Marlene Chakhtoura

Serum 25-Hydroxyvitamin D Levels: Variability, Knowledge Gaps, and the Concept of a Desirable Range.

Hypovitaminosis D is prevalent worldwide but proportions vary widely between regions, depending on genetic and lifestyle factors, the threshold to define deficiency, and accuracy of 25‐hydroxyvitamin D (25OHD) assays used. Latitude, pollution, concealing clothing, sun exposure, gender, dietary habits, and lack of government regulation account for up to 50% in variations in serum 25OHD levels, whereas genetic polymorphisms in the vitamin D pathway account for less than 5%. Organizations/societies have developed guidelines for recommended desirable 25OHD levels and vitamin D doses to reach them, but their applicability across age groups and populations are still debated. This article and the accompanying online Supporting Information highlight sources of variations in circulating 25OHD levels, uncertainties and knowledge gaps, and analytical problems facing 25OHD assays, while keeping efficacy and safety data as the dominant factors when defining a desirable range for 25OHD levels. We propose a desirable range of 20 to 40 ng/mL (50 to 100 nmol/L), provided precise and accurate assays are used. Although slightly lower levels, 15 to 20 ng/mL, may be sufficient for some infants and adults, higher levels, 40 to 60 ng/mL, may still be safe. This desirable range allows physicians to tailor treatment while taking season, lifestyle, vitamin D intake, and other sources of variation into account. We reserve 25OHD measurements for at‐risk patients, defined by disease or lifestyle, and the use of 25OHD assays calibrated against the recommended international standards. Most target groups reach desirable target levels by a daily intake of 400 to 600 IU for children and 800 IU for adults. A total daily allowance of vitamin D of up to 1000 IU in the pediatric age groups, and up to 2000 IU in adults, tailored to an individual patient risk profile, is probably safe over long durations. Additional data are needed to validate the proposed range and vitamin D doses, especially in children, pregnant women, and non‐white populations.

The Role of Vitamin D Deficiency in the Incidence, Progression, and Complications of Type 1 Diabetes Mellitus

The “nonclassic” role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been recently widely recognized. In type 1 diabetes mellitus (T1D), it plays an immunomodulatory role through the vitamin D receptor (VDR) present on pancreatic and immune cells. Specific VDR allelic variants have been associated with T1D in many countries. Furthermore, vitamin D deficiency has been prevalent in T1D, and the seasonal and latitude variability in the incidence of T1D can be partly explained by the related variability in vitamin D level. In fact, retrospective studies of vitamin D supplementation during pregnancy or infancy showed a lower incidence of T1D. We will review the different mechanisms of the vitamin D protective effect against insulitis and present the available data on the role of vitamin D deficiency in the control, progression, and complications of T1D.

Hypovitaminosis D in bariatric surgery: A systematic review of observational studies.

BACKGROUND Obesity is a public health problem that carries global and substantial social and economic burden. Relative to non-surgical interventions, bariatric surgery has the most substantial and lasting impact on weight loss. However, it leads to a number of nutritional deficiencies requiring long term supplementation. OBJECTIVES The aims of this paper are to review 25-hydroxyvitamin D [25(OH)D] status pre and post bariatric surgery, describe the dose response of vitamin D supplementation, and assess the effect of the surgical procedure on 25(OH)D level following supplementation. METHODS We searched Medline, PubMed, the Cochrane Library and EMBASE, for relevant observational studies published in English, from 2000 to April 2015. The identified references were reviewed, in duplicate and independently, by two reviewers. RESULTS We identified 51 eligible observational studies assessing 25(OH)D status pre and/or post bariatric surgery. Mean pre-surgery 25(OH)D level was below 30ng/ml in 29 studies, and 17 of these studies showed mean 25(OH)D levels ≤20ng/ml. Mean 25(OH)D levels remained below 30ng/ml following bariatric surgery, despite various vitamin D replacement regimens, with only few exceptions. The increase in post-operative 25(OH)D levels tended to parallel increments in vitamin D supplementation dose but varied widely across studies. An increase in 25(OH)D level by 9-13ng/ml was achieved when vitamin D deficiency was corrected using vitamin D replacement doses of 1100-7100IU/day, in addition to the usual maintenance equivalent daily dose of 400-2000IU (total equivalent daily dose 1500-9100IU). There was no difference in mean 25(OH)D level following supplementation between malabsorptive/combination procedures and restrictive procedures. CONCLUSION Hypovitaminosisis D persists in obese patients undergoing bariatric surgery, despite various vitamin D supplementation regimens. Further research is needed to determine the optimal vitamin D dose to reach desirable 25(OH)D levels in this population, and to demonstrate whether this dose varies according to the surgical procedure.

