is 2–3 weeks. He remained normocalcemic and asymptomatic after the 25OH vitamin D level dropped below 400 ng/ml (1000 nmol/L).
Some aspects of vitamin D intoxication and approaches for prevention, diagnosis, and treatment of the vitamin D deficiency pandemic are reviewed by the “D-lightful” vitamin D expert, Professor Michael Holick, in the leading article of this guest issue edited by Professor Giovanna Muscogiuri . I am delighted that Prof. Muscogiuri has recruited top experts to review various topics related to vitamin D. This guest issue will publish in two issues, Part 1, June, and Part 2, September 2017.
Professor Holick’s article is followed by an interesting review on vitamin D reducing the incidence of and increasing survival from breast, colorectal, lung, ovarian, pancreatic, and prostate cancer . Since some hormones are also considered neurosteroids [10, 11] and that children with low(er) 25-OH vitamin D levels at 3 months of gestation, at birth, and at age 8 are prone to develop an autism spectrum disorder, Dr. Cannell provides an overview on autism and vitamin D . We recently published a guest issue on metabolism and skin diseases including an article on adipokines in psoriasis [13, 14]. The possible bidirectional links between psoriatic disease and vitamin D is analyzed in this journal issue . The same authors also provide an overview on the impact of environmental pollutants, obesity, and vitamin D status . Obviously, energy balance plays an important role in the current obesity epidemic . Most of this epidemic is driven by an imbalance between energy intake and consumption, likely facilitated by hedonic behavior, change in taste perception, and other factors, with nutrition playing a central role [18, 19]. The important role of nutritionists in the current obesity and vitamin D epidemic is reviewed by Savastano and colleagues in Part 1 of this guest issue . Vitamin D and its implications in diabetes mellitus is analyzed by Grammatiki and colleagues . Interestingly, low vitamin D levels have been found to be associated with a pro-inflammatory state, insulin resistance, glucose intolerance and obesity, which is reviewed by Garbossa and Folli . Adipokines are atherothrombotic risk factors in obese subjects . The last article is written by Gruebler and colleagues who conclude that vitamin D is a strong risk marker for cardiovascular risk factors and disease, similar to what has been reported in men with low testosterone levels [24, 25, 26, 27].
Part 2 of this issue (September), will feature topics in female fertility, polycystic ovarian syndrome and endometriosis,and the relationship to vitamin D [28, 29], followed by immunology related aspects including kidney transplantation, autoimmune endocrine disorders including thyroid and adrenal disease [30, 31, 32, 33]. After an expedition covering extraskeletal aspects of vitamin D, the concluding review focuses on musculoskeletal health .
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In VitaminDWiki Air Pollution reduces Vitamin D
See VitaminDWiki Sunshine vitamin and thyroid – Jan 2017
Martin Robert GrüblerEmail authorWinfried MärzStefan PilzTanja B. GrammerChristian TrummerChristian MüllnerVerena SchwetzMarlene PandisNicolas VerheyenAndreas TomaschitzAntonella FiordelisiDaniela LaudisioErsilia CipollettaGuido Iaccarino
Vitamin D has long been established as an elemental factor of bone physiology. Beyond mineral metabolism, the expression of the vitamin D receptor has been identified throughout the cardiovascular (CV) system. Experimental studies showed beneficial effects of vitamin D on heart and vessels, but vitamin D intoxication in animals also led to hypercalcemia and vascular calcification. Our knowledge has been extended by epidemiological studies that showed that 25-hydroxyvitamin D (25(OH)D) levels are inversely associated with an increased CV risk itself, but also with established CV risk factors, such as arterial hypertension, endothelial dysfunction and atherosclerosis. Conversely, randomized controlled trials could not document significant and consistent effects of vitamin D supplementation on CV risk or events. Potential explanations may lie in differences in reference ranges or the possibility that low vitamin D in CV disease is only an epiphenomenon. In the latter case, the key question is why low 25(OH)D levels are such a strong predictor of health. While we wait for new data, the current conclusion is that vitamin D is a strong risk marker for CV risk factors and for CV diseases itself.
