Correspondence

Normal Serum Vitamin D Levels

N Engl J Med 2005; 352:515-516February 3, 2005

Article

To the Editor:

Kratz et al. report in the October 7 issue1 the revised laboratory reference values for tests commonly ordered at the Massachusetts General Hospital. We noticed that the normative range for 25-hydroxyvitamin D is below what is now the recommended range.2,3 Historical, “normative” data for circulating 25-hydroxyvitamin D levels were based on samples from sun-deprived human subjects, who appeared to be free of disease, with normal circulating 25-hydroxyvitamin D levels assessed by plotting a Gaussian distribution.4 There are many reasons why this method is inaccurate, including such factors as race, lifestyle, use or nonuse of sunscreen, age, and geographic latitude, as well as inappropriately low recommended dietary intake of vitamin D. As a result, investigators have begun to define nutritional vitamin D deficiency by using various biomarkers for circulating 25-hydroxyvitamin D levels, including calcium homeostatic indicators, such as parathyroid hormone, calcium absorption, and bone-mineral density.2,4 Noncalcium homeostatic factors, such as insulin resistance and beta-cell function, have been added to the list of 25-hydroxyvitamin D biomarkers.5 With the use of data from these biomarkers, vitamin D deficiency should be defined as circulating levels of 25-hydroxyvitamin D that are less than 32 ng per milliliter (80 nmol per liter).2

Bruce W. Hollis, Ph.D.
Carol L. Wagner, M.D.
Medical University of South Carolina, Charleston, SC 29425
hollisb@musc.edu

5 References

1. 1

   Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory reference values. N Engl J Med 2004;351:1548-1563[Erratum, N Engl J Med 2004;351:2461.]
   Full Text | Web of Science | Medline

2. 2

   Hollis BW. Circulating 25-hydroxy vitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr (in press).
   

3. 3

   Laboratory reference data. Rochester, Minn.: Mayo Clinic, 2004.
   

4. 4

   Haddad JG, Chyu KJ. Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab 1971;33:922-925
   CrossRef

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   Chiu KC, Chu A, Go V, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820-825
   Web of Science | Medline

Author/Editor Response

Drs. Hollis and Wagner raise an important issue: What is the appropriate normative range for serum 25-hydroxyvitamin D? Clearly, historical “normative” data may underestimate circulating levels of 25-hydroxyvitamin D expected in patients with sufficient vitamin D.1 Currently, however, methodologic and technical issues prevent a direct comparison of values across laboratories.2-4 In fact, there is no consensus on a specific level of 25-hydroxyvitamin D that is indicative of vitamin D deficiency. Reported5 lower limits of the normal range are between 2 and 32 ng per milliliter (5 to 80 nmol per liter) — levels associated with minimized serum parathyroid hormone values. Given the absence of assay standardization and the lack of consensus regarding clinical cutoff values, reference ranges must remain laboratory-specific. As we point out in the introduction to our tables, the reference ranges listed are for tests performed at the Massachusetts General Hospital. Clinical measurements from most immunoassays, and certainly from immunoassays for 25-hydroxyvitamin D, must be interpreted within the clinical context of each patient; one should not rely solely on cutoff values based on so-called normal levels, even those defined with the use of additional biomarkers.

Alexander Kratz, M.D., Ph.D.
Patrick M. Sluss, Ph.D.
Kent B. Lewandrowski, M.D.
Massachusetts General Hospital, Boston, MA 02114

5 References

1. 1

   Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 2003;22:142-146
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2. 2

   Binkley N, Krueger D, Cowgill CS, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab 2004;89:3152-3157
   CrossRef | Web of Science | Medline

