Vitamin D Metabolism and Guidelines for Vitamin D Supplementation

Vitamin D is essential for bone health and is known to be involved in immunomodulation and cell proliferation. Vitamin D status remains a significant health issue worldwide. However, there has been no clear consensus on vitamin D deficiency and its measurement in serum, and clinical practice of vitamin D deficiency treatment remains inconsistent. The major circulating metabolite of vitamin D, 25-hydroxyvitamin D (25(OH)D), is widely used as a biomarker of vitamin D status. Other metabolic pathways are recognised as important to vitamin D function and measurement of other metabolites may become important in the future. The utility of free 25(OH)D rather than total 25(OH)D needs further assessment. Data used to estimate the vitamin D intake required to achieve a serum 25(OH)D concentration were drawn from individual studies which reported dose-response data. The studies differ in their choice of subjects, dose of vitamin D, frequency of dosing regimen and methods used for the measurement of 25(OH)D concentration. Baseline 25(OH)D, body mass index, ethnicity, type of vitamin D (D₂ or D₃) and genetics affect the response of serum 25(OH)D to vitamin D supplementation. The diversity of opinions that exist on this topic are reflected in the guidelines. Government and scientific societies have published their recommendations for vitamin D intake which vary from 400–1000 IU/d (10–25 μg/d) for an average adult. It was not possible to establish a range of serum 25(OH)D concentrations associated with selected non-musculoskeletal health outcomes. To recommend treatment targets, future studies need to be on infants, children, pregnant and lactating women.     

Low Levels of Vitamin D in Neuromyelitis Optica Spectrum Disorder: Association with Disease Disability

Patients with autoimmune disorders often have low levels of 25-hydroxyvitamin D [25(OH)D₃], which correlates with disability or disease activity. Vitamin D may play a role in neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), as an important factor involved in immunological pathways. We investigated the relationship between vitamin D levels and disease related disability and clinical activity in patients with NMOSD. Blood samples from 51 patients with NMOSD who were positive for anti-aquaporin4-antibody (AQP4-ab) and 204 healthy controls were collected for 25(OH)D₃ measurement. Clinical parameters, including expanded disability status scale (EDSS) score, annualized relapse rate (ARR) and time of blood sampling relative to attack, were determined in patients with NMOSD. We found that 25(OH)D₃ levels were significantly lower in patients with NMOSD compared to healthy controls. There was no difference between 25(OH)D3 levels in blood samples taken at relapse or remission, and no association between 25(OH)D3 levels and ARR, but there was an inverse correlation between 25(OH)D3 levels and EDSS scores in patients with NMOSD. It remains to be determined whether low vitamin D levels predispose to NMO and/or modify disease severity, or are secondary to neurological disability. In either case the results could also be of relevance to other neurological diseases such as multiple sclerosis as well as NMO.     

Serum 25-Hydroxyvitamin D Levels and Dry Eye Syndrome: Differential Effects of Vitamin D on Ocular Diseases

Purpose

To investigate associations between serum 25-hydroxyvitamin D levels and dry eye syndrome (DES), and to evaluate the differential effect of vitamin D on ocular diseases including age-related macular disease (AMD), diabetic retinopathy (DR), cataract, and DES.

Methods

A total of 16,396 participants aged >19 years were randomly selected from the Korean National Health and Nutrition Examination Survey. All participants participated in standardized interviews, blood 25-hydroxyvitamin D level evaluations, and comprehensive ophthalmic examinations. DES was defined by a history of clinical diagnosis of dry eyes by a physician. The association between vitamin D and DES was compared to the associations between vitamin D and AMD, DR, cataract, and DES from our previous studies.

