Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases I

Diet, sun, and lifestyle as determinants of vitamin D status Paul Lips,1,2 Natasja M. van Schoor,2,3 and Renate T. de Jongh1 1 Department of Internal Medicine, Endocrine Section, VU University Medical Center, Amsterdam, the Netherlands. 2 EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands. 3 Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands

Address for correspondence: Paul Lips, M.D., Ph.D., Department of Internal Medicine, Endocrine Section, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands. [email protected]

Vitamin D status can be assessed by measuring concentrations of 25-hydroxyvitamin D (25(OH)D). Sunlight is the most important source of vitamin D and stimulates the production of vitamin D3 in the skin during the summer, depending on age, skin pigmentation, clothing style, and sunscreen use. Seasonal variation in serum 25(OH)D is between 10 and 20 nmol/L in adults and almost absent in nursing home residents. Sunscreen use decreases, but does not abolish, vitamin D production in the skin. Clothing style has a large influence on vitamin D production. Furthermore, vitamin D status can be improved by ingestion of fatty fish and the fortification of milk or orange juice. A high dietary calcium intake has a vitamin D–sparing effect, because it increases the half-life of 25(OH)D. A combination of sunlight exposure, nutrition, food fortification, and supplements is desirable to obtain sufficient vitamin D status in the population of most countries throughout the year. Keywords: sun exposure; vitamin D; lifestyle; nutrition; diet

Introduction Vitamin D stimulates the absorption of calcium from the gut and facilitates bone mineralization. It is produced in the skin under the influence of ultraviolet irradiation from the sun and is also absorbed from food. This duality, partly a vitamin and partly not, gives a special place to vitamin D among all other vitamins. Vitamin D status is often critical in young children, older people (over 65 years of age), and other risk groups. The determinants of vitamin D status are factors that influence sun exposure, including season and noncovered skin, obesity (negative influence), the consumption of vitamin D–rich foods, and the use of vitamin D supplements (Fig. 1). These determinants—sun, lifestyle, and diet—are the subjects of this paper. Vitamin D metabolism The most important source of vitamin D is sun exposure. In addition, a modest quantity can be obtained from food. Vitamin D is synthesized in the skin under the influence of sun exposure. The precursor 7-dehydrocholesterol is converted by ultravi-

olet irradiation into previtamin D3 , which is slowly metabolized by a thermal reaction into cholecalciferol or vitamin D3 .1 The first step, the synthesis of previtamin D3 , depends on age, pigmentation, clothing style, and the use of sunblock. Vitamin D3 is also present in some foods, mainly fish, and especially fatty fish. Other foods that contain some vitamin D3 are butter and margarine (added), egg yolk, and liver. Sun is far more important for vitamin D status than food. When sun exposure is low, nutrition becomes more important. Vitamin D3 , coming from the skin or food, is subsequently hydroxylated in the liver into 25-hydroxyvitamin D or calcidiol, the main circulating vitamin D metabolite and parameter of vitamin D status. The second hydroxylation step occurs in the kidney and is stimulated by parathyroid hormone (PTH), leading to 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) or calcitriol, the most active metabolite.2 The active metabolite, 1,25(OH)2 D3 , stimulates the absorption of calcium and phosphate from the gut, leading to adequate serum calcium concentrations for neuromuscular action and bone mineralization. Calcium suppresses PTH secretion by the parathyroid gland doi: 10.1111/nyas.12443


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Diet, sun, lifestyle, and vitamin D

Figure 1. Determinants of vitamin D status. Solid arrows indicate direct sources of vitamin D3 . Dashed arrows indicate indirect influences on vitamin D status.

