Alterations in CD4+ T Cell Cytokines Profile in Female Patients with Hashimoto's Thyroiditis Following Vitamin D Supplementation: A Double-blind, Randomized Clinical Trial.

BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune disease characterized by the destruction of thyroid cells through immune processes involving T helper (Th)1 cytokines. This clinical trial investigates the impact of vitamin D supplementation on serum cytokine levels and gene expression in CD4+ T cells from HT patients, aiming to understand its effects on Th-1, Th-2, Th-17, and regulatory T (Treg) cell-associated factors. METHODS: Female patients were randomly assigned in a double-blind design to either a vitamin D-supplemented group, which received cholecalciferol [1, 25(OH)2D3] at a dose of 50,000 IU, or the placebo group, which received a weekly placebo for a duration of three months. Serum cytokine levels were assessed using enzyme-linked immunosorbent assay (ELISA), while genes' expression levels were measured using real-time PCR. RESULTS: Serum 25-hydroxyvitamin D and levels exhibited a significant increase following vitamin D supplementation, in comparison to the placebo group. Additionally, the vitamin D supplementation resulted in a significant elevation of serum calcium (Ca) levels compared to baseline. In the vitamin D group, there was a significant decrease in both serum levels and expression of the interleukin (IL)-17 gene when compared to baseline, although no statistical difference was observed between the placebo and vitamin D groups. The gene expression of transforming growth factor-beta (TGFß) was significantly increased in the vitamin D group compared to baseline, with no significant difference between the two study groups. Vitamin D treatment had no effect on serum levels of interferon-gamma (IFNϒ) and IL-4. While the gene expression of IL-4 in the vitamin D group did not exhibit a statistically significant increase, the level of GATA3 transcription factor increased significantly when compared to the placebo group. The expression of IFNϒ and transcription factors, T-bet, RORc, and forkhead box protein 3 (FOXP3) in genes did not show significant changes following vitamin D supplementation. CONCLUSION: The findings suggest that vitamin D supplementation may hold potential benefits for autoimmune diseases, such as HT. However, further longitudinal clinical trials are necessary to gain a more comprehensive understanding of the specific effects of vitamin D on HT. CLINICAL TRIAL REGISTRATION NUMBER: IRCT2016110130644N1.

The Effect of Maternal Vitamin D Supplementation on Vitamin D Status of Exclusively Breastfeeding Mothers and Their Nursing Infants: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

The optimal vitamin D supplementation plan during lactation is unclear. We investigated the effect of maternal vitamin D supplementation on mother-infant dyads' vitamin D status during lactation. All controlled trials that compared vitamin D supplements to placebo or low doses of vitamin D in breastfeeding mothers were included. Pooled effect size and the associated 95% CI for each outcome were estimated using random-effects models. A 1-stage random-effect dose-response model was used to estimate the dose-response relation across different vitamin D dosages and serum 25-hydroxy vitamin D [25(OH)D] concentrations. We identified 19 clinical trials with 27 separate comparison groups (n = 3337 breastfeeding mothers). Maternal vitamin D supplement dosages were associated with circulating 25(OH)D concentrations in breastfeeding women in a nonlinear fashion. Supplementation with 1000 IU of vitamin D/d increased serum 25(OH)D concentrations by 7.8 ng/mL, whereas there was a lower increase in concentrations at vitamin D doses of >2000 IU/d (3.07 and 2.05 ng/mL increases between 2000-3000 and 3000-4000 IU/d, respectively). A linear relation was observed between maternal vitamin D supplementation dosage and the infants' circulating 25(OH)D concentrations. Each additional 1000 IU of maternal vitamin D intake was accompanied by a 2.7 ng/mL increase in serum 25(OH)D concentration in their nursing infants. The subgroup analysis showed that maternal vitamin D supplementation was accompanied by a statistically significant increase in infants' 25(OH)D concentration in the trials with a duration of >20 wk, vitamin D supplementation >1000 IU/d, East Indian participants, maternal BMI <25 kg/m2, and studies with an overall low risk of bias. Long-term maternal supplementation with vitamin D at a high dose (>6000 IU/d) effectively corrected vitamin D deficiency in both mothers and infants. Nevertheless, infants with 25(OH)D concentrations over 20 ng/mL may require a relatively low maternal dose to maintain vitamin D sufficiency.

