Why 25-dehydroxyvitamin D is a negative acute-phase reactant
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* Maria J. Antonelli
* Irving Kushner
* Murray Epstein

**To the Editor:** In previous publications, we presented evidence that 25-dehydroxyvitamin D (25[OH]D) in serum behaves as a negative acute-phase reactant, ie, that its concentration decreases in the presence of inflammatory states.1,2 Low levels may thus reflect low vitamin D stores or inflammation, complicating the clinical interpretation of test results.

We have recently become aware of the mechanism underlying this phenomenon: less than 1% of circulating 25(OH)D exists in unbound form, and the majority is tightly bound to vitamin D binding protein, while 10% to 15% is bound to albumin. Both are negative acute-phase proteins.3–5 As the serum concentrations of these proteins decrease, so does that of 25(OH)D. Similarly, the positive acute-phase behavior of copper is explained by the fact that it is bound to ceruloplasmin, a positive acute-phase protein.6

*   Copyright © 2023 The Cleveland Clinic Foundation. All Rights Reserved.

## REFERENCES

1.  Antonelli M, Kushner I. Low serum levels of 25-hydroxyvitamin D accompany severe COVID-19 because it is a negative acute phase reactant. Am J Med Sci 2021; 362(3):333–335. doi:10.1016/j.amjms.2021.06.005
    
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2.  Antonelli MJ, Kushner I, Epstein M. The constellation of vitamin D, the acute-phase response, and inflammation. Cleve Clin J Med 2023; 90(2):85–89. doi:10.3949/ccjm.90a.22048
    
    [FREE Full Text](http://www.ccjm.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NToiY2Nqb20iO3M6NToicmVzaWQiO3M6NzoiOTAvMi84NSI7czo0OiJhdG9tIjtzOjIwOiIvY2Nqb20vOTAvOS81MzUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

3.  Yousefzadeh P, Shapses SA, Wang X. Vitamin D binding protein impact on 25-hydroxyvitamin D levels under different physiologic and pathologic conditions. Int J Endocrinol 2014; 2014:981581. doi:10.1155/2014/981581
    
    [CrossRef](http://www.ccjm.org/lookup/external-ref?access_num=10.1155/2014/981581&link_type=DOI) 

4.  Dahl B, Schiødt FV, Gehrchen PM, Ramlau J, Kiaer T, Ott P. Gc-globulin is an acute phase reactant and an indicator of muscle injury after spinal surgery. Inflamm Res 2001; 50(1):39–43. doi:10.1007/s000110050722
    
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5.  1.  Feingold KR, 
    2.  Anawalt B, 
    3.  Blackman MR, et al.
    
    Liberman U, Bikle DD. Disorders in the action of vitamin D. In: Feingold KR, Anawalt B, Blackman MR, et al., eds. Endotext. South Dartmouth, MA: MDText.com, Inc.; 2023.
    
    

6.  Sattar N, Scott HR, McMillan DC, Talwar D, O’Reilly DS, Fell GS. Acute-phase reactants and plasma trace element concentrations in non-small cell lung cancer patients and controls. Nutr Cancer 1997; 28(3):308–312. doi:10.1080/01635589709514592
    
    [CrossRef](http://www.ccjm.org/lookup/external-ref?access_num=10.1080/01635589709514592&link_type=DOI) 
    
    [PubMed](http://www.ccjm.org/lookup/external-ref?access_num=9343841&link_type=MED&atom=%2Fccjom%2F90%2F9%2F535.atom) 
    
    [Web of Science](http://www.ccjm.org/lookup/external-ref?access_num=A1997YB00900013&link_type=ISI)