Correspondence

Hypovitaminosis D in Medical Inpatients

N Engl J Med 1998; 339:344-346July 30, 1998

Article

To the Editor:

The recent study by Thomas et al. (March 19 issue)1 aroused concern that a substantial proportion of U.S. adults may be deficient in vitamin D. In this Boston-area study, more than half of the patients studied had serum 25-hydroxyvitamin D concentrations ≤15 ng per milliliter (38 nmol per liter). The authors noted an absence of data about the vitamin D status of the general population.1 To fill this gap, we offer recent findings from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994), in which serum 25-hydroxyvitamin D was measured by radioimmunoassay (Incstar, Stillwater, Minn.) in 15,778 noninstitutionalized adults.2,3 Among these subjects, 9 percent had serum 25-hydroxyvitamin D concentrations ≤15 ng per milliliter (Table 1Table 1Serum 25-Hydroxyvitamin D Concentrations in 15,778 Noninstitutionalized Adults in the United States.). Less than 1 percent had very low values (<8 ng per milliliter [20 nmol per liter]), and 5 percent had values >50 ng per milliliter (125 nmol per liter).

Since the mobile centers used in the survey were located in the south during the winter and the north during the summer, there may be a season–latitude effect in these results. We performed exploratory analyses of people studied at latitudes similar to that of Boston during September to assess the importance of this effect. In this sample, the prevalence of serum 25-hydroxyvitamin D concentrations ≤15 ng per milliliter was 13 percent, still considerably lower than that in the medical inpatients studied by Thomas et al. in September (49 percent),1 which suggests that the lower prevalence of low values in the NHANES III study cannot be completely explained by the season–latitude effect.

In summary, the prevalence of vitamin D deficiency among noninstitutionalized U.S. adults is much lower than that reported for medical inpatients. We stress that our results do not apply to institutionalized or homebound people, among whom vitamin D deficiency may be more common.4 Also, our results may underestimate the prevalence of such a deficiency during the winter in people in northern latitudes. Finally, the prevalence in noninstitutionalized U.S. women is not trivial. Our intent is not to minimize the importance of vitamin D deficiency but rather to ensure that its extent in the entire population is known when physicians consider the appropriate steps to address the problem.1,5

Anne C. Looker, Ph.D.
Centers for Disease Control and Prevention, Hyattsville, MD 20782

Elaine W. Gunter, M.T.(A.S.C.P.)
Centers for Disease Control and Prevention, Atlanta, GA 30333

5 References

1. 1

   Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777-783
   Full Text | Web of Science | Medline

2. 2

   National Center for Health Statistics. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988–94. Vital and health statistics. Series 1. No. 32. Washington, D.C.: Government Printing Office, 1994. (DHHS publication no. (PHS) 94-1308.)
   

3. 3

   Gunter EW, Lewis BL, Koncikowski SM. Laboratory methods used for the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Hyattsville, Md.: Centers for Disease Control and Prevention, 1996 (software).
   

4. 4

   Gloth FM III, Gundberg CM, Hollis BW, Haddad JG Jr, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA 1995;274:1683-1686
   CrossRef | Web of Science | Medline

5. 5

   Utiger RD. The need for more vitamin D. N Engl J Med 1998;338:828-829
   Full Text | Web of Science | Medline

To the Editor:

The report by Thomas et al. raises a number of questions about the interpretation of serum 25-hydroxyvitamin D values. For most analytes measured in clinical chemistry departments, the normal range represents the range of values found in 95 percent of the population. The clear implication of the authors' data is that a substantial proportion of the population is vitamin D–deficient, making this approach to establishing reference data for serum 25-hydroxyvitamin D unreliable.

The difficulties in defining a reference range for serum 25-hydroxyvitamin D are well illustrated by the disparity in the results submitted by the participants in the international Vitamin D External Quality Assessment Scheme. A questionnaire asking about reference-range data was distributed in July 1997 to 40 laboratories in eight countries, of which 37 responded. The lower limits of the normal range for serum 25-hydroxyvitamin D concentrations varied between 3 ng per milliliter (8 nmol per liter) in a British laboratory and 18 ng per milliliter (45 nmol per liter) in a U.S. laboratory (Table 1Table 1Lower Limits of Reference Ranges for Serum 25-Hydroxyvitamin D Submitted by Participants in the Vitamin D External Quality Assessment Scheme.). It is difficult to accept that the wide variation in the lower limit of the reference ranges for serum 25-hydroxyvitamin D reflects genuine geographic variations in calcium homeostasis. Indeed, the rigorous application of locally established reference ranges could result in a person's becoming vitamin D–deficient en route from one country to another.