Vitamin D Receptor (VDR) Allelic Variants Correlating with Response to Vitamin D3 Supplementation in Breast Cancer Survivors.

We investigated how vitamin D receptor (VDR) allelic variants affect breast cancer survivors' responses to vitamin D3 supplementation to increase circulating 25-hydroxy vitamin D (25(OH)D) levels. Two hundred and fourteen patients who were diagnosed with breast cancer at least 6 mo, prior to the study and had completed all treatment regimens were assigned to consume 4000 IU of vitamin D3 daily for 12 weeks. Linear and multinomial logistic regression analyses were used to analyze the association of VDR single nucleotide polymorphism (SNPs) with changes in circulating 25(OH)D. The TaqI and BsmI VDR sequence variants modified the effect of vitamin D3 treatment on the plasma 25(OH)D changes (P value = 0.008 for TaqI and P value = 0.0005 for BsmI). Patients with the bb [Q4 vs. Q1 odds ratio(OR) 8.04, 95% confidence interval (CI) 1.55-41.57] and tt [Q4 vs. Q1 OR 4.64 95%CI 1.02-21.02] genotype of BsmI and TaqI had larger increases in plasma 25(OH)D levels compared to those with BB and TT genotype respectively after adjustment for potential confounders. Haplotype analyses suggested the existence of specific combination of alleles that might be associated with circulating 25(OH)D changes. VDR allelic variants modulate vitamin D3 supplementation to increase plasma 25(OH) levels in breast cancer survivors.

Assessment the effect of vitamin D supplementation on plasma vitamin D levels, inflammation, and oxidative stress biomarkers based on vitamin D receptor genetic variation in breast cancer survivors: a protocol for clinical trial.

BACKGROUND: Both human genes and environmental exposures, due to complex interplay, play important role in the cancer etiology. Vitamin D is associated with a reduced risk of incidence and mortality of several human cancers. This study will aim to investigate the possible effects of individual polymorphisms in vitamin D receptor (VDR) as well as effects of VDR haplotypes on response to vitamin D supplementation in breast cancer survivors. METHODS: This is an interventional study in which the effects of vitamin D supplementation on plasma vitamin D levels, inflammatory and antioxidant biomarkers and factors associated with cell proliferation, differentiation, damage, and apoptosis will be investigated stratified by variations in VDR genotype. The present study will be conducted on breast cancer survivors referred to the Shohadaye Tajrish hospital and its associated clinics. One hundred ninety-eight breast cancer survivors will receive 4000 IU of vitamin D3 daily for 12 weeks. VDR Fok1, ApaI, TaqI, BsmI, and Cdx-2 genotype will be determined at the end of the study and responses to vitamin D supplements (inflammatory, antioxidant, cell proliferation, differentiation, damage, and apoptosis biomarkers) will be compared between the three subgroups of each VDR polymorphism as well as different VDR haplotype categories. DISCUSSION: Genetic variation is a fundamental factor influencing individuals' divergent responses to diet, nutritional status, metabolic response, and diet-related health disorders. Furthermore, studies of gene and environment interactions will provide a precise and accurate assessments of individuals' dietary requirements by considering both the genetic and environmental aspects simultaneously. The results of the current study, to some extent, will highlight the discrepancies existing in the findings of different studies regarding vitamin D, VDR, and cancer by considering both the genetic and environmental aspects simultaneously. If responses to vitamin D supplementation could be modified by VDR SNPs, determining the distribution of VDR polymorphisms in both breast cancer survivors and healthy populations will provide a new insight into the vitamin D requirements of individuals to prevent cancer and its related mortality based on their genotypes. Trial registration This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153.

Persistent hypercalcemia with similar familial Hypocalciuric hypercalcemia features: a case report and literature review.