Gerardo Sarno Riccardo Nappi Barbara AltieriGiacomo TirabassiEmanuele MuscogiuriGianmaria SalvioStavroula A. PaschouAristide FerraraEnrico RussoDaniela VicedominiCerbone VincenzoAndromachi VryonidouSilvia Della CasaGiancarlo BalerciaFrancesco OrioParide De Rosa
Kidney transplant is the treatment of choice for end-stage chronic kidney disease. Kidneys generate 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (calcidiol) for circulation in the blood to regulate calcium levels. Transplant patients with low calcidiol levels have an increased risk of metabolic and endocrine problems, cardiovascular disease, type 2 diabetes mellitus, poor graft survival, bone disorders, cancer, and mortality rate. The recommended calcidiol level after transplant is at least 30 ng/mL (75 nmol/L), which could require 1000–3000 IU/d vitamin D3 to achieve. Vitamin D3 supplementation studies have found improved endothelial function and acute rejection episodes. However, since kidney function may still be impaired, raising calcidiol levels may not lead to normal calcitriol levels. Thus, supplementation with calcitriol or an analog, alfacalcidiol, is often employed. Some beneficial effects found include possible improved bone health and reduced risk of chronic allograft nephropathy and cancer.
Silvia SavastanoLuigi BarreaMaria Cristina SavanelliFrancesca NappiCarolina Di SommaFrancesco OrioAnnamaria ColaoEmail author
Low vitamin D status and obesity have concomitantly reached epidemic levels worldwide. Up to now the direction of the association between low vitamin D status and obesity, the exact mechanisms responsible for this association and the clinical usefulness to increase vitamin D status for reducing adiposity still warrant further evaluation. The aim of the present review was to examine the current evidence linking low vitamin D status and obesity in relation to the role of the nutritionist. On the one side, considering obesity as a causal factor, low sun exposure in obese individuals due to their sedentary lifestyle and less outdoor activity, vitamin D sequestration in adipose tissue, and volumetric dilution of ingested or cutaneously synthesized vitamin D3 in the large fat mass of obese patients, might represent some of the factors playing a major role in the pathogenesis of the low vitamin D status. On the other side, the expression of both vitamin D3 receptors and enzymes responsible for vitamin D3 metabolism in adipocytes depicted a role for the low vitamin D status per se in the development of obesity by modulating adipocyte differentiation and lipid metabolism. Nutritionists need to accurately address the aspects influencing the low vitamin D status in obesity and the vitamin D supplementation in obese individuals.
John Jacob Cannell
An increasing amount of evidence points to the possibility that gestational and early childhood vitamin D deficiency [25(OH)D < 40 ng/ml] cause some cases of autism. Vitamin D is metabolized into a seco-steroid hormone that regulates about 3% of the 26,000 genes in the coding human genome. It is also a neurosteroid that is active in brain development, having effects on cellular proliferation, differentiation, calcium signaling, neurotrophic and neuroprotective actions; it also appears to have an effect on neurotransmission and synaptic plasticity. Children who are, or who are destined to become, autistic have lower 25(OH)D levels at 3 months of gestation, at birth and at age 8 compared to their unaffected siblings. Two open label trials found high dose vitamin D improves the core symptoms of autism in about 75% of autistic children. A few of the improvements were remarkable. The vitamin D doses used in these children were 300 IU/KG/day up to a maximum of 5000 IU/day (highest final 25(OH)D level reached was 45 ng/ml). The other study used 150,000 IU/month IM as well as 400 IU/day [highest final 25(OH)D level was 52 ng/ml]. These two open label trials were recently confirmed with a randomized controlled trial (RCT) using 300 IU/kg/day with a maximum of 5000 IU/day and resulted in effects similar to the two open label studies. In terms of prevention, a recent small study showed vitamin D supplementation during pregnancy (5000 IU/day) and during infancy and early childhood (1000 IU/day) significantly reduced the expected incidence of autism in mothers who already had one autistic child from 20% to 5%. Vitamin D is safe; for example, over the last 15 years, Poison Control reports there have been approximately 15,000 cases of vitamin D overdose. However only three of these 15,000 people developed clinical toxicity and no one died. Given those facts, practitioners might consider treating autism with 300 IU/kg/day, and seek to prevent autism by supplementing pregnant and lactating women (5000 IU/day) and infants and young children (150 IU/kg/day) checking 25(OH)D levels every 3 months. These doses will increase 25(OH)D blood levels to those recommended by the Endocrine Society. As the American Academy of Pediatrics recommends vitamin D supplementation during infancy and childhood, pediatricians and family practitioners should evaluate the current evidence on autism and vitamin D and act accordingly.
Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications - free
Carol L. WagnerBruce W. HollisKalliopi KotsaHana FakhourySpyridon N. Karras
Pregnancy represents a time of rapid bodily change, which includes physical proportions, physiology and responsibility. At this context, maternal vitamin D stores have been the objective of extensive scientific research during the last decades, focusing on their potential effects on maternal an neonatal health. A growing body of observational studies indicated that maternal hypovitaminosis D (as defined by maternal 25-hydroxyvitamin D [25(OH)D] levels <20 ng/ml or <50 nmol/l) is a significant risk factor for adverse neonatal outcomes including asthma, multiple sclerosis and other neurological disorders. On that basis, this review aims to provide to the reader new insights into the vitamin D requirements and function during pregnancy supported by recent data and will not discuss the classical roles of vitamin D and skeletal function during pregnancy. In addition, we will focus on recent results that demonstrate that maternal vitamin D supplementation could reduce neonatal respiratory and neurological complications, suggesting that available guidelines should be updated, since it remains unclear why these recommendations are not updated according to recent results. Also, with regard to randomized controlled trials (RCT’s) for vitamin D, we consider that they are largely doomed to fail. The reasons for this are many and specific cases of this failure will be presented in this text.
The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: A review of the epidemiology, clinical trials, and mechanisms
Meis Moukayed William B. Grant
Global cancer incidence and mortality rates are high and increasing. Thus, it is imperative to find novel solutions to preventing cancer incidence and treating it at an affordable yet efficacious manner. The solar UVB-vitamin D-cancer hypothesis was first proposed in 1980 based on a geographical ecological study. Since then, numerous ecological and observational studies as well as studies of mechanisms have provided support for the hypothesis. However, observational studies have not provided consistent support, in part due to using a single blood draw from any season to use for serum 25-hydroxyvitamin D [25(OH)D] concentration in prospective studies with long follow-up times. Case-controls studies, in which blood is drawn near time of diagnosis, and prospective studies in which blood is drawn in the sunnier half of the year, are more likely to find significant inverse relations between 25(OH)D and cancer incidence. Three vitamin D plus calcium clinical trials have found significant reduction in all-cancer incidence. This paper reviews the evidence for vitamin D in reducing incidence of and increasing survival from breast, colorectal, lung, ovarian, pancreatic, and prostate cancer. The epidemiological evidence provides strong support for all of these types of cancer except for non-aggressive prostate cancer. Studies of the cellular mechanisms of vitamin D action in different cancer cell types, strongly indicate that vitamin D can exert protective and anti-tumorigenic activities that would retard cellular transformation, hyperplasia and cancer progression. Based on the scientific evidence reviewed in this paper, individuals and health providers can consider increasing 25(OH)D concentrations through sensible sun exposure and/or vitamin D supplementation to reduce risk of and, in conjunction with standard care, treat cancer. Public health acceptance of vitamin D for cancer prevention and treatment requires stronger support from vitamin D clinical trials.