We believe the concept of a lower limit of the normal range for serum 25-hydroxyvitamin D should be abandoned in favor of a “target” concentration, derived by measurements of serum parathyroid hormone as a surrogate marker for vitamin D repletion. Although this would require serum parathyroid hormone and 25-hydroxyvitamin D measurements in a large sample of the general population, the mechanisms for this are already in place (e.g., NHANES in the United States). A target value for serum 25-hydroxyvitamin D established by this method should be largely unaffected by such external influences as diet or exposure to sunlight. This would be helpful to the increasing number of clinicians using assays for serum 25-hydroxyvitamin D to assess vitamin D nutrition.

Donal O'Shea, M.D., M.R.C.P.I.
Graham D. Carter, M.Sc.
Charing Cross Hospital, London W6 8RF, United Kingdom

Author/Editor Response

The authors reply:

To the Editor: Looker and Gunter report that 13 percent of adults evaluated in NHANES III who lived at latitudes similar to that of Boston had serum 25-hydroxyvitamin D concentrations ≤15 ng per milliliter during September.1 The difference between the prevalence of serum 25-hydroxyvitamin D concentrations ≤15 ng per milliliter during September in this subgroup of people from NHANES III and the prevalence in medical inpatients in Boston during the same month (13 percent vs. 49 percent) narrows if the prevalence in the normal adults is compared with that in the medical inpatients with no risk factors for hypovitaminosis D (13 percent vs. 24 percent). Still, the groups probably differed in factors such as age, diet, sun exposure, altitude, and skin pigmentation, as well as in that the medical inpatients had various illnesses. We do not know whether the remaining difference is due to the illnesses or to differences in the other factors.

In a recent study of outpatients in a bone health clinic in Boston, 41 percent had serum 25-hydroxyvitamin D levels <20 ng per milliliter (50 nmol per liter).2 The differences in the reported prevalence of hypovitaminosis D are not particularly important; what is important is that a substantial proportion of normal adults, and an even higher proportion of hospitalized adults, have hypovitaminosis D, which can easily be corrected.

O'Shea and Carter highlight the difficulty in establishing a normal range for serum 25-hydroxyvitamin D. We agree that the use of the 95 percent confidence interval for the population is not a reasonable way to define the lower limit of normal values for serum 25-hydroxyvitamin D. There are problems, however, with using measurements of serum parathyroid hormone as a surrogate for 25-hydroxyvitamin D, even if the relation between serum parathyroid hormone and serum 25-hydroxyvitamin D concentrations is carefully defined by using measurements from a large sample of the general population. Some people with normal vitamin D stores have secondary hyperparathyroidism when calcium intake is restricted. Moreover, many people with low vitamin D stores have normal serum parathyroid hormone concentrations, possibly because of high calcium intake or rapid loss of calcium from the skeleton. Because there are likely to be important nonskeletal effects of vitamin D, we might do this latter group of people a disservice by failing to diagnose their vitamin D deficiency merely because they have normal serum parathyroid hormone concentrations.

We favor a physiologically based definition of hypovitaminosis D in which the lower limit of the normal range for serum 25-hydroxyvitamin D is defined as the concentration at which the mean serum parathyroid hormone concentrations begin to increase in population studies. Another approach is to determine the minimal serum 25-hydroxyvitamin D concentration at which serum parathyroid hormone concentrations no longer decrease when vitamin D and calcium are administered. These approaches have the advantages of being clinically useful and of not being subject to geographic or seasonal variations that affect population-based normal ranges.

Joel S. Finkelstein, M.D.
Melissa K. Thomas, M.D., Ph.D.
Massachusetts General Hospital, Boston, MA 02114

2 References

1. 1

   National Center for Health Statistics. Plan and operation of the Third National Health and Nutrition Survey, 1988–94. Vital and health statistics. Series 1. No. 32. Washington, D.C.: Government Printing Office, 1994. (DHHS publication no. (PHS) 94-1308.)
   

