Bioavailable 25-hydroxyvitamin Research Articles

Prognostic value of circulating vitamin D binding protein, total, free and bioavailable 25-hydroxy vitamin D in patients with colorectal cancer.

Numerous studies have suggested that there was a significantly positive association between circulating total 25-hydroxyvitamin D (25(OH)D) and survival in colorectal cancer patients. Moreover, plasma vitamin D was also found significantly associated with the concentration of vitamin D binding protein (VDBP). However, there was no paper to clarify the prognostic value of VDBP, free and bioavailable 25(OH)D in colorectal carcinogenesis. The aim of this study was to comprehensively assess the prognostic value of VDBP, total, free and bioavailable 25(OH)D in stage I-III colorectal cancer patients. A total of 206 colorectal cancer patients were enrolled in this prospective study. Preoperative plasma total 25(OH)D and VDBP concentrations were measured by direct enzyme-linked immunosorbent assay, and albumin concentration was measured by Beckman automatic biochemical analyzer. Free and bioavailable 25(OH)D concentrations were calculated based on the concentrations of plasma VDBP, total 25(OH) D and albumin. X-title program was used to determine the optimal cut-off values of VDBP, total, free and bioavailable 25(OH)D. Results showed that elevated free and bioavailable 25(OH)D were significantly associated with better 5-year overall survival (OS) by univariate analysis. By multivariate cox analysis, we also found that the high level of free 25(OH)D (HR = 0.442, 95%CI = 0.238–0.819, P < 0.010) could be identified as an independent factor for better OS. In conclusion, our study suggested that higher levels of free and bioavailable 25(OH)D were associated with better OS in stage I-III colorectal cancer patients. Moreover, free 25(OH)D could be considered as an independent prognostic biomarker for OS.

Free and Bioavailable 25-Hydroxyvitamin D Levels in Patients With Primary Hyperparathyroidism

To evaluate free and bioavailable 25-hydroxyvitamin D (25[OH]D) levels in primary hyperparathyroidism (PHPT) patients. Fifty PHPT patients and 50 healthy age-, gender-, and body mass index (BMI)-matched control subjects were enrolled. Levels of 25(OH)D were determined by a radioimmunoassay and vitamin D-binding protein (DBP) were determined by an enzyme-linked immunosorbent assay. Free and bioavailable 25(OH)D were calculated utilizing equations that use average binding coefficients for DBP and albumin. There was no significant difference in age and BMI between PHPT patients and controls (P>.05). Levels of 25(OH)D, DBP, and DBP-bound 25(OH)D were lower in PHPT patients compared to controls (P<.01). There was no significant difference in free and bioavailable 25(OH)D levels between PHPT patients and controls (P>.05). Levels of intact parathyroid hormone were inversely correlated with free (r = -0.217; P<.05) and bioavailable 25(OH)D levels (r = -0.296; P<.01). Serum total 25(OH)D levels were lower, while free and bioavailable 25(OH)D remained similar in patients with PHPT compared to controls. We suggest that low 25(OH)D levels might not reflect true vitamin D nutrition status in PHPT patients. 25(OH)D = 25-hydroxyvitamin D BMI = body mass index DBP = vitamin D-binding protein iPTH = intact parathyroid hormone PHPT = primary hyperparathyroidism.

Three doses of vitamin D, bone mineral density, and geometry in older women during modest weight control in a 1-year randomized controlled trial.

Studies examining how bone responds to a standard dose of vitamin D supplementation have been inconsistent. In addition, the effects of higher doses on BMD and quality are not known. Postmenopausal women undergoing weight control to improve health outcomes are particularly at risk for bone loss and might benefit from supplemental vitamin D intake above the recommended allowance. This 1-year-long, randomized, double-blind controlled study addresses whether vitamin D supplementation, in healthy overweight/obese older women, affects BMD and bone structural parameters. In addition, bone turnover and serum total, free, and bioavailable 25-hydroxyvitamin D (25OHD) responses to one of three daily levels of vitamin D3 (600, 2000, 4000IU) with 1.2 Ca g/day during weight control were examined. Fifty-eight women (age, 58 ± 6years; body mass index, 30.2 ± 3.8kg/m2, serum 25OHD, 27.3 ± 4.4ng/mL) were randomized to treatment. After 1year, serum 25OHD concentrations increased to 26.5 ± 4.4, 35.9 ± 4.5, and 41.5 ± 6.9ng/mL, in groups 600, 2000, and 4000IU, respectively, and differed between groups (p < 0.01). Weight change was similar between groups (-3.0 ± 4.1%). Cortical (Ct) thickness of the tibia changed by -1.5 ± 5.1%, +0.6 ± 3.2%, and +2.0 ± 4.5% in groups 600, 2000, and 4000IU, respectively, and each group was significantly different from each other (p < 0.05). The decline in Ct thickness was prevented with higher vitamin D3 supplementation, but there were no other significant changes due to treatment over 1year. Whether these findings translate to changes in biomechanical properties leading to reduced fracture risk should be addressed in future studies.

