Why should we measure free 25(OH) vitamin D? Tsuprykov, Oleg; Chen, Xin; Hocher, Carl-Friedrich ...
The Journal of steroid biochemistry and molecular biology,
June 2018, 2018-06-00, 20180601, Volume:
180
Journal Article
Peer reviewed
•Free 25(OH)D is superior over total 25(OH)D in liver and kidney pathologies, and in pregnancy.•In other health conditions the literature does not clear provide evidences of such benefits.•However, ...measuring both free and total 25(OH)D is an ideal choice to assess real vitamin D status.
Vitamin D, either in its D2 or D3 form, is essential for normal human development during intrauterine life, kidney function and bone health. Vitamin D deficiency has also been linked to cancer development and some autoimmune diseases. Given this huge impact of vitamin D on human health, it is important for daily clinical practice and clinical research to have reliable tools to judge on the vitamin D status. The major circulating form of vitamin D is 25-hydroxyvitamin D (25(OH)D), although it is not the most active metabolite, the concentrations of total 25-hydroxyvitamin D in the serum are currently routinely used in clinical practice to assess vitamin D status. In the circulation, vitamin D – like other steroid hormones – is bound tightly to a special carrier – vitamin D-binding protein (DBP). Smaller amounts are bound to blood proteins – albumin and lipoproteins. Only very tiny amounts of the total vitamin D are free and potentially biologically active. Currently used vitamin D assays do not distinguish between the three forms of vitamin D – DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D. Diseases or conditions that affect the synthesis of DBP or albumin thus have a huge impact on the amount of circulating total vitamin D. DBP and albumin are synthesized in the liver, hence all patients with an impairment of liver function have alterations in their total vitamin D blood concentrations, while free vitamin D levels remain mostly constant. Sex steroids, in particular estrogens, stimulate the synthesis of DBP. This explains why total vitamin D concentrations are higher during pregnancy as compared to non-pregnant women, while the concentrations of free vitamin D remain similar in both groups of women. The vitamin D-DBP as well as vitamin D-albumin complexes are filtered through the glomeruli and re-uptaken by megalin in the proximal tubule. Therefore, all acute and chronic kidney diseases that are characterized by a tubular damage, are associated with a loss of vitamin D-DBP complexes in the urine. Finally, the gene encoding DBP protein is highly polymorphic in different human racial groups. In the current review, we will discuss how liver function, estrogens, kidney function and the genetic background might influence total circulating vitamin D levels and will discuss what vitamin D metabolite is more appropriate to measure under these conditions: free vitamin D or total vitamin D.
Vitamin D deficiency is a worldwide pandemic. The aim of this study was to evaluate associations of plasma 25(OH)D levels with the likelihood of coronavirus disease 2019 (COVID‐19) infection and ...hospitalization. The study population included the 14 000 members of Leumit Health Services, who were tested for COVID‐19 infection from February 1st to April 30th, 2020, and who had at least one previous blood test for the plasma 25(OH)D level. ‘Suboptimal’ or ‘low’ plasma 25(OH)D level was defined as plasma 25‐hydroxyvitamin D, or 25(OH)D, concentration below the level of 30 ng/mL. Of 7807 individuals, 782 (10.02%) were COVID‐19‐positive, and 7025 (89.98%) COVID‐19‐negative. The mean plasma vitamin D level was significantly lower among those who tested positive than negative for COVID‐19 19.00 ng/mL (95% confidence interval (CI) 18.41–19.59) vs. 20.55 (95% CI: 20.32–20.78). Univariate analysis demonstrated an association between the low plasma 25(OH)D level and increased likelihood of COVID‐19 infection crude odds ratio (OR) of 1.58 (95% CI: 1.24–2.01, P < 0.001), and of hospitalization due to the SARS‐CoV‐2 virus crude OR of 2.09 (95% CI: 1.01–4.30, P < 0.05). In multivariate analyses that controlled for demographic variables, and psychiatric and somatic disorders, the adjusted OR of COVID‐19 infection 1.45 (95% CI: 1.08–1.95, P < 0.001) and of hospitalization due to the SARS‐CoV‐2 virus 1.95 (95% CI: 0.98–4.845, P = 0.061) were preserved. In the multivariate analyses, age over 50 years, male gender and low–medium socioeconomic status were also positively associated with the risk of COVID‐19 infection; age over 50 years was positively associated with the likelihood of hospitalization due to COVID‐19. We concluded that low plasma 25(OH)D levels appear to be an independent risk factor for COVID‐19 infection and hospitalization.