Results

The odds of DES non-significantly decreased as the quintiles of serum 25-hydroxyvitamin D levels increased (quintile 5 versus 1, OR = 0.85, 95%CI: 0.55–1.30, P for trend = 0.076) after adjusting for potential confounders including age, sex, hypertension, diabetes, smoking status, and sunlight exposure times. The relative odds of DES (OR = 0.70, 95% CI: 0.30–1.64) and cataract (OR = 0.76, 95% CI: 0.59–0.99) were relatively high, while those of DR (OR = 0.37, 95% CI: 0.18–0.76) and late AMD (OR = 0.32, 95% CI: 0.12–0.81) were lower in men.

Conclusions

The present study does not support an association between serum 25-hydroxyvitamin D levels and DES. The preventive effect of serum 25-hydroxyvitamin D may be more effective for DR and late AMD than it is for cataract and DES.     

Interactions between Serum Vitamin D Levels and Vitamin D Receptor Gene FokI Polymorphisms for Renal Function in Patients with Type 2 Diabetes

Background

We aimed to examine associations among serum 25-hydroxyvitamin D (25OHD) levels, 1,25-dihyroxyvitamin D (1,25OHD) levels, vitamin D receptor (VDR) polymorphisms, and renal function based on estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes.

Methods

In a cross-sectional study of 410 patients, chronic kidney disease (CKD) stage assessed by eGFR was compared with 25OHD, 1,25OHD, and VDR FokI (rs10735810) polymorphisms by an ordered logistic regression model adjusted for the following confounders: disease duration, calendar month, use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers or statins, and serum calcium, phosphate, and intact parathyroid hormone levels.

Results

1,25OHD levels, rather than 25OHD levels, showed seasonal oscillations; peak levels were seen from May to October and the lowest levels were seen from December to February. These findings were evident in patients with CKD stage 3∼5 but not stage 1∼2. eGFR was in direct proportion to both 25OHD and 1,25OHD levels (P<0.0001), but it had stronger linearity with 1,25OHD (r = 0.73) than 25OHD (r = 0.22) levels. Using multivariate analysis, 1,25OHD levels (P<0.001), but not 25OHD levels, were negatively associated with CKD stage. Although FokI polymorphisms by themselves showed no significant associations with CKD stage, a significant interaction between 1,25OHD and FokITT was observed (P = 0.008). The positive association between 1,25OHD and eGFR was steeper in FokICT and CC polymorphisms (r = 0.74) than FokITT polymorphisms (r = 0.65).

Conclusions

These results suggest that higher 1,25OHD levels may be associated with better CKD stages in patients with type 2 diabetes and that this association was modified by FokI polymorphisms.     

Maternal Serum and Breast Milk Vitamin D Levels: Findings from the Universiti Sains Malaysia Pregnancy Cohort Study

Background

Vitamin D deficiency has become a global health issue in pregnant women. This study aimed to assess the adequacy of maternal vitamin D status by measuring maternal serum and breast milk 25-hydroxyvitamin D [25(OH)D] levels and to determine the association between maternal serum and milk 25(OH)D levels.

Methods

Data was obtained from the Universiti Sains Malaysia Pregnancy Cohort Study. This study was conducted from April 2010 to December 2012 in the state of Kelantan, Malaysia. Blood samples from pregnant women aged 19 to 40 years were drawn in the second and third trimesters of pregnancy, while breast milk samples at delivery, 2, 6 and 12 months postpartum were collected to analyze for 25(OH)D levels. A total of 102 pregnant women were included in the analysis.

Results

Vitamin D deficiency [25(OH)D <50 nmol/L] was detected in 60% and 37% of women in the second and third trimesters of pregnancy, respectively. There were 6% and 23% of women who reached normal level of vitamin D status in the second trimester and the third trimester, respectively. Multivitamin intakes during pregnancy were significantly associated with higher serum 25(OH)D levels in the second trimester (β = 9.16, p = 0.005) and the third trimester (β = 13.65, p = 0.003). 25(OH)D levels in breast milk during the first year of lactation ranged from 1.01 to 1.26 nmol/L. Higher maternal serum 25(OH)D level in the second trimester of pregnancy was associated with an elevated level of 25(OH)D in breast milk at delivery (β = 0.002, p = 0.026).