Serum parathyroid hormone is related to genetic variation in vitamin D binding protein with respect to total, free, and bioavailable 25-hydroxyvitamin D in middle-aged Caucasians – a cross-sectional study

Vitamin D binding protein (DBP) binds vitamin D and its plasma metabolites, including 25-hydroxyvitamin D (25(OH)D), in the circulation. Only a small fraction circulates free (free 25(OH)D). Genetic variation of the GC gene, encoding DBP, has been associated with 25(OH)D concentrations. The roles of DBP and free 25(OH)D concentrations in the biological actions of vitamin D remain unclear. We assessed the relationship between GC gene variants rs4588, rs7041, and rs705124, and serum total 25(OH)D, free and bioavailable 25(OH)D, and serum DBP and parathyroid hormone (PTH) concentrations in 622 Caucasian females (421) and males (201) aged 37–47 years. Concentrations of 25(OH)D, DBP, and PTH were measured from fasting blood samples. Dietary intakes of vitamin D and Ca were evaluated using 1-month food use frequency data, which were collected by a validated Food Frequency Questionnaire on vitamin D and calcium intakes. The subjects filled in the questionnaire covering overall health, medications, use of vitamin D and calcium supplements, and holidays in sunny locations. Three SNPs in the GC gene were genotyped: rs4588, rs7041, and rs705124. The SNPs rs4588 and rs7041 combine to form six common diplotypes. Free and bioavailable 25(OH)D were calculated by using specific binding coefficients. Differences among the diplo- and haplotypes of the GC gene in measures of 25(OH)D, DBP, and PTH were tested by analysis of covariance (ANCOVA) using appropriate covariates. We found significant variation among the SNPs rs4588 and rs7041 variants in DBP, total, free, and bioavailable 25(OH)D, and PTH. DBP concentration was lowest in genotype GC2/2 in both diplotypes and haplotypes (p = 0.039 and 0.039, respectively). The lowest 25(OH)D concentrations were found in diplotype variants GC1S/2, GC1S/F, and GC2/2 (p = 0.033), but free and bioavailable 25(OH)D concentrations were highest in the GC2/2 variant after corrected with a genotype-specific binding coefficient (p < 0.001 in both groups). Surprisingly, one of the lowest PTH concentrations was also present in variant GC2/2 in diplotypes (p = 0.040 of the overall ANCOVA analysis of PTH). Among SNP rs705124, there was a difference only in PTH concentrations (p = 0.013). Our findings indicate that genetic variation of the DBP coding gene, and free concentrations of 25(OH)D may be relevant when vitamin D status, metabolism, and action are investigated.

Vitamin D status in primary hyperparathyroidism: effect of genetic background.

Primary hyperparathyroidism (PHPT) is associated with hypovitaminosis D as assessed by serum total 25-hydroxyvitamin D (TotalD) levels. The aim of this study is to evaluate whether this is also the case for the calculated bioavailable 25-hydroxyvitamin D (BioD) or free 25-hydroxyvitamin D (FreeD), and whether the vitamin D status is influenced by genetic background. We compared vitamin D status of 88 PHPT patients each with a matched healthy family member sharing genetic background, i.e., first-degree relative (FDR), or not, namely an in-law relative (ILR). We compared TotalD and vitamin D-binding protein (DBP), using the latter to calculate BioD and FreeD. We also genotyped two common DBP polymorphisms (rs7041 and rs4588) likely to affect the affinity for and levels of vitamin D metabolites. TotalD was lower (p<0.001) in PHPT (12.3±6.6ng/mL) than either family member group (FDR: 19.4±12.1 and ILR: 23.2±14.1), whether adjusted for DBP or not. DBP levels were also significantly lower (p<0.001) in PHPT (323±73mg/L) versus FDR (377±98) or ILR (382±101). The differences between PHPT and control groups for TotalD, BioD, and FreeD were maintained after adjustment for season, gender, and serum creatinine. 25-hydroxyvitamin D, evaluated as total, free, or bioavailable fractions, is decreased in PHPT. No difference was seen between first-degree relative and in-law controls, suggesting that neither genetic nor non-genetic background greatly influences the genesis of the hypovitaminosis D seen in PHPT.