BACKGROUND: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are the most important differential diagnosis of parathyroid hormone (PTH)-dependent hypercalcemia. The clinical features of FHH and PHPT can overlap in some cases. Therefore, these two diseases must be differentiated to prevent unnecessary parathyroidectomy. Here, we present a case that was not entirely matched with any of the known differential diagnoses of hypercalcemia. CASE PRESENTATION: A 19-year-old girl with no history of any disease presented with persistent hypercalcemia without any specific musculoskeletal complaint. We found persistent hypercalcemia in her routine laboratory data from 3 years ago; while no data was available during the childhood period. Her dietary calcium intake was normal. She did not mention any history of renal stone, bone fracture as well as family history of hypercalcemia. Biochemical features showed normal values of serum creatinine, high normal serum calcium (range, 10.3-11.3 mg/dL; (normal range: 8.8-10.4)), and non-suppressed PTH levels (range, 37.2-58.1 pg/mL; (normal range: 10-65)). Serum 25 OH vitamin D level at the first visit was 16.1 ng/mL that treated by vitamin D supplementation. Since then, all 25 OH vitamin D levels were in the acceptable range. After correction of vitamin D deficiency during the follow-up period the calcium creatinine clearance ratio(s) (CCCR) were calculated in the range of 0.009 to 0.014 (means below 1%). The clinical and laboratory data indicate more FHH rather than PHPT. Genetic studies were negative for the common genes associated with FHH (CASR, GNA11, and AP2S1 genes) and multiple endocrine neoplasia type1 (MEN1). On the other hand, no evidence of autoimmunity was found in her to support an autoimmune FHH-like syndrome. Hence, the case did not match completely to any diagnosis of FHH and PHPT, so we decided to follow her. CONCLUSION: We presented a patient with FHH phenotype whose common genetic tests were negative. Further research is needed to ascertain other causes leading to similar manifestations.

Effect of vitamin D receptor polymorphisms on plasma oxidative stress and apoptotic biomarkers among breast cancer survivors supplemented vitamin D3.

We investigated whether plasma oxidative stress and apoptotic biomarkers were associated with the VDR polymorphisms in breast cancer survivors supplemented with vitamin D3. Two hundred fourteen breast cancer survivors received 4000 IU of vitamin D3 daily for 12 weeks. Linear regression was used to analyze whether the effect of vitamin D3 supplementation on response variables was associated with the selected VDR single nucleotide polymorphisms executing by 'association' function in the R package 'SNPassoc'. Linear regression analyses adjusted for age, BMI and on-study plasma 25(OH)D changes indicated that the aa genotype of the ApaI [codominant model (aa vs. AA): -0.21 (-0.39 to -0.03); recessive model (aa vs. AA and Aa): -0.20 (-0.37 to -0.03)] and bb genotypes of the BsmI [recessive model (bb vs. BB and Bb): -0.20 (-0.39 to -0.01)] on VDR were associated with greater decrease in plasma Bcl2. Our findings indicated that, the Ff genotype of FokI was accompanied by higher increase in plasma MDA levels [codominant model (Ff vs. FF): 0.64 (0.18-1.11); dominant model (ff and Ff vs. FF): 0.52 (0.09-0.05)]. This observed association was not remained statistically significant after correction for multiple testing. Haplotype score analyses revealed statistically significant association between the FokI BsmI ApaI haplotype and circulating MDA changes (P-value for global score = 0.001) after false-discovery rate correction. Our study suggests that genetic variations in the VDR do not powerfully modify the effects of vitamin D3 intake on biomarkers associated with antioxidant activity, oxidative stress and apoptosis in breast cancer survivors.

Prevalence of calcium and vitamin D deficiency and their association with feto-maternal outcomes in a sample of Iranian pregnant women.