2. 2

   Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998;351:805-806
   CrossRef | Web of Science | Medline

Citing Articles (18)

Citing Articles

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   James P. Kesby, Darryl W. Eyles, Thomas H.J. Burne, John J. McGrath. (2011) The effects of vitamin D on brain development and adult brain function. Molecular and Cellular Endocrinology 347:1-2, 121-127
   CrossRef

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   Diana Andrea Fernandes de Abreu, Emmanuel Nivet, Nathalie Baril, Michel Khrestchatisky, François Roman, François Féron. (2010) Developmental vitamin D deficiency alters learning in C57Bl/6J mice. Behavioural Brain Research 208:2, 603-608
   CrossRef

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   D.A. Fernandes de Abreu, D. Eyles, F. Féron. (2009) Vitamin D, a neuro-immunomodulator: Implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology 34, S265-S277
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   Darryl Eyles, Cameron Anderson, Pauline Ko, Alun Jones, Andrew Thomas, Thomas Burne, Preben Bo Mortensen, Bent Nørgaard-Pedersen, David Michael Hougaard, John McGrath. (2009) A sensitive LC/MS/MS assay of 25OH vitamin D3 and 25OH vitamin D2 in dried blood spots. Clinica Chimica Acta 403:1-2, 145-151
   CrossRef

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   Ghada El-Hajj Fuleihan. (2009) Vitamin D Deficiency in the Middle East and its Health Consequences for Children and Adults. Clinical Reviews in Bone and Mineral Metabolism 7:1, 77-93
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   Kamilia Tai, Allan G. Need, Michael Horowitz, Ian M. Chapman. (2008) Glucose tolerance and vitamin D: Effects of treating vitamin D deficiency. Nutrition 24:10, 950-956
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   Sima Hashemipour, Bagher Larijani, Hossein Adibi, Mojtaba Sedaghat, Mohammad Pajouhi, Mohammad Hasan Bastan-Hagh, Akbar Soltani, Ebrahim Javadi, Ali Reza Shafaei, Reza Baradar-Jalili, Arash Hossein-Nezhad. (2006) The status of biochemical parameters in varying degrees of vitamin D deficiency. Journal of Bone and Mineral Metabolism 24:3, 213-218
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   Robert P. Heaney. (2005) The Vitamin D requirement in health and disease. The Journal of Steroid Biochemistry and Molecular Biology 97:1-2, 13-19
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   F. Féron, T.H.J. Burne, J. Brown, E. Smith, J.J. McGrath, A. Mackay-Sim, D.W. Eyles. (2005) Developmental Vitamin D3 deficiency alters the adult rat brain. Brain Research Bulletin 65:2, 141-148
   CrossRef

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    Thomas H.J. Burne, Axel Becker, Jillanne Brown, Darryl W. Eyles, Alan Mackay-Sim, John J. McGrath. (2004) Transient prenatal Vitamin D deficiency is associated with hyperlocomotion in adult rats. Behavioural Brain Research 154:2, 549-555
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    (2004) Position of the American Dietetic Association and Dietitians of Canada: Nutrition and Women’s Health. Journal of the American Dietetic Association 104:6, 984-1001
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    John J. McGrath, François P. Féron, Thomas H.J. Burne, Alan Mackay-Sim, Darryl W. Eyles. (2004) Vitamin D3—implications for brain development. The Journal of Steroid Biochemistry and Molecular Biology 89-90, 557-560
    CrossRef

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    S. A. Skull, J. Y. Y. Ngeow, B. A. Biggs, A. Street, P. R. Ebeling. (2003) Vitamin D deficiency is common and unrecognized among recently arrived adult immigrants from The Horn of Africa. Internal Medicine Journal 33:1-2, 47-51
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    John McGrath, Francois Feron, Darryl Eyles, Alan Mackay-Sim. (2001) Vitamin D: the neglected neurosteroid?. Trends in Neurosciences 24:10, 570-571
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    Jankees Ridder. (2001) Vitamine-D-deficiëntie, niet alleen bij migrantenvrouwen. Huisarts en Wetenschap 44:10, 295-298
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    Melissa K. Thomas, Marie B. Demay. (2000) VITAMIN D DEFICIENCY AND DISORDERS OF VITAMIN D METABOLISM. Endocrinology & Metabolism Clinics of North America 29:3, 611-627
    CrossRef

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    Fuleihan, Ghada El-Hajj, Deeb, Mary, . (1999) Hypovitaminosis D in a Sunny Country. New England Journal of Medicine 340:23, 1840-1841
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    (1999) Position of The American Dietetic Association and Dietitians of Canada. Journal of the American Dietetic Association 99:6, 738-751
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