Vitamin D deficiency is recognized as a significant health concern in which there is heightened interest because of the potential impact on COVID‐19 risk. In a landmark study involving a large Israeli population, Milana Morgenstern and colleagues found that the plasma level of vitamin D is lower among individuals who have tested positive for COVID‐19 and have been hospitalized. This indicates that low vitamin D status is an independent risk factor for severe COVID‐19; male gender and low‐medium socioeconomic status were also shown to be positively associated with the risk of infection. Moreover, age (being > 50 years old) was associated with COVID‐19 hospitalization.
•Higher prevalence of vitamin D deficiency was demonstrated in PD patients compared to control subjects.•Severity and stage of Parkinson’s disease were significantly associated with lower 25OHD ...concentration.•A higher frequency of G allele of CYP2R1 polymorphism was observed in all subgroups with vitamin D deficiency.
Vitamin D is a steroid hormone, known to be involved in the pathogenesis of various neurodegenerative disorders, including Parkinson’s disease (PD).
We aimed to clarify the relationship between hypovitaminosis D and the predisposition for PD and its clinical presentation. An additional aim was to examine the specific gene polymorphisms associated with vitamin D level.
Total level of 25(OH)-vitamin D (25(OH)D) was measured in the serum of parkinsonian patients (n = 113) and controls (n = 82) using a commercial immunoassay. Genetic analyses were performed using Taqman assays on Real Time PCR amplification system.
Higher frequency of vitamin D deficiency (<50 nmol/L) was observed in PD patients, compared to controls (40.7% and 23.2%, respectively, P = 0.010). It was also a positive predictive marker of PD (OR, 2.27; 95% CI, 1.206–4.298; P < 0.011). Significantly higher UPDRS (35.85 ± 1.35 and 32.09 ± 0.99, respectively, P = 0.023) and HY scores (2(1.5–2.5) and 1.5(1.0–2.0), respectively, P = 0.005) were present in patients with 25(OH)D level < 50 nmol/L compared to patients with 25(OH)D level ≥ 50 nmol/L. Despite some trends observed, differences in allelic and genotypic distribution between controls and patients, as well as between subgroups, did not reach the level of significance (P > 0.05).
Findings of this study confirm the hypothesis of a significant relationship between hypovitaminosis D and PD. We demonstrated higher prevalence of vitamin D deficiency in PD patients, as well as its predictive potential for the onset and progression of PD.
Our goal was to determine total and directly measured free 25-hydroxy vitamin D (25(OH)D) serum levels in humans with a range of 25(OH)D levels and clinical conditions associated with low and high ...vitamin D binding protein levels. Serum samples and clinical data were collected from 106 subjects: 62 without cirrhosis or pregnancy, 24 cirrhotic patients with albumin <2.9g/dL, and 20 pregnant women. Total 25(OH)D (LC/MS/MS) and “free” 25(OH)D (immunoassay) were measured. Total 25(OH)D was significantly lower in liver disease patients but free 25(OH)D concentrations were significantly higher in this group (p<.001). Neither total nor free 25(OH)D concentrations were significantly different in pregnant women vs. the comparator group. There were significant direct positive relationships between free 25(OH)D and total 25(OH)D concentrations for the entire dataset and for each group (p<.0001), however slopes of relationships differed in the cirrhotic group compared to pregnant women or the comparator group. In cirrhotics: y (free 25(OH)D)=2.52+0.29×X(total 25 (OH)D), r2=.51, p<.001; y=1.45+0.09×X; r2=.77, p<.0001 for pregnant women; and y=1.11+0.12×X; r2=.72, p<.0001 for the comparator group). Conclusions: directly measured free 25(OH)D serum concentrations and relationships between total and free 25(OH)D vary with clinical conditions, and may differ from those predicted by indirect estimation methods.
This article is part of a Special Issue entitled ‘Vitamin D Workshop’.
Introduction
: Low 25-hydroxyvitamin D (25(OH)D) level in hemodialysis (HD) patients is associated with high bone turnover, secondary hyperparathyroidism, and decreased bone mineral density (BMD).
...Objective
: To investigate the efficacy of equivalent doses of pulse oral cholecalciferol versus intramuscular (IM) cholecalciferol in correcting serum 25(OH)D levels in HD patients with vitamin D deficiency.