Guidelines on vitamin D replacement in bariatric surgery: Identification and systematic appraisal

INTRODUCTION Bariatric surgery is the most effective therapeutic option to reduce weight in morbidly obese individuals, but it results in a number of mineral and vitamin deficiencies. Clinical Practice Guidelines (CPGs) attempt to balance those benefits and harms to provide guidance to physicians and patients. OBJECTIVES We compare and evaluate the quality of the evidence and of the development process of current CPGs that provide recommendations on vitamin D replacement in patients undergoing bariatric surgery, using a validated tool. METHODS We searched 4 databases, with no time restriction, to identify relevant and current CPGs. Two reviewers assessed eligibility and abstracted data, in duplicate. They evaluated the quality of CPGs development process using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) tool that consists of 6 domains. A content expert verified those assessments. RESULTS We identified 3 eligible CPGs: (1) the Endocrine Society (ES) guidelines (2010); (2) the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic & Bariatric Surgery (ASMBS) guidelines (update 2013); and (3) the Interdisciplinary European (IE) guidelines on Metabolic and Bariatric Surgery (latest update 2014). The ES and the AACE/TOS/ASMBS guidelines recommended high doses of vitamin D, varying from 3000IU daily to 50,000IU 1-3 times weekly. Vitamin D doses were not mentioned in the IE guidelines. The recommendations were based on a low quality of evidence, if any, or limited to a single high quality trial, for some outcomes. In terms of quality, only the IE guidelines described their search methodology but none of the CPGs provided details on evidence selection and appraisal. None of the three CPGs rigorously assessed the preferences of the target population, resource implications, and the applicability of these guidelines. According to the AGREE II tool, we rated the ES guidelines as average in quality, and the other two as low in quality. CONCLUSION Current CPGs recommendations on vitamin D supplementation in bariatric surgery differ between societies. They do not fulfill criteria for optimal guideline development, in part possibly due to limited resources, and are based on expert opinion. Thus, the pressing need for high quality randomized trials to inform CPGs, to be developed based on recommended standards.

Effect of vitamin D replacement on maternal and neonatal outcomes: a randomised controlled trial in pregnant women with hypovitaminosis D. A protocol

Introduction The vitamin D recommended doses during pregnancy differ between societies. The WHO guidelines do not recommend routine prenatal supplementation, but they underscore the fact that women with the lowest levels may benefit most. The effects of routine supplementation during pregnancy on maternal and neonatal clinical outcomes have not been investigated in the Middle East, where hypovitaminosis D is prevalent. Our hypothesis is that in Middle Eastern pregnant women, a vitamin D dose of 3000 IU/day is required to reach a desirable maternal 25-hydroxyvitamin D [25(OH)D] level, and to positively impact infant bone mineral content (BMC). Methods and analysis This is a multicentre blinded randomised controlled trial. Pregnant women presenting to the Obstetrics and Gynaecology clinics will be approached. Eligible women will be randomised to daily equivalent doses of cholecalciferol, 600 IU or 3000 IU, from 15 to 18 weeks gestation until delivery. Maternal 25(OH)D and chemistries will be assessed at study entry, during the third trimester and at delivery. Neonatal anthropometric variables and 25(OH)D level will be measured at birth, and bone and fat mass assessment by dual-energy X-ray absorptiometry scan at 1 month. A sample size of 280 pregnant women is needed to demonstrate a statistically significant difference in the proportion of women reaching a 25(OH)D level ≥50 nmol/L at delivery, and a difference in infant BMC of 6 (10)g, for a 90% power and a 2.5% level of significance. The proportions of women achieving a target 25(OH)D level will be compared between the two arms, using χ2. An independent t test will be used to compare mean infant BMC between the two arms. The primary analysis is an intention-to-treat analysis of unadjusted results. Ethics and dissemination The protocol has been approved by the Institutional Review Board at the American University of Beirut-Lebanon (IM.GEHF.22). The trial results will be published in peer-reviewed medical journals and presented at scientific conferences. Trial registration number NCT02434380.

Continuous positive airway pressure and type 2 diabetes mellitus.