Michael F. Holick
Vitamin D deficiency and insufficiency is a global health issue that afflicts more than one billion children and adults worldwide. The consequences of vitamin D deficiency cannot be under estimated. There has been an association of vitamin D deficiency with a myriad of acute and chronic illnesses including preeclampsia, childhood dental caries, periodontitis, autoimmune disorders, infectious diseases, cardiovascular disease, deadly cancers, type 2 diabetes and neurological disorders. This review is to put into perspective the controversy surrounding the definition for vitamin D deficiency and insufficiency as well as providing guidance for how to treat and prevent vitamin D deficiency.
Luigi BarreaMaria Cristina SavanelliCarolina Di SommaMaddalena NapolitanoMatteo MegnaAnnamaria ColaoSilvia Savastano
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Psoriasis is a chronic immune-mediated inflammatory skin disease. Psoriasis lesions are characterized by hyper-proliferation of epidermal keratinocytes associated with inflammatory cellular infiltrate in both dermis and epidermis. The epidermis is the natural source of vitamin D synthesis by sunlight action. Recently, a role for vitamin D in the pathogenesis of different skin diseases, including psoriasis, has been reported. Indeed, significant associations between low vitamin D status and psoriasis have been systematically observed. Due to its role in proliferation and maturation of keratinocytes, vitamin D has become an important local therapeutic option in the treatment of psoriasis. To date, the successful treatment based on adequate dietary intake of vitamin D or oral vitamin D supplementation in psoriasis represent an unmet clinical need and the evidence of its beneficial effects remains still controversial. This information is important either for Dermatologists and Nutritionists to increases the knowledge on the possible bi-directional relationships between low vitamin D status and psoriasis and on the potential usefulness of vitamin D in psoriasis with the aim not only to reduce its clinical severity, but also for delineating the risk profile for co-morbidities cardiac risk factors that may result from psoriasis. In the current review, we analyzed the possible bi-directional links between psoriatic disease and vitamin D.
Giovanna Muscogiuri Barbara AltieriCristina de AngelisStefano PalombaRosario PivonelloAnnamaria ColaoFrancesco Orio
In the last decades several studies suggested that vitamin D is involved in the modulation of the reproductive process in women due to the expression of VDR and 1α-hydroxylase in reproductive tissues such as ovary, uterus, placenta, pituitary and hypothalamus. Vitamin D has also a role in the regulation of sex hormone steroidogenesis. Increasing evidence suggests that vitamin D might have a regulatory role in polycystic ovary syndrome (PCOS)-associated symptoms, including ovulatory dysfunction, insulin resistance and hyperandrogenism. Vitamin D deficiency also has been reported to contribute to the pathogenesis of endometriosis due to its immunomodulatory and anti-inflammatory properties. Although most of the studies supported a role of vitamin D in the onset of these diseases, randomized controlled trials to assess the efficacy of vitamin D supplementation have never been performed. In this review we critically discuss the role of vitamin D in female fertility, starting from in vitro and in vivo studies, focusing our attention on the two most frequent causes of female infertility: PCOS and endometriosis.