Serum Bioavailable Vitamin D Concentrations and Bone Mineral Density in Women After Obesity Surgery.

Low bone mass after obesity surgery may arise as a consequence of chronic malabsorption of calcium and vitamin D. However, we have not found any role of serum 25-hydroxyvitamin D or of polymorphisms in the vitamin D receptor gene in previous studies. To investigate the circulating bioavailable 25-hydroxyvitamin D in women after bariatric procedures and its association with bone mass. The study consisted of 91 women on follow-up for 7 ± 2years after bariatric surgery. We measured bone mineral density (BMD), serum parathormone (PTH), 25-hydroxyvitamin D, and vitamin D binding protein (VDBP). All patients were genotyped for two variants in the coding region of VDBP (rs4588 and rs7041). Bioavailable 25-hydroxyvitamin D was calculated in double homozygotes. We found a negative correlation between bioavailable 25-hydroxyvitamin D and PTH (r = -0.373, P = 0.018), but not with BMD at lumbar spine (r = -0.065, P = 0.682) or hip (r = -0.029, P = 0.857). When adjusting by age, similar results were found for PTH (r = -0.441, P = 0.005), BMD at lumbar spine (r = -0.026, P = 0.874) and hip (r = -0.096, P = 0.561). After multivariate linear regression, forcing bioavailable 25-hydroxyvitamin D into the model resulted in a weak significant association with BMD at the lumbar spine (β = - 0.247, P = 0.025). Serum bioavailable 25-hydroxyvitamin D concentrations are not associated with bone mass loss after bariatric surgery in women. The negative association with serum PTH levels suggests that vitamin D supplementation partly improves secondary hyperparathyroidism, yet other mechanisms may contribute to low bone mass after bariatric surgery.

Bioavailable Vitamin D in Obese Children: The Role of Insulin Resistance.

Studies examining vitamin D levels in association with childhood obesity usually do not consider the effect of insulin on vitamin D-binding protein and do not calculate the unbound, bioavailable vitamin D. This study aimed to evaluate in a group of children 1) the concentrations of both total 25-hydroxyvitamin D and bioavailable fraction, and 2) the potential role of insulin resistance in modulating the concentrations of bioavailable vitamin D. Design, Setting, and Patients or Other Participants: This was a cross-sectional study at a University Pediatric Department in which 63 obese children and 21 lean controls were enrolled. Total 25-hydroxyvitamin D and vitamin D-binding protein were measured, two single-nucleotide polymorphisms in the coding region of the vitamin D-binding protein (rs4588 and rs7041) were studied, and the vitamin D bioavailable fraction was calculated. Obese children showed total 25-hydroxyvitamin D levels lower compared with nonobese children (21.3 ± 6.7 ng/mL vs 29.6 ± 11.7 ng/mL; P = .0004). Bioavailable 25-hydroxyvitamin D levels were not different among the two groups (3.1 ± 1.6 ng/mL vs 2.6 ± 1.2 ng/mL; P > .05). Insulin-resistant children showed higher bioavailable levels of 25-hydroxyvitamin D compared with noninsulin-resistant children (3.4 ± 1.4 ng/mL vs 2.0 ± 0.9 ng/mL; P = .013) and an inverse correlation between insulin resistance and vitamin D-binding protein was found (r:= -0.40; P = .024). Obese children present levels of bioavailable 25-hydroxyvitamin D similar to those of normal-weight children due to reduced concentration of vitamin D-binding protein. The insulin resistance could play a role in this reduced concentration.