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   Lips P, Chapuy MC, Dawson-Hughes B, Pols HA, Holick MF. An international comparison of serum 25-hydroxyvitamin D measurements. Osteoporos Int 1999;9:394-397
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   Carter GD, Carter R, Jones J, Berry J. How accurate are assays for 25-hydroxyvitamin D? Data from the international vitamin D external quality assessment scheme. Clin Chem 2004;50:2195-2197
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   Pal BR, Marshall T, James C, Shaw NJ. Distribution analysis of vitamin D highlights differences in population subgroups: preliminary observations from a pilot study in UK adults. J Endocrinol 2003;179:119-129
   CrossRef | Web of Science | Medline

Citing Articles (28)

Citing Articles

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   Bruce W Hollis, Donna Johnson, Thomas C Hulsey, Myla Ebeling, Carol L Wagner. (2011) Vitamin D supplementation during pregnancy: Double-blind, randomized clinical trial of safety and effectiveness. Journal of Bone and Mineral Research 26:10, 2341-2357
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2. 2

   C. Berti, H.K. Biesalski, R. Gärtner, A. Lapillonne, K. Pietrzik, L. Poston, C. Redman, B. Koletzko, I. Cetin. (2011) Micronutrients in pregnancy: Current knowledge and unresolved questions. Clinical Nutrition
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   Billie Bonevski, Afaf Girgis, Parker Magin, Graeme Horton, Irena Brozek, Bruce Armstrong. (2011) Prescribing sunshine: A cross-sectional survey of 500 Australian general practitioners' practices and attitudes about vitamin D. International Journal of Cancern/a-n/a
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   Aasis Unnanuntana, Brian J. Rebolledo, Joseph M. Lane. 2011. The Role of Vitamin D in Orthopedic Surgery. , 927-944.
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   Bruce W. Hollis. 2011. Detection of Vitamin D and Its Major Metabolites. , 823-844.
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   Laura K. DeLong, Sarah Wetherington, Nikki Hill, Meena Kumari, Bryan Gammon, Scott Dunbar, Vin Tangpricha, Suephy C. Chen. (2010) Vitamin D Levels, Dietary Intake, and Photoprotective Behaviors Among Patients With Skin Cancer. Seminars in Cutaneous Medicine and Surgery 29:3, 185-189
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   John M. Brehm, Brooke Schuemann, Anne L. Fuhlbrigge, Bruce W. Hollis, Robert C. Strunk, Robert S. Zeiger, Scott T. Weiss, Augusto A. Litonjua. (2010) Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. Journal of Allergy and Clinical Immunology 126:1, 52-58.e5
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8. 8

   Bruce W. Hollis. (2010) Assessment and Interpretation of Circulating 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D in the Clinical Environment. Endocrinology & Metabolism Clinics of North America 39:2, 271-286
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9. 9

   Robert J. Freishtat, Sabah F. Iqbal, Dinesh K. Pillai, Catherine J. Klein, Leticia M. Ryan, Angela S. Benton, Stephen J. Teach. (2010) High Prevalence of Vitamin D Deficiency among Inner-City African American Youth with Asthma in Washington, DC. The Journal of Pediatrics 156:6, 948-952
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10. 10

    Suhrad G. Banugaria, Stephanie L. Austin, Anne Boney, Thomas J. Weber, Priya S. Kishnani. (2010) Hypovitaminosis D in glycogen storage disease type I. Molecular Genetics and Metabolism 99:4, 434-437
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    Jill Mallory. (2010) Integrative Care of the Mother-Infant Dyad. Primary Care: Clinics in Office Practice 37:1, 149-163
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    Storm Weaver, David B. Doherty, Camilo Jimenez, Nancy D. Perrier. (2009) Peer-Reviewed, Evidence-Based Analysis of Vitamin D and Primary Hyperparathyroidism. World Journal of Surgery 33:11, 2292-2302
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13. 13

    Amit Agarwal, Sushil Kumar Gupta, Ranjith Sukumar. (2009) Hyperparathyroidism and Malnutrition with Severe Vitamin D Deficiency. World Journal of Surgery 33:11, 2303-2313
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14. 14