Conclusions

This study shows that high proportions of Malay pregnant women are at risk of vitamin D deficiency. Maternal vitamin D status in the second trimester of pregnancy was found to influence vitamin D level in breast milk at delivery.     

Relationship between Body Mass Composition,Bone Mineral Density,Skin Fibrosis and 25(OH) Vitamin D Serum Levels in Systemic Sclerosis

A reduced bone mineral density (BMD) is observed in several rheumatic autoimmune diseases, including Systemic Sclerosis (SSc); nevertheless, data concerning the possible determinants of bone loss in this disease are not fully investigated. The aim of this study is to evaluate the relationship between BMD, body mass composition, skin sclerosis and serum Vitamin D levels in two subsets of SSc patients. 64 post-menopausal SSc patients, classified as limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) SSc, were studied. As control, 35 healthy post-menopausal women were recruited. Clinical parameters were evaluated, including the extent of skin involvement. BMD at lumbar spine, hip, femoral neck and body mass composition were determined by dual-energy X-ray absorptiometry. Serum calcium, phosphorus, alkaline phosphatase, urine pyridinium cross-links, intact parathyroid hormone and 25-hydroxyvitamin D (25OHD) were measured. BMD at spine, femoral neck and total hip was significantly lower in SSc patients compared to controls. In dcSSc subset, BMD at spine, femoral neck and total hip was significantly lower compared to lcSSc. No differences in both fat and lean mass were found in the three study groups even if patients with dcSSc showed a slightly lower total body mass compared to healthy controls. Total mineral content was significantly reduced in dSSc compared to both healthy subjects and lcSSc group. Hypovitaminosis D was observed both in healthy post-menopausal women and in SSc patients, but 25OHD levels were significantly lower in dcSSc compared to lcSSc and inversely correlated with the extent of skin thickness. These results support the hypothesis that the extent of skin involvement in SSc patients could be an important factor in determining low circulating levels of 25OHD, which in turn could play a significant role in the reduction of BMD and total mineral content.     

Glycated Haemoglobin Is Inversely Related to Serum Vitamin D Levels in Type 2 Diabetic Patients

Objective

A correlation between glucose control and 25(OH)D metabolism has been suggested by previous studies. However, this correlation has not yet been evaluated considering the impact of chronic complications of type 2 diabetes, especially the presence of nephropathy. Thus, the aim of this study was to determine the correlation between A1C and 25(OH)D in a well characterized cohort of type 2 diabetic patients.

Research Design and Methods

We cross-sectionally examined the association between A1C and serum 25(OH) D in 715 type 2 diabetic patients attending our clinic during the years 2011–2012. The average age was 68±12 years (range 26–94 years). The relation between A1C and serum 25(OH)D levels was modelled by multiple linear regression analyses.

Results

Serum 25(OH)D levels were inversely associated with A1C levels (r = −0.116, p = .003). This relation maintains its independence in the multivariate analysis after adjusting for age, sex, A1C, BMI, treatment and duration of diabetes and nephropathy.

Conclusions

In type 2 diabetic patients, high A1C levels are associated with low concentrations of serum 25(OH)D independently of duration of diabetes, diabetic treatment and nephropathy. Future studies are needed to clarify the biological relation between glucose control and vitamin D metabolism in type 2 diabetes.     

Low Serum 25-Hydroxyvitamin D Levels Are Associated with Dry Eye Syndrome

Background

Dry eye syndrome (DES) is a common tear film and ocular surface disease that results in discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. Systemic diseases associated with DES include diabetes mellitus, rheumatoid arthritis, depression, anxiety, thyroid disease, allergic diseases, irritable bowel syndrome, chronic pain syndrome, and hyperlipidemia. Interestingly, it has been found that most of these are associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) or inadequate sunlight exposure.