Patients and Methods
: In a prospective randomized open-label clinical trial, 80 HD patients with 25(OH)D level <20 ng/mL and serum intact parathyroid hormone (iPTH) level >100 pg/mL were enrolled in the study. Patients were divided into two groups. Group I: 40 HD patients received oral cholecalciferol 25 000 IU weekly for 12 weeks. Group II: 40 HD patients received a single dose of IM cholecalciferol 300 000 IU. Patients were maintained on their regular medications as alfacalcidol or phosphate binders. Serum calcium, phosphorus, 25(OH)D, alkaline phosphatase and iPTH were monitored at 0, 6
th
, and 12
th
week of intervention.
Results
: Significant increase in serum 25(OH)D level in group II patients who received IM (intramuscular) cholecalciferol, with delta mean a change of vitamin D level was 2.92 ±7.29 ng/mL over three months in comparison to the insignificant change in oral cholecalciferol group. Additionally there was a significant increase in the mean of serum calcium in comparison to oral cholecalciferol group, while we found a statistically significant decrease in alkaline phosphatase level in both groups too (P<0.05). The mean of iPTH levels was reduced significantly with IM cholecalciferol dose (1064.00 ± 787.60 to 609.9 ± 551.41 pg/mL;
P
<0.05).
Conclusion
: Intramuscular cholecalciferol dose is more effective at increasing 25(OH) D levels in dialysis patients than oral supplementation, achieves more increase in serum calcium and reduce iPTH levels. However, the longer duration of treatment is required to achieve recommended levels of vitamin D and suppress high iPTH levels.
To evaluate the relationship between 25-hydroxy vitamin D (25(OH)D) levels and disease severity in hospitalized COVID-19 positive pregnant women
The COVID-19 (+) pregnant women (confirmed by PCR ...test) were classified as asymptomatic, mild symptomatic, and severe disease according to their symptoms and laboratory results. Severe COVID-19 criteria were respiratory symptoms and/or findings. The following laboratory results were considered as poor prognostic factors: the number of lymphocytes <800/µl and/or CRP value >10 times the upper limit of the normal range and/or ferritin value >500 ng/ml and/or D-Dimer value >1000 µg/l. The patients were divided into two groups; asymptomatic or mild symptomatic group (Group 1), and severe disease and/or poor prognostic factor group (Group 2). The 25(OH)D levels were compared between groups. ROC curve analysis was used to analyze the cutoff value for vitamin D to predict the severity of COVID-19.
25(OH)D levels were found to be statistically significantly lower in group 2 (15.5 (10.25) ng/ml in Group 1, 13 (12) ng/ml in Group 2, p = .010). The 25(OH)D level under 14.5 ng/ml was associated with severe COVID-19 and/or poor prognostic factors (p = .010). The risk of severe COVID-19 and/or having poor prognostic factors was 1.87 times higher among pregnant women who had 25(OH)D levels below 14.5 ng/ml. This value was found to have 54.1% sensitivity and 61.3% specificity in predicting severe COVID-19 and/or poor prognostic laboratory findings in pregnant women
There is a relationship between vitamin D status and the severity of COVID-19 in pregnant women. During the pandemic period, vitamin D supplementation for pregnant women should gain more importance.
•Two siblings from consaguineous parents with a novel CYP2R1 nutation leads to complete 25(OH)D deficiency.•The first CYP2R1 mutation reported in a Sudanese family and the 6th ever described.•With ...the high consanguinity rate in the Middle East and Africa, awareness should be elevated for genetic rickets.
The aim of this study was to identify the genetic basis of two female siblings - born to consanguineous Sudanese parents - diagnosed clinically as having the rare condition of 25-hydroxylase deficiency (vitamin D-dependent rickets type 1B). The initial diagnosis was established based on clinical data, laboratory and radiological findings retrospectively. Primers for all exons (5) of human CYP2R1 (NM_024514) were generated followed by Sanger sequencing on exons 1–5 for both girls and their parents. Homozygosity for a point mutation (c.85C > T) was detected, leading to a nonsynonymous variant at position 29 in exon 1, resulting in a premature stop codon (p.Q29X). This is a previously unknown variant that leads to a severely truncated protein and predicted to be among the 0.1 % most deleterious genomic variants(CADD score 36). To our knowledge, this family represents the first case series from Sudan with a confirmed CYP2R1 gene mutation and the 6th world-wide. With the lack of genetic facilities, diagnosis should be suspected by the persistently low 25 hydroxyvitamin D level in spite of proper treatment and after ruling out liver disease and malabsorption. Patients in this case series showed healing of rickets when treated with high doses of 1,25-dihydroxyvitamin D3 (1,25(OH)D3; calcitriol) and oral calcium.