and thus indirectly leads to a decrease in serum 1,25(OH)2 D3 . Phosphate decreases the activity of the 1␣-hydroxylase enzyme in the kidney, a second negative feedback loop. The 1␣-hydroxylase enzyme is also present in many organs where it can locally hydroxylate 25(OH)D into 1,25(OH)2 D for local paracrine action. This has long been known from pathological situations, such as sarcoidosis, and other granulomatous and lymphoproliferative diseases. Opinions differ regarding the role and importance of the paracrine action of 1,25(OH)2 D.3 Required serum 25(OH)D concentrations and required intake Clinical vitamin D deficiency develops when serum 25(OH)D falls below 25 nmol/L. In a recent Australian survey, it appeared that signs of decreased bone mineralization and increased bone turnover following secondary hyperparathyroidism developed with serum 25(OH)D of 15 nmol/L or lower.4 However, a very low 25(OH)D concentration can often be observed without any signs or symptoms in the patient. More subtle signs of inadequate vitamin D status are observed when serum 25(OH)D is between 25 and 50 nmol/L. The serum concentration of PTH decreases when serum 25(OH)D increases from 25 to 50 nmol/L or even to 75 nmol/L. Bone mineral density of the hip and spine showed a positive relationship with serum 25(OH)D up to almost 90 nmol/L in the National Health and Nutrition

Examination Survey (NHANES).5 Bone turnover markers, such as deoxypyridinoline and osteocalcin, are higher when serum 25(OH)D is low and decrease with an improvement in vitamin D status. In the Longitudinal Aging Study Amsterdam (LASA), serum osteocalcin and urinary deoxypyridinolin decreased with increasing serum 25(OH)D up to 40 nmol/L. In addition, bone mineral density of the hip increased with increasing serum 25(OH)D up to 50 nmol/L, and physical performance increased with serum 25(OH)D up to 60 nmol/L.6 The Institute of Medicine has set the required serum 25(OH)D at 50 nmol/L.7 The Endocrine Society, however, states that serum 25(OH)D levels should be higher than 75 nmol/L.8 To obtain serum 25(OH)D levels of 50 nmol/L, a daily intake of vitamin D3 of 600–800 IU is required, which is the recommended dietary allowance (RDA) according to the Institute of Medicine.7 The Endocrine Society recommends higher doses. In this paper, vitamin D deficiency is defined as serum 25(OH)D levels lower than 25 nmol/L, while levels between 25 and 50 nmol/L are referred to as vitamin D insufficiency. Sunlight and seasonal variation The precursor 7-dehydrocholesterol is metabolized in the skin into previtamin D3 by ultraviolet irradiation. Previtamin D3 is then converted by a thermal reaction into vitamin D3 . Factors influencing vitamin D production are shown in Figure 1. There is a strong seasonal variation in the production of

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Table 1. Skin type, skin reaction to sun exposure, and minimal erythematous dose (MED)12,13

Skin type I II III IV V VI

Skin color

Skin reaction

MED (J/m2 )

White, red hair, or fair White, fair, blue eyes Mediterranean, blue or brown eyes Asian, brown eyes Light-skinned black, Indian Dark-skinned black

Always burns, never tans Burns easily Mild burn, tans average Rarely burns, tans easily No burn No burn

200 250 300 450 600 1000

vitamin D3 ; in October, the production was approximately 10% of that in June in Boston.1 In winter, the production ceases in all temperate climates but continues throughout the year between both tropics (e.g., most of Africa and Latin America, India, Indonesia, and northern Australia). In Western Europe, vitamin D3 can be produced by sun exposure from April until September, and in southern Europe, it can be produced from March until October. Previtamin D3 shows a linear increase with exposure time to ultraviolet light.1 Seasonal variation of serum 25(OH)D levels follows a sinusoidal curve with a maximum at the end of summer or beginning of autumn, and a nadir at the end of winter.9–11 In these studies, seasonal variation was between 7 and 20 nmol/L, and in the New Zealand study, 63% of the population was predicted to have serum 25(OH)D levels lower than 50 nmol/L in late winter or early spring.10 As shown by results from LASA, the seasonal variation was higher in people aged 55–65 years as compared with people aged 65–88 years.11 In nursing home residents who were severely vitamin D deficient, the seasonal variation was minimal.12 Obesity also blunts seasonal variation of serum 25(OH)D levels.10 Although sun exposure is the most important source of vitamin D, season as a proxy for skin exposure to ultraviolet light was a more important predictor of vitamin D status than sun exposure itself (measured by polysulphane badges in combination with a sunlight exposure diary).13 The production of vitamin D3 depends on skin pigmentation. Skin types vary between type I (white skin with red hair) to type VI (black skin), and the minimal erythematous dose (MED) varies from 200 J/m2 for skin type I to 1000 J/m2 for skin type VI.14,15 With skin type VI, the production of previtamin D3 is 20% of that with skin type I (Table 1). The mean serum 25(OH)D concentrations were


