Janice B Schwartz1, J Christopher Gallagher2, Rolf Jorde3,4, Vivian Berg4, Jennifer Walsh5, Richard Eastell5, Amy L Evans5, Simon Bowles5, Kim E Naylor5, Kerry S Jones6, Inez Schoenmakers6,7,8, Michael Holick9, Eric Orwoll10, Carrie Nielson10, Martin Kaufmann11, Glenville Jones11, Roger Bouillon12, Jennifer Lai1, Davide Verotta13, Daniel Bikle1,14. 1. Department of Medicine, University of California, San Francisco, California. 2. Creighton University Medical Center, Omaha, Nebraska. 3. Tromso Endocrine Research Group, UiT the Arctic University of Norway, Tromsø, Norway. 4. Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway. 5. Mellanby Centre for Bone Research, University of Sheffield, Sheffield, United Kingdom. 6. MRC Elsie Widdowson Laboratory, Cambridge, United Kingdom. 7. Department of Medicine, Norwich Medical School, Faculty of Medicine and Health Sciences, Norwich, United Kingdom. 8. University of East Anglia, Norwich, United Kingdom. 9. Boston University School of Medicine, Boston, Massachusetts. 10. Oregon Health and Science University, Portland, Oregon. 11. Queen's University, Kingston, Ontario, Canada. 12. KuLeuven, Gasthuisbert, Leuven, Belgium. 13. Departments of Bioengineering and Therapeutic Sciences and Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. 14. Department of Dermatology, University of California, San Francisco, San Francisco, California.
Abstract
Context: The optimal measure of vitamin D status is unknown. Objective: To directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans. Design: Cross-sectional analysis. Setting: Seven academic sites. Patients: A total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79). Interventions: Merge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype. Main outcome measures: Distribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates). Results: Free 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype. Conclusions: 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.
Context: The optimal measure of vitamin D status is unknown. Objective: To directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans. Design: Cross-sectional analysis. Setting: Seven academic sites. Patients: A total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79). Interventions: Merge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype. Main outcome measures: Distribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates). Results: Free 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype. Conclusions: 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.
Authors: John Aloia; Ruban Dhaliwal; Mageda Mikhail; Albert Shieh; Alexandra Stolberg; Louis Ragolia; Melissa Fazzari; Steven A Abrams Journal: J Clin Endocrinol Metab Date: 2015-08-27 Impact factor: 5.958
Authors: J B Schwartz; J Lai; B Lizaola; L Kane; P Weyland; N A Terrault; N Stotland; D Bikle Journal: J Steroid Biochem Mol Biol Date: 2013-11-15 Impact factor: 4.292
Authors: Eric Orwoll; Janet Babich Blank; Elizabeth Barrett-Connor; Jane Cauley; Steven Cummings; Kristine Ensrud; Cora Lewis; Peggy M Cawthon; Robert Marcus; Lynn M Marshall; Joan McGowan; Kathy Phipps; Sherry Sherman; Marcia L Stefanick; Katie Stone Journal: Contemp Clin Trials Date: 2005-10 Impact factor: 2.226
Authors: J B Schwartz; J Lai; B Lizaola; L Kane; S Markova; P Weyland; N A Terrault; N Stotland; D Bikle Journal: J Clin Endocrinol Metab Date: 2014-01-31 Impact factor: 5.958
Authors: Michael F Holick; Rachael M Biancuzzo; Tai C Chen; Ellen K Klein; Azzie Young; Douglass Bibuld; Richard Reitz; Wael Salameh; Allen Ameri; Andrew D Tannenbaum Journal: J Clin Endocrinol Metab Date: 2007-12-18 Impact factor: 5.958
Authors: Christine A Simpson; Jane H Zhang; Dirk Vanderschueren; Lei Fu; Teresita C Pennestri; Roger Bouillon; David E C Cole; Thomas O Carpenter Journal: J Clin Endocrinol Metab Date: 2020-04-01 Impact factor: 5.958
Authors: JoAnn E Manson; Shari S Bassuk; Nancy R Cook; I-Min Lee; Samia Mora; Christine M Albert; Julie E Buring Journal: Circ Res Date: 2020-01-02 Impact factor: 17.367