Barbara Altieri Giovanna MuscogiuriLuigi BarreaChantal MathieuCarla V. ValloneLuca MascitelliGiorgia BizzaroVincenzo M. AltieriGiacomo TirabassiGiancarlo BalerciaSilvia SavastanoNicola BizzaroCristina L. RonchiAnnamaria ColaoAlfredo PontecorviSilvia Della Casa
In the last few years, more attention has been given to the “non-calcemic” effect of vitamin D. Several observational studies and meta-analyses demonstrated an association between circulating levels of vitamin D and outcome of many common diseases, including endocrine diseases, chronic diseases, cancer progression, and autoimmune diseases. In particular, cells of the immune system (B cells, T cells, and antigen presenting cells), due to the expression of 1α-hydroxylase (CYP27B1), are able to synthesize the active metabolite of vitamin D, which shows immunomodulatory properties. Moreover, the expression of the vitamin D receptor (VDR) in these cells suggests a local action of vitamin D in the immune response. These findings are supported by the correlation between the polymorphisms of the VDR or the CYP27B1 gene and the pathogenesis of several autoimmune diseases. Currently, the optimal plasma 25-hydroxyvitamin D concentration that is necessary to prevent or treat autoimmune diseases is still under debate. However, experimental studies in humans have suggested beneficial effects of vitamin D supplementation in reducing the severity of disease activity. In this review, we summarize the evidence regarding the role of vitamin D in the pathogenesis of autoimmune endocrine diseases, including type 1 diabetes mellitus, Addison’s disease, Hashimoto’s
thyroiditis, Graves’ disease and autoimmune polyendocrine syndromes. Furthermore, we discuss the supplementation with vitamin D to prevent or treat autoimmune diseases.
M. GrammatikiE. RaptiS. KarrasR. A. AjjanKalliopi Kotsa
The incidence of both type 2 and type 1 diabetes mellitus has been increasing worldwide. Vitamin D deficiency, or the awareness of its prevalence, has also been increasing. Vitamin D may have a role in the pathogenic mechanisms predisposing to type 2 diabetes by modulating insulin resistance and/or pancreatic β-cell function. Vitamin D status or elements involved in its activation or transport may also be involved in the development of type 1 diabetes mellitus through immunomodulatory role . Based on these observations a potential association between vitamin D and diabetes has been hypothesized. In this review we discuss up to date evidence linking vitamin D with the development of diabetes. Moreover, the role of vitamin D supplementation in the prevention of both types of diabetes is analysed together with its role in improving glycemic control in diabetic patients. We also address the potential role of vitamin D deficiency in the development of macro- and microvascular complications in diabetes. Finally, we provide recommendation for Vitamin D therapy in diabetes in view of current evidence and highlight areas for potential future research in this area.
Harjit Pal Bhattoa Jerzy KonstantynowiczNatalia LaszczMarek Wojcik Pawel Pludowski
Perhaps the role of Vitamin D supplementation has been most exhaustively studied in calcium absorption, skeletal wellbeing, muscular potency, balance and risk of falling. Nonetheless, new data has emerged and the recent research on sarcopenia makes the topic increasingly interesting. Given the socioeconomic burden of the musculoskeletal consequences of hypovitaminosis D it is vital to keep abreast with the latest literature in the field. The recommended Vitamin D supplementation dose should suffice to increase the serum 25 hydroxyvitamin D level to 30 ng/mL (75 nmol/L) and this level should be optimally maintained with a maintenance dose, particularly for those diagnosed with osteoporosis.
Giacomo Tirabassi Gianmaria SalvioBarbara AltieriCristina L. RonchiSilvia Della CasaAlfredo PontecorviGiancarlo Balercia
An emerging branch of research is examining the linkage between Vitamin D and nonskeletal disorders, including endocrine diseases. In this regard, a still little studied aspect concerns the involvement of vitamin D in adrenal gland disorders. Adrenal gland disorders, which might be theoretically affected by vitamin D unbalance, include adrenal insufficiency, Cushing’s syndrome, adrenocortical tumors and hyperaldosteronism. In this review, we provide an updated document, which tries to collect and discuss the limited evidence to be found in the literature about the relationship between vitamin D and adrenal disorders. We conclude that there is insufficient evidence proving a causal relationship between vitamin D levels and adrenal disorders. Evidence coming from cross-sectional clinical studies can hardly clarify what comes first between vitamin D unbalance and adrenal disease. On the other hand, longitudinal studies monitoring the levels of vitamin D in patients with adrenal disorders or, conversely, the possible development of adrenal pathologies in subjects affected by impaired vitamin D levels would be able to elucidate this still unclear issue.