Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations

Schwartz, Janice B.; Gallagher, J. Christopher; Jorde, Rolf; Berg, Vivian; Walsh, Jennifer; Eastell, Richard; Evans, Amy; Bowles, Simon; Naylor, Kim; Jones, Kerry S.; Schoenmakers, Inez; Holick, Michael F.; Orwoll, Eric S.; Nielson, Carrie M.; Kaufmann, Martin; Jones, Glenville; Bouillon, Roger; Lai, Jennifer C.; Verotta, Davide; Bikle, Daniel D.

doi:10.1210/jc.2018-00295

Cited by 79 publications

(72 citation statements)

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“…In a recent cross‐sectional multicentre study of 1661 subjects, F25D was measured in 279 normal subjects, 90 patients with cirrhosis, 20 pregnant, 479 prediabetes and 79 nursing home patients. This study showed that mean levels of F25D were 10.75 pmol L −1 in normal subjects and were significantly lower compared to patients with cirrhosis, with a mean 17.75 pmol L −1 and prediabetes, with a mean 13.75 pnol L −1 .…”

Section: Discussionmentioning

confidence: 48%

“…Although a previous study reported lower levels of serum DBP in African American people [7], we know that the explanation for this result was due to the monoclonal antibody used in the assay that did not detect all of the DBP genotypes, whereas the polyclonal antibody detects all DBP genotypes [16]. It has been reported that vitamin D showed a small nonsignificant decrease in serum DBP levels in a study in Norway of vitamin D 20 000 IU given weekly [15].…”

Section: Discussionmentioning

confidence: 85%

“…In a recent cross-sectional multicentre study of 1661 subjects, F25D was measured in 279 normal subjects, 90 patients with cirrhosis, 20 pregnant, 479 prediabetes and 79 nursing home patients. [16] This study showed that mean levels of F25D were 10.75 pmol L À1 in normal subjects and were significantly lower compared to patients with There are a few studies that show F25D to be a better clinical measurement than T25D. In a short 12-week study of weekly 50 000 IU D2 or D3, the decrease in serum PTH at 4 weeks was more highly correlated with F25D than T25D but after 8-12 weeks of treatment this was no longer true [17].…”

Section: Discussionmentioning

confidence: 99%

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Effect of vitamin D supplementation on total and free 25 hydroxyvitamin D and parathyroid hormone. An analysis of two randomized controlled trials

Smith

Gallagher

2019

J Intern Med

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Background It is questionable as to whether total serum 25 hydroxyvitamin D (T25D) levels are lower in African Americans. We measured serum T25D, free 25hydroxyvitamin D (F25D) and serum parathyroid hormone (PTH) in African American and Caucasian women and studied the effect of vitamin D dosing to determine if differences by race or age occur. Methods Healthy young and older Caucasian and African American women who were vitamin D insufficient were randomized in two clinical trials to escalating daily doses of vitamin D from 400 to 4800 IU and placebo for 12 months. Results Baseline F25D and T25D were significantly lower in young but not older African American compared to Caucasian women. At baseline, the rate of change, or slope, in F25D with T25D was significantly greater in younger women than in older women, but difference in the rate of change in F25D with T25D is similar in African American and Caucasian women. After vitamin D supplementation, there was an increase in F25D, and the dose response was not significantly different by age or race. The ratio of F25D/T25D decreased in all groups once T25D exceeded ~60 nmol L−1. There was a progressive decrease in serum PTH with increasing vitamin D doses and the per cent change was similar for F25D and T25D. Conclusion Serum F25D and T25D are lower in younger African American women, and since dietary vitamin D is similar in the groups, it is likely that the cause of low serum 25OHD in African American women is due to reduced UV exposure and reduced skin production of vitamin D.