Methods

In this cross-sectional data analysis, noninstitutionalized adults aged ≥19 years (N = 17,542) who participated in Korean National Health and Nutrition Examination Survey 2010–2012 were included. Information regarding duration of sunlight exposure was collected from the survey participants. Serum 25(OH)D and zinc levels were measured. The confounding variables were age, gender, sunlight exposure time, region of residence, obesity, serum 25(OH)D level, diabetes mellitus, rheumatoid arthritis, depression, thyroid disorder, atopic dermatitis, history of ocular surgery, regular exercise, and walking exercise.

Results

Mean serum 25(OH)D levels of subjects with and without DES were 16.90 ± 6.0 and 17.52 ± 6.07 (p<0.001). Inadequate sunlight exposure time (odds ratio [OR], 1.554; 95% confidence interval [CI], 1.307–1.848), urban residence (OR, 1.669; 95% CI, 1.456–1.913), indoor occupation (OR, 1.578; 95% CI, 1.389–1.814), and low serum 25(OH)D level (OR, 1.158; 95% CI, 1.026–1.308) were the risk factors for DES. After adjusting for age, sex, obesity, diabetes mellitus, rheumatoid arthritis, depression, thyroid disorder, atopic dermatitis, history of ocular surgery, regular exercise, and occupation, low serum 25(OH)D level (OR, 1.178; 95% CI, 1.010–1.372) and deficient sunlight exposure time (OR, 1.383; 95% CI, 1.094–1.749) were the risk factors for diagnosed DES.

Conclusion

Low serum 25(OH)D levels and inadequate sunlight exposure are associated with DES in Korean adults. These results suggest that sufficient sunlight exposure or vitamin D supplementation may be useful in DES treatment.     

中国北方地区血清钙、维生素D水平与乳腺癌的相关性研究

目的:探讨中国北方地区血清钙、维生素D水平与乳腺癌及相关临床因素的关系.方法:选取2007年12月至2012年7月哈尔滨医科大学附属肿瘤医院794例女性乳腺癌患者及976例乳腺良性肿瘤患者,并以128例健康妇女为对照,取空腹血清采用原子吸收分光光度法检测三组血清钙含量,采用放免法检测三组中162例血清25(OH)D含量,结合相关临床资料进行分析.结果:乳腺癌组血清钙含量为2.26± 0.12 mmol/L,乳腺良性肿瘤组血清钙含量为2.26±0.09 mmol/L,正常对照组血清钙含量为2.25±0.24 mmol/L,经方差分析,三组总体均数差别无统计学意义(P＞0.05);乳腺癌患者的血清钙水平与年龄、TNM分期、BMI、绝经情况、乳腺癌家族遗传史无关(P＞0.05).乳腺癌组血清25(OH)D含量为41.91±7.55 ng/mL,乳腺良性肿瘤血清25(OH)D含量为54.62±7.48 ng/mL,正常对照组血清25(OH)D含量为56.15±8.87 ng/mL,经方差分析,乳腺癌患者血清25(OH)D含量低于乳腺良性肿瘤组,差别有统计学意义(P＜0.05),乳腺良性肿瘤组与正常对照组差别无统计学意义(P＞0.05);乳腺癌患者的维生素D水平与年龄、TNM分期、BMI、绝经情况有关(P＜0.05),而与乳腺癌家族遗传史无关(P＞0.05).结论:中国北方地区的乳腺癌患者血清钙水平与乳腺良性肿瘤患者无明显差异.乳腺癌患者的维生素D水平低于乳腺良性肿瘤患者,并且与年龄、TNM分期、BMI、绝经情况有关.维生素D水平降低可能与乳腺癌的发生有关,高水平的维生素D可能会降低女性患乳癌的风险.     

