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Editorial

See corresponding article on page 1519.

A vitamin D nutritional cornucopia: new insights concerning theserum 25-hydroxyvitamin D status of the US population1,2

Anthony W Norman

It is generally agreed that the serum concentration of 25-

hydroxyvitamin D [25(OH)D] in healthy persons is the best

indicator of the vitamin D status of patients with vitamin Dre-

lated disease states(1). Thereport by Lookeret al (2)in this issue

of the Journal provides a cornucopia of new insights into the

vitamin D nutritional status of US citizens from 1988 through

2004. In particular, this report compares serum 25(OH)D con-

centrations of 20 289 participants in the National Health andNutrition Examination Survey (NHANES) 20002004 with

those of 18 158 participants in NHANES III (19881994). For

the first time, results were reported for children 111 y old,

pregnant women, and the Mexican American population.

Themostimportantfinding inthe reportis that themeanserum

25(OH)D concentrations of persons 12 y old fell by 520

nmol/L between 19881994 and 20002004. Assay changes,

which were unrelated to changes in 25(OH)D status, accounted

for a portion of this apparent difference between the 2 study

groups; nevertheless, at the end of the complex analysis, there

still was a significant (7.1 nmol/L) reduction in 25(OH)D con-

centrations in males (except Mexican Americans) but not in most

female groups. Thisresult is potentially disturbing if it representsthe beginning of the downward trend in serum 25(OH)D con-

centrations that has been seen over the past 1015 y. It will

therefore be essential to repeat this study after another decade.

The vitamin D cornucopia that Looker et al provided contains a

variety of other novel and important observations. These include

differences in 25(OH)D status 1) by ethnicity and sex in non-

Hispanic whites, non-Hispanic blacks, and Mexican Americans; 2)

by age group (15, 611, 1219, 20 49, 50 69, or70 y old); 3)

by season (NovemberMarch or AprilOctober); and4) by preg-

nancy status. In addition, a second vitamin D cornucopia can be

found under Supplementary data in the current online issue. This

material contains extensive data on 4 topics: 1) a comparison of

25(OH)Dassay methods; 2) seasonal variations in serum 25(OH)Dby race-ethnicity in persons12 y old;3) the prevalence of serum

25(OH)D concentrations 25 nmol/L (an indication of nutritional

vitamin D deficiency); and 4) the prevalence of serum 25(OH)D3concentrations below selected thresholds by age, sex, and race-

ethnicity.

Some readers may be troubled by 2 technical aspects of thestudy

by Looker et al.A potentially confounding problemis thattherewas

anevolutionin25(OH)Dassaymethodology betweenthe firststudy

in 19881994 and the second study in 20002004. Possible assay

differences wereassessedby repeatingmeasurementsof the 25(OH)D

concentrations in 150 stored serum samples from NHANES III

with thesamplesfrom the20002004 samples. Lookeret al used

sophisticated statistical techniques to tease out the shift in the

meanserum 25(OH)D concentrations between the 2 decades that

was due to changes in assay methods. This problem was recently

discussed in detail (3). However, there still is a need for signif-

icant improvements in 25(OH)D assays so that consistent and

precise assay results may be obtained over multiyear periods.

The second potential concern relates to the protocol used inNHANES; that is, the serum samples were collected in the US

southern latitudes (35 N) only in NovemberMarch and in the

US northern latitudes (35 N) only in AprilOctober. Thus, the

magnitude of the seasonal fall in 25(OH)D concentrations in the

winter in the northern latitudes is underestimated, as is the increase

in concentrations in thesummerin thesouthern latitudes.Ideally, in

a study focusing on serum25(OH)Dconcentrations,there shouldbe

no bias of the time of the year for the latitude at which the serum

samples were collected. These same concerns also apply to the

involvement of the vitamin D endocrine system with the disease

process of cancer. Epidemiologic studies have suggested a direct

link between greater sunlight (ultraviolet B light) production of

vitamin D3in populations living at lower latitudes and lower inci-

dences of breast, colon, prostate, and ovarian cancers and non-

Hodgkinlymphoma(4).Other studies have shown thatpersonswith

lowserumconcentrations of 25(OH)D(ie,8 nmol/L) had a higher

incidence of cancer (5), which reinforces the need to improve vita-

min D nutritional status.

The study by Looker et al is particularly important, given the

current concerns about the appropriate recommendations for the

daily intake of vitamin D3 (6, 7).The current adequate intakeallow-

ance of vitamin D, recommended in 1997, is considered by many

scientists to betoolow andto be focused only on vitamin Dsactions

on calcium andboneissues (1).However,over the past decade, new

evidence has shown that there are 5 additional physiologic systems

in which the vitamin D receptor and its cognate steroid hormone,

1,25-dihydroxyvitamin D3[1,25(OH)2D3], generate biologi-

cal responses (8). These are the immune, pancreas, heart-

cardiovascular, muscle, and brain systems; the control of the cell

1 From the Department of Biochemistry and Division of Biomedical Sci-

ences, University of California, Riverside, CA.2 Reprints not available. Address correspondence to AW Norman, Depart-

ment of Biochemistry and Division of Biomedical Sciences, University of

California, Riverside, 5456 Boyce Hall, Riverside, CA 92521. E-mail:

anthony.norman@ucr.edu.

doi: 10.3945/ajcn.2008.27049.

1455Am J Clin Nutr2008;88:14556. Printed in USA. 2008 American Society for Nutrition

8/11/2019 A Vitamin D Nutritional Cornucopia

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cycle and thus of the disease process of cancer is also involved.