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Effect of vitamin D supplementation on total and free 25 hydroxyvitamin D and parathyroid hormone. An analysis of two randomized controlled trials

Smith

Gallagher

2019

J Intern Med

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“…The measurements of free 25OHD obtained with the immunoassay are well consistent with the measurements using symmetric dialysis and centrifugal ultrafiltration. (22,23,26,27) The intraassay coefficients of variance were, respectively, 11.2% and 3.1% for total and free 25OHD for masked, replicate quality control samples.…”

Section: Determination Of 25ohd Fractionsmentioning

confidence: 96%

“…Hence, total 25OHD measurements might be misleading in the settings of liver pathology, whereas analysis of free and/or bioavailable 25OHD could provide further insights. (20)(21)(22)(23) Nevertheless, whether free or bioavailable 25OHD brings additional benefits over routine total 25OHD estimation in relation to the prognosis of liver cancer is unclear.…”

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confidence: 99%

Serum Bioavailable, Rather Than Total, 25‐hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival

Fang

Long²,

Zhang

et al. 2020

Hepatology

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BaCKgRoUND aND aIMS:Free and bioavailable 25-hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival. appRoaCH aND ReSUltS: We included 1,031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum-free 25OHD levels were measured using a two-step enzyme-linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer-specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C-reactive protein, Barcelona Clinic Liver Cancer stage, and cancer treatment. The multivariable-adjusted HRs in the highest versus lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend = 0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend = 0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS. CoNClUSIoNS:Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population-based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis. (Hepatology 2020;0:1-14).

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The Free Hormone Hypothesis: When, Why, and How to Measure the Free Hormone Levels to Assess Vitamin D, Thyroid, Sex Hormone, and Cortisol Status

Bikle

2020

JBMR Plus

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The free hormone hypothesis postulates that only the nonbound fraction (the free fraction) of hormones that otherwise circulate in blood bound to their carrier proteins is able to enter cells and exert biologic effects. In this review, I will examine four hormone groups-vitamin D metabolites (especially 25OHD), thyroid hormones (especially thyroxine [T4]), sex steroids (especially testosterone), and glucocorticoids (especially cortisol)-that are bound to various degrees to their respective binding proteins-vitamin D-binding protein (DBP), thyroid-binding globulin (TBG), sex hormone-binding globulin (SHBG), and cortisol-binding globulin (CBG)-for which a strong case can be made that measurement of the free hormone level provides a better assessment of hormonal status than the measurement of total hormonal levels under conditions in which the binding proteins are affected in levels or affinities for the hormones to which they bind. I will discuss the rationale for this argument based on the free hormone hypothesis, discuss potential exceptions to the free hormone hypothesis, and review functions of the binding proteins that may be independent of their transport role. I will then review the complications involved with measuring the free hormone levels and the efforts to calculate those levels based on estimates of binding constants and levels of both total hormone and total binding protein. In this review, the major focus will be on DBP and free 25OHD, but the parallels and differences with the other binding proteins and hormones will be highlighted. Vitamin D and its metabolites, thyroid hormones, sex steroids, and glucocorticoids are transported in blood bound to serum proteins. The tightness of binding varies depending on the hormone and the binding protein such that the percent free varies from 0.03% for T4 and 25OHD to 4% for cortisol with testosterone at 2%. Although the major function of the primary carrier proteins (DBP, TBG, SHBG, and CBG) may be to transport their respective lipophilic hormones within the aqueous media that is plasma, these proteins may have other functions independent of their transport function. For most tissues, these hormones enter the cell as the free hormone presumably by diffusion (the free hormone hypothesis), although a few tissues such as the kidney and reproductive tissues express megalin/cubilin enabling by endocytosis protein-bound hormone to enter the cell. Measuring the free levels of these proteinbound hormones is likely to provide a better measure of the true hormone status than measuring the total levels in situations where the levels and/or affinities of the binding proteins are altered. Methods to measure free hormone levels are problematic as the free levels can be quite low, the methods require separation of bound and free that could disturb the steady state, and the means of separating bound and free are prone to error. Calculation of free levels using existing data for association constants between the hormone and its binding protein are likewise prone to error beca...

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Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations

Abstract: Total 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.

Cited by 79 publications

References 37 publications

Effect of vitamin D supplementation on total and free 25 hydroxyvitamin D and parathyroid hormone. An analysis of two randomized controlled trials

Effect of vitamin D supplementation on total and free 25 hydroxyvitamin D and parathyroid hormone. An analysis of two randomized controlled trials

Serum Bioavailable, Rather Than Total, 25‐hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival

The Free Hormone Hypothesis: When, Why, and How to Measure the Free Hormone Levels to Assess Vitamin D, Thyroid, Sex Hormone, and Cortisol Status

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