BACKGROUND: Calcium and vitamin D deficiency is common among Iranian women of childbearing age and poses adverse effects on pregnancy outcomes. The aim of the current study was to determine the prevalence of vitamin D and calcium in a sample of Iranian pregnant women and to assess its correlation with the feto-maternal outcomes. METHODS: In this prospective cross-sectional study, a sample of pregnant women between 15 to 45 years who were in the third trimester were recruited from a number of hospitals in Tehran. Data were collected by the means of a self-developed questionnaire, interviews, physical examination, and paraclinical tests including measuring the serum level of calcium, vitamin D, parathormone (PTH) and phosphorous (Pi). The questionnaire obtained information on age, level of education, socio-economic status, parity, gravidity, calcium intake during pregnancy, as well as feto-maternal outcomes. RESULTS: We included a total number of 233 singleton pregnancies. Most of the subjects (58.4%) had vitamin D deficiency and 12.0% suffered from severe vitamin D deficiency. Vitamin D deficiency was adversely associated with the years of education (p= 0.007), serum level of parathormone (p< 0.001). The Metabolic Equivalent of Task (MET) (p< 0.001), the exercise sequence per week (p< 0.001), sun exposure (p< 0.001), higher rate of sunscreen usage (p= 0.011) and higher BMI (p= 0.005). Vitamin D deficiency was associated with higher rate of cesarean delivery (p= 0.024), higher rate of diastolic hypertension (p= 0.019), higher rate of neonatal jaundice (p= 0.009) and higher rate of neonatal respiratory infections (p< 0.001). Serum level of PTH was a significant risk factor for severe vitamin D deficiency while calcium D supplementation, MET and sunscreen were significant protective factors. CONCLUSION: The prevalence of vitamin D deficiency during pregnancy among Iranian women is extremely high and is associated with adverse pregnancy outcomes including cesarean delivery, neonatal jaundice and neonatal respiratory infections. Low vitamin D supplementation and sun exposure, lack of physical activity and high BMI are the etiologies. Increasing the knowledge along with vitamin D supplementation during the pregnancy is recommended in Iranian population.

Correction to: Vitamin D receptor gene polymorphisms affecting changes in visceral fat, waist circumference and lipid profile in breast cancer survivors supplemented with vitamin D3.

Following publication of the original article [1], the authors reported that one of the co-authors has a mistake in the author name.

Vitamin D receptor gene polymorphisms affecting changes in visceral fat, waist circumference and lipid profile in breast cancer survivors supplemented with vitamin D3.

OBJECTIVE: We investigated whether vitamin D receptor (VDR) polymorphisms are associated with circulating metabolic biomarkers and anthropometric measures changes in breast cancer survivors supplemented with vitamin D3. METHODS: One hundred sixty-eight breast cancer survivors admitted to Shohaday-e-Tajrish hospital received 4000 IU of daily vitamin D3 supplements for 12 weeks. Anthropometric measurements as well dietary, physical activity and plasma metabolic biomarkers assessments were performed before and after intervention. VDR polymorphisms were considered as the main exposures. Multivariate multiple linear regression analyses were used to determine the association between the VDR single-nucleotide polymorphisms (SNPs) and changes in metabolic and anthropometric measures in response to vitamin D3 supplementation. RESULTS: One hundred twenty-five (85%) women had insufficient and inadequate levels of plasma 25-hydroxy vitamin D (25(OH)D) at baseline. Compared to the AA genotype of the ApaI, the aa category showed greater increase in muscle mass [71.3(10.7131.9)] and higher decrease in LDL-C [- 17.9(- 33.6, - 2.3)] levels after adjustment for potential confounders. In addition, the heterozygous genotype (Bb) of the BsmI VDR was associated with higher increase in WC following vitamin D3 supplementation, compared to BB [2.7(0.1,5.3)]. Haplotype score analyses indicate a significant association between inferred haplotypes from BsmI, ApaI, TaqI and FokI, BsmI and Cdx2 VDR polymorphisms and on-study visceral fat changes. CONCLUSIONS: Findings of this study showed that genetic variation in the VDR gene was associated with changes in cardio-metabolic parameters in breast cancer survivors, supplemented with vitamin D3, results could provide a novel insight into better understanding of which subset of individuals benefit most from normalization of vitamin D status. TRIAL REGISTRATION: This trial has been registered on the Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153 and was approved by the ethics committees of the National Nutrition and Food Technology Research Institute (NNFTRI), Shahid Beheshti University of Medical Sciences (SBMU).

Vitamin D Receptor Genetic Variation and Cancer Biomarkers among Breast Cancer Patients Supplemented with Vitamin D3: A Single-Arm Non-Randomized Before and After Trial.