Clinical Trial of the Effect of Vitamin B12 in Elderly Subjects with Low Serum B12 Levels

A clinical trial of the effect of vitamin B₁₂ therapy was conducted in 39 elderly subjects who had been found, in a community screening survey, to have low levels of serum B₁₂ without a macrocytic anaemia or neuropathy. The study produced no evidence which suggests that in such subjects B₁₂ is superior to placebo in effecting an improvement in psychiatric state or general well-being. There was a clear tendency for all the subjects to show an improvement during the trial, but this probably represents the therapeutic effect of involvement in a research exercise of this kind.     

Serum Folate and Vitamin B12 Levels in Children from Mozambique

In order to investigate the behaviour of biochemical parameters in children from Mozambique, we have determined the serum levels of folic acid and vitamin B12, two well known markers of nutritional anemia.     

Serum Vitamin D,Vitamin D Binding Protein,and Risk of Colorectal Cancer

Background

We previously reported a positive association between serum 25-hydroxyvitamin D (25(OH)D) and colorectal cancer risk. To further elucidate this association, we examined the molar ratio of 25(OH)D to vitamin D binding protein (DBP), the primary 25(OH)D transport protein, and whether DBP modified the association between 25(OH)D and colorectal cancer risk.

Methods

In a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, controls were 1∶1 matched to 416 colorectal cancer cases based on age and date of blood collection. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free, unbound circulating 25(OH)D.

Results

Comparing highest to lowest quartiles, DBP was not associated with colorectal cancer risk (OR = 0.91; 95% CI: 0.58, 1.42, p for trend  = 0.58); however, a positive risk association was observed for the molar ratio of 25(OH)D:DBP (OR = 1.44; 95% CI: 0.92, 2.26, p for trend  = 0.04). In stratified analyses, the positive association between 25(OH)D and colorectal cancer was stronger among men with DBP levels above the median (OR = 1.89; 95% CI: 1.07, 3.36, p for trend  = 0.01) than below the median (OR = 1.20; 95% CI: 0.68, 2.12, p for trend  = 0.87), although the interaction was not statistically significant (p for interaction  = 0.24).

Conclusion

Circulating DBP may influence the association between 25(OH)D and colorectal cancer in male smokers, with the suggestion of a stronger positive association in men with higher DBP concentrations. This finding should be examined in other populations, especially those that include women and non-smokers.     

多囊卵巢综合征患者中血清维生素D和Vaspin水平的表达及其临床意义

摘要 目的：研究多囊卵巢综合征（PCOS）患者中血清维生素D和脂肪特异性丝氨酸蛋白酶抑制剂（Vaspin）水平的表达及其临床意义。方法：选择2019年1月～2021年12月湖南省妇幼保健院收治的51例PCOS患者,记作研究组。另取同期月经规律健康体检者50例纳入对照组。比较两组基线资料、血清25羟维生素D[25-(OH)D]和Vaspin水平、糖脂代谢指标、胰岛素抵抗指数（HOMA-IR）以及胰岛β细胞功能指数（HOMA-β）。并以Pearson相关性分析法分析PCOS患者血清25-(OH)D、Vaspin水平与各项指标的关系。结果：研究组腰臀比（WHR）、体质指数（BMI）、血清Vaspin水平、空腹血糖（FPG）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、空腹胰岛素（FINS）、HOMA-β及HOMA-IR均高于对照组,血清25-(OH)D水平、高密度脂蛋白胆固醇（HDL-C）均低于对照组（均P＜0.05）。经Pearson相关性分析可得：血清25-(OH)D水平和WHR、BMI、FPG、TG、LDL-C、FINS、HOMA-β以及HOMA-IR均呈负相关,与HDL-C呈正相关;血清Vaspin水平和除HDL-C外的上述各项指标均呈正相关,与HDL-C呈负相关。结论：PCOS患者血清维生素D存在明显低表达,而Vaspin水平呈明显高表达,且两者表达水平和糖脂代谢、胰岛β细胞功能、胰岛素抵抗均密切相关,检测两指标水平有助于评估PCOS患者病情进展。     

Association of Low Serum 25-Hydroxyvitamin D Levels in Pregnancy with Glucosehomeostasis and Obstetric And Newborn Outcomes