approximately 25 nmol/L less in African-Americans than in Caucasians in the NHANES.16 However, even people with very pigmented skin can obtain high 25(OH)D concentrations, as was observed in The Gambia.17 Sun exposure may increase serum 25(OH)D levels up to more than 100 nmol/L and even more in life guards.18 A further increase to toxic levels does not occur because previtamin D3 is also metabolized into inactive metabolites during long-term exposure to ultraviolet irradiation. Sunscreen use decreases the production of vitamin D3 in the skin but does not abolish it. In the ICEPURE (Impact of Climatic and Environmental Factors on Personal Ultraviolet Radiation Exposure and Human Health) study, 62 volunteers received 40 standard erythematous doses (SED) of sun exposure during one week of holidays, equivalent to approximately 40% of yearly exposure. The group with broad spectrum sunscreen (ultraviolet B (UVB) and ultraviolet A (UVA), 2 mg/cm2 , three times daily) showed a mean increase of 13 nmol/L in serum 25(OH)D. The group with small-spectrum sunscreen (UVB, 2 mg/cm2 , three times daily) showed an increase of 19 nmol/L in serum 25(OH)D, while the increase in the control group (usual care, i.e., sunscreen use as was used before the study) was 28 nmol/L.19 This indicates that sunscreen may reduce vitamin D3 production in the skin by approximately 50% or more, but does not completely abolish it. In addition, glass windows block most UVB light, but car side windows may not. UVB light may also pass though plastic windows. Vitamin D3 production decreases with age, and in older people it may be approximately one fourth of that in younger people.1 However, the production capacity of the skin is very large. Nursing home residents were exposed to artificial ultraviolet light on a surface of 1000 cm2 of skin on their backs. They were exposed to half of the MED three times

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per week over 12 weeks and serum 25(OH)D levels increased from 18 to 60 nmol/L, similar to the increase observed in a group that received oral vitamin D3 400 IU/day. The mean serum 25(OH)D levels in the control group did not change and remained below 20 nmol/L.12 Once weekly, half-body irradiation with artificial ultraviolet light with a half MED for 8 weeks led to a mean increase of 15 nmol/L in serum 25(OH)D levels. This increase was higher when baseline serum 25(OH)D was lower.20 These studies demonstrate the high capacity of the skin to synthesize vitamin D3 . Even in older people, adequate vitamin D status may be obtained through skin exposure to ultraviolet light. Lifestyle One’s lifestyle can include staying outdoors, clothing style, and physical exercise—which are all determinants of sun exposure—and obesity (Fig. 1). Outdoor life is an important determinant of vitamin D status and may explain the reverse gradient of serum 25(OH)D with latitude in Europe.21,22 People in southern Europe tend to stay indoors or in the shade more than those in northern European countries. Clothing style is also an important determinant of vitamin D status. In a study in 48 young adult Turkish women, mean serum 25(OH)D levels were 56 nmol/L in those with Western-style clothing, 32 nmol/L in women wearing a hijab, and 9 nmol/L in women wearing a niqab, which includes complete covering of the face and arms.23 A similar vitamin D status was observed in women in Jordan, with differences observed according to clothing style.24 Vitamin D status was poor in women in Saudi Arabia where clothing that completely covers the skin is the rule.25 In non-Western immigrants in the Netherlands, vitamin D status was poor in Moroccan and Turkish women (skin type III or IV), whereas it was better in black Ghanese women (skin type VI). This difference is likely caused by a clothing style that covers less skin in the Ghanese women.26 Obesity is another determinant of vitamin D status. Results from LASA showed that mean serum 25(OH)D levels were almost 15 nmol/L lower in the highest quartile of total body fat than in the lowest quartile, both in women and in men.27 In general, body mass index (BMI) is an important determinant of vitamin D status. Physical exercise is also associated with better vitamin D status. In LASA, cycling and gardening were determinants of vitamin