Obstructive sleep apnea (OSA) is a sleep disorder, increasingly recognized. It is commonly present in obese persons, treated with continuous positive airway pressure (CPAP), being the gold standard. The disorder has been associated with diabetes mellitus and possibly related to hypoxia per se, increased sympathetic activity, disturbed hypothalamic-pituitary-adrenal axis and increased inflammatory cytokines and leptin, all of which can adversely affect both glucose metabolism and insulin sensitivity. Given this association and the presence of common risk factors, this review assessed the impact of CPAP on diabetes mellitus through various metabolic parameters including HbA1c, nocturnal glucose and insulin resistance, in addition to the effect of CPAP on the prevention of diabetes mellitus. Results have been conflicting; Randomized controlled trials are recommended to allow objective and definite conclusions.

Vitamin D Metabolism in Bariatric Surgery

Hypovitaminosis D is common in obese patients and persists after roux-en-Y gastric bypass and sleeve gastrectomy. Several societies recommend screening for vitamin D deficiency before bariatric surgery, and replacement doses of 3000 IU/d and up to 50,000 IU 1 to 3 times per week, in case of deficiency, with periodic monitoring. These regimens are mostly based on expert opinion. Large trials are needed to assess the vitamin D dose response, by type of bariatric surgery, and evaluate the effect on surrogate markers of skeletal outcomes. Such data are essential to derive desirable vitamin D levels in this population.

Incretin Based Therapies: Bone Protective Effects

Type 2 Diabetes Mellitus (T2D) and osteoporosis have been found recently to be tightly correlated. In fact, T2D can result in bone loss through different mechanisms resulting in alteration of bone matrix and inhibition of bone formation. Fracture risk also increases significantly. New antidiabetic agents, dipeptidyl peptidase-4 inhibitors and glucagon like peptide -1 agonists have shown promise in many fields beyond glycemic control. Benefits on the skeletal system are multiple through direct stimulation of osteoblasts, inhibition of advanced glycation end products and inhibition of bone resorption. However, clinical evidence in humans is still not enough to allow definitive conclusions.

Vitamin D in the Middle East and North Africa

Purpose The Middle East and North Africa (MENA) region registers some of the lowest serum 25‑hydroxyvitamin D [25(OH)D] concentrations, worldwide. We describe the prevalence and the risk factors for hypovitaminosis D, completed and ongoing clinical trials, and available guidelines for vitamin D supplementation in this region. Methods This review is an update of previous reviews published by our group in 2013 for observational studies, and in 2015 for randomized controlled trials (RCTs) from the region. We conducted a comprehensive search in Medline, PubMed, and Embase, and the Cochrane Library, using MeSH terms and keywords relevant to vitamin D, vitamin D deficiency, and the MENA region, for the period 2012–2017 for observational studies, and 2015–2017 for RCTs. We included large cross-sectional studies with at least 100 subjects/study, and RCTs with at least 50 participants per arm. Results We identified 41 observational studies. The prevalence of hypovitaminosis D, defined as a 25‑hydroxyvitamin D [25(OH)D] level below the desirable level of 20 ng/ml, ranged between 12–96% in children and adolescents, and 54–90% in pregnant women. In adults, it ranged between 44 and 96%, and the mean 25(OH)D varied between 11 and 20 ng/ml. In general, significant predictors of low 25(OH)D levels were female gender, increasing age and body mass index, veiling, winter season, use of sun screens, lower socioeconomic status, and higher latitude. We retrieved 14 RCTs comparing supplementation to control or placebo, published during the period 2015-2017: 2 in children, 8 in adults, and 4 in pregnant women. In children and adolescents, a vitamin D dose of 1000–2000 IU/d was needed to maintain serum 25(OH)D level at target. In adults and pregnant women, the increment in 25(OH)D level was inversely proportional to the dose, ranging between 0.9 and 3 ng/ml per 100 IU/d for doses ≤2000 IU/d, and between 0.1 and 0.6 ng/ml per 100 IU/d for doses ≥3000 IU/d. While the effect of vitamin D supplementation on glycemic indices is still controversial in adults, vitamin D supplementation may be protective against gestational diabetes mellitus in pregnant women. In the only identified study in the elderly, there was no significant difference between 600 IU/day and 3750 IU/day doses on bone mineral density. We did not identify any fracture studies. The available vitamin D guidelines in the region are based on expert opinion, with recommended doses between 400 and 2000 IU/d, depending on the age category, and country. Conclusion Hypovitaminosis D is prevalent in the MENA region, and doses of 1000–2000 IU/d may be necessary to reach a desirable 25(OH)D level of 20 ng/ml. Studies assessing the effect of such doses of vitamin D on major outcomes, and confirming their long term safety, are needed.