We investigated whether vitamin D receptor (VDR) polymorphisms were associated with cancer biomarkers, i.e., E-cadherin, matrix metallopeptidase 9 (MMP9), interferon ß (IFNß), soluble intercellular adhesion molecule-1 (s-ICAM-1), soluble vascular cell adhesion molecule-1 (s-VCAM-1), tumor necrosis factorα (TNFα), interleukin 6 (IL6), plasminogen activator inhibitor-1(PAI-1), and human high sensitivity C-reactive protein (hs-CRP), among breast cancer survivors who received vitamin D3 supplementation. In a single-arm non-randomized pre- and post trial, 176 breast cancer survivors who had completed treatment protocol including surgery, radio and chemotherapy were enrolled in the study and received 4000 IU of vitamin D3 daily for 12 weeks. The association between the VDR SNPs (ApaI, TaqI, FokI, BsmI and Cdx2) and response variable changes was assessed using linear regression, utilizing the "association" function in the R package "SNPassoc". We observed that women with AA and GA [codominant model (AA compared to GG) and (GA compared to GG); dominant model (AA & GA compared to GG)] genotypes of Cdx2 showed higher increase in plasma MMP9 levels compared to the GG category. In addition, carriers of BsmI bb showed greater decrease in circulating TNFα levels after vitamin D3 supplementation [recessive model (bb compared to BB & Bb]. Likewise, significant associations were identified between haplotypes of VDR polymorphisms and on-study plasma MMP9 changes. However, our results indicate that VDR genetic polymorphisms were not associated with longitudinal changes in the remaining cancer biomarkers. Overall, our findings suggest that changes in certain inflammatory biomarkers in breast cancer survivors with low plasma 25(OH)D levels, supplemented with vitamin D3, may depend on VDR SNPs and haplotypes.

Can Supplementation with Vitamin D Modify Thyroid Autoantibodies (Anti-TPO Ab, Anti-Tg Ab) and Thyroid Profile (T3, T4, TSH) in Hashimoto's Thyroiditis? A Double Blind, Randomized Clinical Trial.

Hashimoto's thyroiditis (HT) is the most prevalent autoimmune disorder characterized by the destruction of thyroid cells caused by leukocytes and antibody-mediated immune processes accompanied by hypothyroidism. In recent years, evidence has emerged pointing to various roles for vitamin D, including, proliferation and differentiation of normal and cancer cells, cardiovascular function, and immunomodulation. Vitamin D deficiency has been especially demonstrated in HT patients. The aim of this study was to investigate the effect of vitamin D on circulating thyroid autoantibodies and thyroid hormones profile (T4, T3, and TSH) in females with HT. Forty-two women with HT disease were enrolled in this randomized clinical trial study and divided into vitamin D and placebo groups. Patients in the vitamin D and placebo groups received 50 000 IU vitamin D and placebo pearls, weekly for 3 months, respectively. The serum levels of 25-hydroxy vitamin D [25(OH) D], Ca++ion, anti-thyroperoxidase antibody (anti-TPO Ab), anti-thyroglobulin antibody (anti-Tg Ab), T4, T3, and TSH were measured at the baseline and at the end of the study using enzyme-linked immunosorbent assays. The results of this study showed a significant reduction of anti-Tg Ab and TSH hormone in the Vitamin D group compared to the start of the study; however, there was a no significant reduction of anti-TPO Ab in the Vitamin D group compared to the placebo group (p=0.08). No significant changes were observed in the serum levels of T3 and T4 hormones. Therefore, vitamin D supplementation can be helpful for alleviation of the disease activity in HT patients; however, further well controlled, large, longitudinal studies are needed to determine whether it can be introduced in clinical practice.

Effects of vitamin D supplements on frequency of CD4+ T-cell subsets in women with Hashimoto's thyroiditis: a double-blind placebo-controlled study.