Diet, sun, lifestyle, and vitamin D

D status both in women and men.28 Part of this association may be explained by the sun exposure during physical activity that is performed outdoors. Nutrition and food fortification Dairy products, egg yolk, and meat contain small quantities of vitamin D (Fig. 1), while fish, especially fatty fish, has a higher vitamin D content. For example, one herring contains 700–800 IU of vitamin D. In a Japanese study, mean serum 25(OH)D levels were 65 nmol/L in people who consumed fish four times or more per week, 54 nmol/L in those who consumed fish one to three times per week, and 49 nmol/L in people who did not eat any fish.29 The adequate vitamin D status in Norwegian adults in Tromso is likely due to the high consumption of fish, cod liver, and cod liver oil, leading to a mean intake of 356 IU/day, three times as much as in other Western European countries, and serum 25(OH)D levels that are higher than 50 nmol/L in 85% of the study population.30 Fortification of milk (10 ␮g = 400 IU per U.S. quart = 946 mL) has been practiced for many years in the United States, leading to a higher vitamin D intake and better vitamin D status than in Europe.31 In Europe, only margarine is fortified with vitamin D, usually at a quantity of 7.5 ␮g (300 IU)/100 g. The effect of fortification of margarine (10 ␮g/100 g) and milk (5 ␮g/L) with vitamin D on vitamin D intake was estimated at 0.3 ␮g/day (12 IU/day) for margarine and 2.6 ␮g/day (104 IU/day) for milk.32 Fortification of orange juice with vitamin D2 or D3 may increase mean serum 25(OH)D with 15–25 nmol/L, with regular consumption.33 Fortification of dietary supplements carries the risk of vitamin D intoxication, as was recently seen in young children receiving 4000 times as much vitamin D in a fish oil supplement, as was stated on the product.34 An interaction between dietary calcium intake and vitamin D status has been observed.35 A high calcium intake suppresses parathyroid activity and decreases serum PTH. This will decrease the turnover of vitamin D metabolites. In a study in rats, a high calcium intake increased the half-life of 25(OH)D, while a low calcium intake caused an increased metabolic clearance of 25(OH)D.36 These observations have been confirmed recently.37 Similarly, increased serum PTH levels, as exist in primary or secondary hyperparathyroidism, decrease the half-life of 25(OH)D.38

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Diet, sun, lifestyle, and vitamin D

Lips et al.

Risk groups Risk groups for vitamin D deficiency include premature and dysmature children, children younger than 5 years of age in general, pregnant women, older (65+) people, and non-Western immigrants. In particular, children consuming a macrobiotic diet carry a high risk of vitamin D deficiency.39 Vitamin D status declines with age; serum 25(OH)D levels are below 50 nmol/L in approximately 75% of people around 80 years of age and even more often in geriatric patients and institutionalized people.40 In addition, vitamin D status is poor in non-Western immigrants and asylum seekers.26,41 Serum 25(OH)D levels were lower than 25 nmol/L in more than 40% of Turkish and Surinamese people in a general practitioner survey conducted in four cities in the Netherlands.26 Pregnant nonWestern immigrants often have very poor vitamin D status. In a survey conducted in The Hague, serum 25(OH)D levels were lower than 25 nmol/L in more than 80% of Turkish and Moroccan pregnant women.42 Similar data were reported from Melbourne, where 80% of veiled or dark-skinned women had serum 25(OH)D levels below the reference range (

Diet, sun, and lifestyle as determinants of vitamin D status.

Vitamin D status can be assessed by measuring concentrations of 25-hydroxyvitamin D (25(OH)D). Sunlight is the most important source of vitamin D and ...
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