Vitamin D-Binding Protein in Healthy Pre- and Postmenopausal Women: Relationship with Estradiol Concentrations

To examine the relationship between endogenous serum estradiol and vitamin D-binding protein (DBP) and total, free, and bioavailable 25-hydroxyvitamin D (25OHD) concentrations in pre- and postmenopausal women. In 165 healthy women (ages, 26 to 75 years) not taking any form of exogenous estrogen, the serum concentrations of estradiol, 25OHD, DBP, parathyroid hormone, and albumin were measured. Free and bioavailable 25OHD (free + albumin-bound) levels were calculated from total 25OHD, DBP, and serum albumin levels. Premenopausal women had higher serum 25OHD (31.5 ± 7.9 ng/mL), DBP (45.3 ± 6.2 mg/dL), and estradiol (52.8 ± 35.0 pg/mL) levels than postmenopausal women (26.5 ± 4.9 ng/mL, 41.7 ± 5.7 mg/dL, and 12.9 ± 4.9 pg/mL), respectively. In addition, the calculated free and bioavailable 25OHD levels were higher in pre- than postmenopausal women (P<.05). Serum estradiol correlated with DBP (r = 0.22; P<.01) and total 25OHD (r = 0.27; P<.01). In multivariate regression models (with or without serum 25OHD), estradiol was independently associated with DBP (P<.05). Lower estradiol level is one of the factors that contribute to lower DBP levels in older women. Our data indicate that besides well-known factors such as age, gender, and race, serum estradiol concentrations are also a physiologic predictor of DBP concentration.

Circulating vitamin D binding protein, total, free and bioavailable 25-hydroxyvitamin D and risk of colorectal cancer.

Epidemiological investigation have suggested that there is a significantly inverse association between circulating 25-hydroxyvitamin D (25(OH)D) and the risk for developing colorectal cancer (CRC) in humans. However, little is known about the role of vitamin D binding protein (VDBP) in colorectal carcinogenesis. Blood samples were collected from 212 CRC patients and 212 controls matched with age, gender and blood collection time. We used logistic regression to calculate the odds ratios and 95% confidence intervals for further estimation of the association of the quartiles of VDBP, total, free and bioavailable 25(OH)D with CRC risk. The results revealed that there was no significant association between circulating VDBP concentrations and CRC in the present study, and that a negative association existed between total 25(OH)D and the risk of CRC, which was unchanged after adjustment for VDBP. Higher levels of free and bioavailable 25(OH)D were significantly associated with decreased risk of CRC. After stratifying by VDBP, high levels of total, free and bioavailable 25(OH)D were associated significantly with decreased CRC risk among participants with circulating VDBP below the median. These findings indicate that VDBP is not directly associated with the risk of CRC, but it modulates circulating free and bioavailable 25(OH)D concentration.

Prospective Study of Vitamin D Status at Initiation of Care in Critically Ill Surgical Patients and Risk of 90-Day Mortality*

1) To characterize vitamin D status at initiation of critical care in surgical ICU patients and 2) to determine whether this vitamin D status is associated with the risk of prolonged hospital length of stay, 90-day readmission, and 90-day mortality. Prospective cohort study. A teaching hospital in Boston, MA. Hundred surgical ICU patients. None. Mean (± SD) serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were 17 ± 8 ng/mL and 32 ± 19 pg/mL, respectively. Mean calculated bioavailable 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were 2.5 ± 2.0 ng/mL and 6.6 ± 5.3 pg/mL, respectively. Receiver-operating characteristic curve analysis demonstrated that all of four vitamin D measures predicted the three clinical outcomes; total 25-hydroxyvitamin D was not inferior to the other measures. Median (interquartile range) hospital length of stay was 11 days (8-19 d). Poisson regression analysis, adjusted for biologically plausible covariates, demonstrated an association of total 25-hydroxyvitamin D with hospital length of stay (incident rate ratio per 1 ng/mL, 0.98; 95% CI, 0.97-0.98). The 90-day readmission and mortality rates were 24% and 22%, respectively. Even after adjustment for biologically plausible covariates, there remained significant associations of total 25-hydroxyvitamin D with readmission (odds ratio per 1 ng/mL, 0.84; 95% CI, 0.74-0.95) and mortality (odds ratio per 1 ng/mL, 0.84; 95% CI, 0.73-0.97). Serum 25-hydroxyvitamin D levels within 24 hours of ICU admission may identify patients at high risk for prolonged hospitalization, readmission, and mortality. Randomized trials are needed to assess whether vitamin D supplementation can improve these clinically relevant outcomes in surgical ICU patients.