•The T2DM patients with painful DPN have significantly higher prevalence of severe deficiency than without painful DPN.•The T2DM patients with painful DPN have significantly lower vitamin D level ...than without painful DPN.•The lower vitamin D deficiency and higher HbA1c are predictors of painful DPN.•The vitamin D levels is not correlated to inflammatory status in painful DPN.•Duration of sun exposure was only the controlling factor for vitamin D in painful DPN patients.
Several clinical studies have shown an association between vitamin D deficiency and painful diabetic peripheral neuropathy (DPN). However, it is still unclear whether vitamin D status and inflammatory markers correlate in patients with painful DPN. In this context, we aimed to investigate the associations between serum vitamin D levels and inflammatory status in Kurdish type 2 diabetes patients (T2DM) with painful DPN and without painful DPN. A clinical case-control study was conducted on 86 Kurdish patients with T2DM. The patients were divided into two groups: the case group consisted of 45 patients with painful DPN and the control group consisted of 41 age- and sex-matched diabetics without DPN. In T2DM patients with and without painful DPN, the prevalence of severe vitamin D deficiency was observed in 46.67% and 21.95% of the patients, respectively (p = 0.0283). The mean serum 25(OH)-vitamin D level in patients with painful DPN (mean = 12.00, SD = 5.78) was significantly lower than in patients without DPN (mean = 16.36, SD = 7.86; p = 0.0041). Regression analysis revealed that vitamin D deficiency (p = 0.0120) and higher glycated hemoglobin (HbA1c) (p = 0.00003) were identified as predictive risk factors for painful DPN. However, there was no significant association between inflammatory status and vitamin D levels. The duration of sun exposure was the only controlling factor for vitamin D in painful DPN patients. In the Kurdish population, lower vitamin D and high HbA1c levels were predictive factors for painful DPN.
To assess the effect of maternal serum 25(OH)-vitamin D levels during the second trimester of pregnancy on the risk for gestational diabetes (GDM), pregnancy and infantile outcomes.
This study is ...based on the Western Australian Pregnancy Cohort (Raine) study. Maternal serum 25(OH)-vitamin D concentrations of 890 pregnant women were evaluated at 18 weeks pregnancy and grouped into serum Vitamin D quartiles (>30, 30–49, 50–74 and >75 nmol/L). Results: Participants with de-seasonalized 25 (OH)-vitamin D levels <30 nmol/L were more likely to develop GDM, but not after controlling for ethnicity. Women with high body mass index (BMI) >30 were at a greater risk of developing GDM. Additionally, women with GDM were at a greater risk of primary caesarean delivery. Maternal serum levels of 25(OH)-vitamin D were positively associated with birth weight, body length and head circumference of the neonate.
Low maternal serum levels of 25(OH)-vitamin D are associated with GDM gestational diabetes, and race/ethnicity may modify this relationship. High pre-gestational BMI may predict GDM risk. GDM in pregnancy may increase the risk for delivery by caesarean section. Maternal 25(OH)-vitamin D is associated with anthropometric measures of the neonate.
Much concern was directed toward exploring the relationship between vitamin D and migraine. There is strong evidence that vitamin D supplementation can decrease frequency, severity, and duration of ...migraine headache attacks. The aim of this work was to investigate the difference in serum levels of 25 (OH)-vitamin D between patients with migraine and healthy controls, to determine the differences in headache characteristics according to vitamin D status, and to correlate serum 25 (OH)-vitamin D level with duration, frequency, and severity of migraine headache attacks.
This is a case-control study conducted on 40 patients diagnosed with migraine and 40 healthy controls. History was taken from patients with migraine regarding headache characteristics. Migraine severity scale (MIGSEV) and Headache Impact Test-6 (HIT-6) were used for migraine assessment. Serum 25(OH)-vitamin D was measured for all patients and controls using enzyme-linked immunosorbent assay (ELISA).
Patients with migraine had significantly lower 25(OH)-vitamin D serum level in comparison to controls (
-value=0.019). The incidence of aura, phonophobia/photophobia, autonomic manifestations, allodynia, and resistance to medications were significantly higher in migraineurs with vitamin D deficiency than those with normal vitamin D. There was a statistically significant negative correlation between 25(OH)-vitamin D serum level and attack duration in hours (
-value˂0.001), frequency of the attacks/month (
-value˂0.001), MIGSEV scale (
-value=0.001), and HIT-6 scale (
-value=0.001).
Patients with migraine had significant vitamin D deficiency compared to healthy controls. Such deficiency significantly affects headache characteristics, duration, frequency, and severity of headache attacks.
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