BACKGROUND: Vitamin D is a modulator of immune functions. Investigations on the mechanisms of vitamin D action and pathogenesis of Hashimoto's thyroiditis (HT) have revealed that vitamin D can reduce damages to thyroid cells caused by autoreactive immune cells. METHODS: Totally, 48 female patients with HT disease were introduced to the study by endocrinologists. Patients were divided into two major groups of 24 individuals and treated weekly with 50,000 IU of cholecalciferol (vitamin D group) or placebo (placebo group) using oral administration for 3 months. Eventually, 17 of the 24 patients in each group finished the study. Before and after supplementation, frequencies of Th1, Th17, Th2 and Tr1 cells and mean fluorescent intensity (MFI) of the associated cytokines, including IFN-γ, IL-17, IL-4 and IL-10, were assessed using flow cytometry. Furthermore, gene expression of IL-10 was assessed using real-time PCR. RESULTS: Results of this study showed that cholecalciferol supplementation caused a significant decrease in Th17/Tr1 ratio. The proportion and MFI of Th1, Th2, Tr1 and Th17 cells included no significant changes in vitamin D group, compared to those in placebo group. Expression rate and MFI of IL-10 increased in both groups. This increase was higher in vitamin D group than placebo group with no significance. CONCLUSIONS: In this novel preliminary clinical trial study, supplementation with cholecalciferol in HT patients for 3 months changed the balance of CD4+ T-cell subsets to improve the disease control. However, further studies are necessary to investigate effects of vitamin D on immune functions in HT patients.

Effects of Cinnamon Consumption on Glycemic Indicators, Advanced Glycation End Products, and Antioxidant Status in Type 2 Diabetic Patients.

The aim of the current study was to determine the effect of a daily intake of three grams of cinnamon over eight weeks on glycemic indicators, advanced glycation end products, and antioxidant status in patients with type 2 diabetes. In a double-blind, randomized, placebo controlled clinical trial study, 44 patients with type 2 diabetes, aged 57 ± 8 years, were randomly assigned to take either a three g/day cinnamon supplement (n = 22) or a placebo (n = 22) for eight weeks. We measured the fasting blood glucose, insulin, hemoglobinbA1c, homeostasis model assessment for insulin resistance (HOMA-IR), carboxymethyl lysine, total antioxidant capacity, and malondialdehyde levels at the beginning and the end of the study. Thirty-nine patients (20 in the intervention group and 19 in the control group) completed the study. After an eight-week intervention, changes in the level of fasting blood glucose, insulin, hemoglobinbA1c, HOMA-IR, carboxymethyl lysine, total antioxidant capacity, and malondialdehyde were not significant in either group, nor were any significant differences between groups observed in these glycemic and inflammatory indicators at the end of the intervention. Our study revealed that cinnamon supplementation had no significant effects on glycemic and inflammatory indicators in patients with type 2 diabetes.

Can an Educational Intervention Improve Iodine Nutrition Status in Pregnant Women? A Randomized Controlled Trial.

BACKGROUND: Because of their increased need for iodine, pregnant women are among the high-risk groups for iodine deficiency. The purpose of this study was to evaluate the effectiveness of an educational program on the iodine nutrition status of pregnant women. METHODS: In this randomized controlled trial, 100 pregnant women were randomly selected from five healthcare centers in the southern region of Tehran, the capital of Iran. In the intervention group, pregnant women received a four-month educational program, which included two face-to-face educational sessions, using a researcher-designed educational pamphlet in the second and third trimesters, and two follow-up telephone calls. Knowledge, attitude, and practice (KAP) scores, urinary iodine concentration (UIC), and salt iodine content were assessed at baseline and four months after the intervention. RESULTS: At baseline, there were significant associations between knowledge and attitude (r = 0.38, p = 0.03) between practice and UIC (r = 0.28, p = 0.01) and between UIC and iodine content of salt (r = 0.24, p = 0.009). Although a significant difference was found in mean KAP scores between the two groups after the educational intervention, scores were significantly higher in the intervention group compared with controls (p < 0.01). There were no significant differences in UIC and iodine content of salt between the two groups at follow-up. CONCLUSIONS: Despite educational intervention increasing KAP among women regarding the importance of iodine and iodized salt consumption during pregnancy, their iodine status did not improve. Considering the main socio-environmental determinants of iodine deficiency, in particular, the monitoring of salt fortification, prescribing iodine containing supplements as well as improving health literacy in pregnant women seem essential strategies.