ObjectiveTo evaluate the association of maternal serum 25-hydroxyvitamin D (25[OH]D) status with glucose homeostasis and obstetric and newborn outcomes in women screened for gestational diabetes mellitus (GDM).MethodsConsecutive women were screened for GDM at 24 to 28 weeks’ gestation during the months of maximal sunlight exposure in Spain (June through September). Serum 25(OH)D levels and parameters of glucose homeostasis were measured. Outcomes of the delivery and newborn were collected.ResultsTwo hundred sixty-six women were screened. Vitamin D deficiency (25[OH]D < 20 ng/mL) was observed in 157 women (59%). We observed an inverse correlation between 25(OH)D levels and hemoglobin A_1c, homeostasis model assessment of insulin resistance, serum insulin, and fasting and 1-hour oral glucose tolerance test glucose levels (P <.001). With a 25(OH)D concentration less than 20 ng/mL, the odds ratios were 3.31 for premature birth (95% confidence interval, 1.52-7.19; P <.002) and 3.93 for cesarean delivery (95% confidence interval, 2.00-7.73; P <.001). A 25(OH)D concentration of 20 ng/mL had 79% sensitivity and 51% specificity for cesarean delivery and 80% sensitivity and 45% specificity for premature birth. The cutoffs with the best combination of sensitivity and specificity were 16 ng/mL for cesarean delivery (62.9% sensitivity and 61.2% specificity) and 14 ng/mL for premature birth (66.7% sensitivity and 71.0% specificity).ConclusionsIn the population we sampled, vitamin D deficiency is very common during pregnancy. Lower 25(OH)D levels are associated with disorders of glucose homeostasis and adverse obstetric and newborn outcomes.(Endocr Pract. 2012;18:676-684)     

Seasonal Variation Of Vitamin D And Serum Thyrotropin Levels And Its Relationship In A Euthyroid Caucasian Population

Objective: It is unclear whether seasonal variations in vitamin D concentrations affect the hypothalamo-pituitary-thyroid axis. We investigated the seasonal variability of vitamin D and serum thyrotropin (TSH) levels and their interrelationship.Methods: Analysis of 401 patients referred with nonspecific symptoms of tiredness who had simultaneous measurements of 25-hydroxyvitamin D3 (25&lsqb;OH]D3) and thyroid function. Patients were categorized according to the season of blood sampling and their vitamin D status.Results: 25(OH)D3 levels were higher in spring-summer season compared to autumn-winter (47.9 ± 22.2 nmol/L vs. 42.8 ± 21.8 nmol/L; P = .02). Higher median (interquartile range) TSH levels were found in autumn-winter (1.9 &lsqb;1.2] mU/L vs. 1.8 &lsqb;1.1] mU/L; P = .10). Across different seasons, 25(OH)D3 levels were observed to be higher in lower quartiles of TSH, and the inverse relationship was maintained uniformly in the higher quartiles of TSH. An independent inverse relationship could be established between 25(OH)D3 levels and TSH by regression analysis across both season groups (autumn-winter: r = -0.0248; P<.00001 and spring-summer: r = -0.0209; P<.00001). We also observed that TSH varied according to 25(OH)D3 status, with higher TSH found in patients with vitamin D insufficiency or deficiency in comparison to patients who had sufficient or optimal levels across different seasons.Conclusion: Our study shows seasonal variability in 25(OH)D3 production and TSH secretion in euthyroid subjects and that an inverse relationship exists between them. Further studies are needed to see if vitamin D replacement would be beneficial in patients with borderline thyroid function abnormalities.Abbreviations: 25(OH)D2 = 25-hydroxyvitamin D2; 25(OH)D3 = 25-hydroxyvitamin D3; AITD = autoimmune thyroid disease; FT4 = free thyroxine; TFT = thyroid function test; TSH = thyrotropin; UVB = ultraviolet B