    H. C. Hoeck, B. Li, P. Qvist. (2009) Changes in 25-Hydroxyvitamin D3 to oral treatment with vitamin D3 in postmenopausal females with osteoporosis. Osteoporosis International 20:8, 1329-1335
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15. 15

    (2009) Chapter 3.1: Diagnosis of CKD–MBD: biochemical abnormalities. Kidney International 76, S22-S49
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16. 16

    P. Mikosch, M. Reed, H. Stettner, R. Baker, A.B. Mehta, D.A. Hughes. (2009) Patients with Gaucher disease living in England show a high prevalence of vitamin D insufficiency with correlation to osteodensitometry. Molecular Genetics and Metabolism 96:3, 113-120
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17. 17

    Kelly Gemmel, Heena P. Santry, Vivek N. Prachand, John C. Alverdy. (2009) Vitamin D deficiency in preoperative bariatric surgery patients. Surgery for Obesity and Related Diseases 5:1, 54-59
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18. 18

    Carol L. Wagner, Sarah N. Taylor, Bruce W. Hollis. (2008) Does Vitamin D Make the World Go ‘Round’?. Breastfeeding Medicine 3:4, 239-250
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    Anna P. Ralph, Paul M. Kelly, Nicholas M. Anstey. (2008) L-arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis. Trends in Microbiology 16:7, 336-344
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    Dorothy Teegarden, Kimberly M. White, Roseann M. Lyle, Michael B. Zemel, Marta D. Van Loan, Velimir Matkovic, Bruce A. Craig, Dale A. Schoeller. (2008) Calcium and Dairy Product Modulation of Lipid Utilization and Energy Expenditure. Obesity 16:7, 1566-1572
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21. 21

    Natasha Khazai, Suzanne E. Judd, Vin Tangpricha. (2008) Calcium and vitamin D: Skeletal and extraskeletal health. Current Rheumatology Reports 10:2, 110-117
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22. 22

    Ann E. Warner, Sarah A. Arnspiger. (2008) Diffuse Musculoskeletal Pain Is Not Associated With Low Vitamin D Levels or Improved by Treatment With Vitamin D. JCR: Journal of Clinical Rheumatology 14:1, 12-16
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23. 23

    Prakash Chandra, Linda L. Wolfenden, Thomas R. Ziegler, Junqiang Tian, Menghua Luo, Arlene A. Stecenko, Tai C. Chen, Michael F. Holick, Vin Tangpricha. (2007) Treatment of vitamin D deficiency with UV light in patients with malabsorption syndromes: a case series. Photodermatology, Photoimmunology & Photomedicine 23:5, 179-185
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24. 24

    Tatu J. Mäkinen, Jessica J. Alm, Hanna Laine, Erkki Svedström, Hannu T. Aro. (2007) The incidence of osteopenia and osteoporosis in women with hip osteoarthritis scheduled for cementless total joint replacement. Bone 40:4, 1041-1047
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    John O. Elliott, Mercedes P. Jacobson, Zulfi Haneef. (2007) Homocysteine and bone loss in epilepsy. Seizure 16:1, 22-34
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    Laura A. Basile, Sarah N. Taylor, Carol L. Wagner, Ron L. Horst, Bruce W. Hollis. (2006) The Effect of High-Dose Vitamin D Supplementation on Serum Vitamin D Levels and Milk Calcium Concentration in Lactating Women and Their Infants. Breastfeeding Medicine 1:1, 27-35
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27. 27

    Jennifer J Kelly, Arnold M Moses. (2005) Osteoporosis in men: the role of testosterone and other sex-related factors. Current Opinion in Endocrinology & Diabetes 12:6, 452-458
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28. 28

    Chantal Mathieu, Klaus Badenhoop. (2005) Vitamin D and type 1 diabetes mellitus: state of the art. Trends in Endocrinology & Metabolism 16:6, 261-266
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