Acting through the vitamin D receptor, the steroid hormone

1,25(OH)2D can produce a wide array of favorable biological

effects that collectively are projected to contribute to the im-

provement of human health. The sphere of influence of the vi-

tamin D endocrine system, updated to include physiologic sys-

tems beyond calcium and bone, is shown in Figure 1.

The size of the NHANES study group is large, and one of its

greatest values is that it provides the opportunity for study of the

nutritional status of major ethnic groups in the US population. The25(OH)D data from a properly diverse study group will allow ap-

propriatehealth-care decisions to be made foreach ethnicsubgroup.

It is essential that the next chapter of the NHANES process will

include appropriate measurements and evaluations to provide in-

sight into the 25(OH)D nutritional status of all 6 of the physiologic

systems that make up the vitamin D endocrine system.

In summary, the report of Looker et al should be required

reading for all nutritionists, clinicians, and vitaminD aficionados

who are decisionmakerswith regard to 25(OH)D assays, vitamin

D nutritional policy, and the care of patients with vitamin Dre-

lated diseases.

The author had no personal or financial conflict of interest.

REFERENCES1. Food and Nutrition Board, Institute of Medicine. Dietary reference

intakes for calcium, magnesium, phosphorus, vitamin D, and fluo-ride: dietary reference intakes for calcium, magnesium, phosphorus,

vitamin D, and fluoride. Washington, DC: National Academy Press,1997:250-87.

2. Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF,Yetley EA. Serum 25-hydroxyvitamin D status of the US population:

1988 1994 compared with 20002004. Am J ClinNutr2008;88:151927.

3. Binkley N, Krueger D, Gemar D, Drezner MK. Correlation among

25-hydroxy-vitamin D assays. J Clin Endocrinol Metab 2008;93:18048.

4. Grant WB. An estimate of premature cancer mortality in the U.S. due to

inadequate dosesof solarultraviolet-Bradiation. Cancer2002;94:186775.

5. Garland CF, Gorham ED, Mohr SB, et al. Vitamin D and prevention ofbreast cancer: pooled analysis. J Steroid Biochem Mol Biol 2007;103:70811.

6. Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent need to

recommend an intake of vitamin D that is effective. Am J Clin Nutr2007;85:64950.

7. Norman AW, Bouillon R, Whiting SJ, Vieth R, Lips P. 13th Workshopconsensus for vitamin D nutritional guidelines. J Steroid Biochem Mol

Biol 2007;103:204 5.

8. Norman AW. From vitamin D to hormone D: fundamentals of the vita-min D endocrine system essential for good health. Am J Clin Nutr2008;88(suppl):491S9S.

VITAMIN D ENDOCRINE SYSTEM

PLACENTALPRODUCTION

1,25(OH) 2D324R,25(OH)

2D

3

EXTRARENAL PRODUCTION

KIDNEY25(OH) D3

24R,25(OH) 2D3 1,25(OH) 2 D3

PARATHYROIDHORMONE

24-HYDROXYLASE 1-HYDROXYLASE(+)

(+)(+) (-)

HO

OH

OH HO

OH

OH

24R,25(OH) 2D31,25(OH) 2 D3

BLOOD24R,25(OH)2D3

BLOOD1,25(OH) 2 D3

(-)SHORT

FEEDBACK

LOOP

(-)LONG

FEEDBACK

LOOP

BLOOD

Pi

Ca

HO

110

5

3

6 7

12

915

11

8

24

2520

14

Ca2+ , Pi, H+

DIETARYSOURCES BLOOD LIVER

BLOOD

BLOOD

25(OH) D3

VITAMIN D3

HO

OH

37 CHEMICALLYCHARACTERIZEDMETABOLITES

HO

1

3

6

7

9

15

11

8

25

(SUNLIGHT)

7-DEHYDROCHOLESTEROL(PRESENT IN SKIN)

(HORMONAL ORIGIN)

HO

1

3

57

1510

25

HEAT

ENDOCRINE MODULATORSESTROGEN

CALCITONINGROWTH HORMONEPROLACTININSULINGLUCOCORTICOID

CALCIUM HOMEOSTASIS

CLASSIC TARGET ORGANS

BONEINTESTINE

KIDNEY

REABSORPTION OF Ca2+ & Pi

ABSORPTION OF Ca2+

MOBILIZATION / ACCRETION OF Ca2+ & Pi

24R,25(OH)2D3RECEPTORS

CHONDROCYTE

FRACTURE HEALING CALLUS

OF 1,25(OH)2D3(in 10 tissues)

PARACRINE

VDR PRESENT IN 37 TISSUES

Genomic and/or Rapid

Responses

HEART-

-CARDIOVASCULAR

PANCREAS

INSULIN

SECRETION

IMMUNE SYSTEM

INNATE

ADAPTIVE

CANCER

TREATMENT

PREVENTION

Brain Muscle

SELECTED BIOLOGICAL RESPONSES

AWN 2008

FIGURE 1. Summary of the vitamin D endocrine system. Target organs for the steroid hormone 1,25-dihydroxyvitamin D3[1,25(OH)2D3] are defined

by thepresence ofthe vitaminD receptor (VDR);37 tissues areknownto possessthe VDR(8). Theparacrineproduction of 1, 25(OH)2D3 is known to occurin at least 10 tissues (8). New evidence shows that 5 additional physiologic systems (immune, pancreas, heart-cardiovascular, muscle, and brain systems) andthe traditional intestinal-bone calcium system are responsible for producing biological vitamin Drelated responses that are important to good health.

1456 EDITORIAL