Associations among vitamin D binding protein polymorphisms and concentrations and total, free, and bioavailable serum 25-hydroxyvitamin D concentrations in finnish adults

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Serum free and bio-available 25-hydroxyvitamin D correlate better with bone density than serum total 25-hydroxyvitamin D

In the circulation 25-hydroxyvitamin D (25(OH)D) is bound to vitamin D-binding protein (DBP) and albumin. Only a small fraction is in the unbound, free form. According to the ‘free-hormone-hypothesis’ only the free form is biologically active. Genetic differences in DBP may affect the binding to 25(OH)D and thereby the amount of free 25(OH)D. In the present study sera were obtained from 265 postmenopausal women with low bone mass density (BMD). Serum 25(OH)D, DBP and albumin were measured and the free and bio-available (free + albumin-bound) 25(OH)D calculated. Based on genotyping of the polymorphisms rs7041 and rs4588, the six common DBP phenotypes were identified and the free and bio-available 25(OH)D calculated according to the corresponding binding coefficients. Relations between measures of 25(OH)D and PTH and BMD were evaluated with linear regression adjusted for age and BMI. The calculated amount of free and bio-available 25(OH)D was 0.03% and 13.1%, respectively, of the measured total serum 25(OH)D. Adjusting for DBP phenotype affected the calculated free and bio-available 25(OH)D levels up to 37.5%. All measures of 25(OH)D correlated significantly with PTH, whereas a significant association with BMD was only seen for the free and bio-available 25(OH)D measures. Adjusting for the DBP phenotypes improved the associations. These relations were almost exclusively seen in subjects not using vitamin D and/or calcium supplements. In conclusion, the free and bio-available forms of 25(OH)D may be a more informative measure of vitamin D status than total 25(OH)D. Adjustment for DBP phenotype may improve this further.

Insulin Resistance Indices Are Inversely Associated With Vitamin D Binding Protein Concentrations

We hypothesized that, similar to the coordinated homeostatic regulation of most hormones, the concentration of free and bioavailable 25-hydroxyvitamin D [25(OH)D] will be tightly controlled by total 25(OH)D and vitamin D binding protein (VDBP) and that the VDBP concentrations will be associated with insulin resistance status. Our primary objective was to investigate associations between total, free, and bioavailable 25(OH)D and VDBP. We also evaluated the relationships of VDBP with insulin resistance indices. The study design was cross-sectional in the setting of a university children's hospital. The relative concentration of bioavailable 25(OH)D to total 25(OH)D [bioavailable 25(OH)D/total 25(OH)D was expressed as a percentage [percentage bioavailable 25(OH)D]. Subjects were 47, postmenarchal, female adolescents, with a mean age of 15.8±1.4 years, a mean body mass index of 23.1±4.0 kg/m2. The total 25(OH)D was strongly associated with VDBP (rho=0.57, P<.0001). At lower total 25(OH)D concentrations, the concentration of bioavailable 25(OH)D relative to total 25(OH)D was higher (23.8% vs 14.9%, P<.0001), whereas the relative concentration of free 25(OH)D was similar (P=.44). VDBP was inversely associated with fasting insulin (rho=-0.51, P=.0003) and homeostatic model assessment of basal insulin resistance (rho=-0.45, P=.002) and positively with whole-body insulin sensitivity (rho=0.33, P=.02); these relationships persisted after adjusting for percentage fat and attenuated after adjusting for race. Our data suggest that VDBP concentrations are regulated by total 25(OH)D levels to maintain adequate concentrations of bioavailable 25(OH)D. VDBP concentrations are inversely associated with hyperinsulinemia and insulin resistance.

Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans

BackgroundLow levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D–binding protein has not been considered in the assessment of vitamin D deficiency.MethodsIn the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D–binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D–binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants.ResultsMean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D–binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D–binding protein, 168±3 μg per milliliter vs. 337±5 μg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D–binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P=0.71) and within quintiles of parathyroid hormone concentration.ConclusionsCommunity-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D–binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.)