European Journal of Clinical Nutrition (2015) 69, 693–696 © 2015 Macmillan Publishers Limited All rights reserved 0954-3007/15 www.nature.com/ejcn

ORIGINAL ARTICLE

High prevalence of vitamin D deficiency in patients with xeroderma pigmetosum-A under strict sun protection A Kuwabara1, N Tsugawa2, K Tanaka3, Y Uejima1, J Ogawa1, N Otao1, N Yamada1, T Masaki4, C Nishigori4, S Moriwaki5 and T Okano2 BACKGROUND/OBJECTIVES: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by defective repair of ultraviolet (UV) irradiation-induced DNA damage and high risk of skin cancer. Thus, these patients require strict photoprotection. Considering the importance of UV-mediated cutaneous vitamin D production, such rigorous photoprotection would cause vitamin D deficiency. Then, we have studied the vitamin D status in patients with XP-A, a group requiring the most strict photoprotection. SUBJECTS/METHODS: Twenty-one patients with XP-A (aged 6–25) were evaluated for their vitamin D intake, serum levels of 25-hydroxy-vitamin D (25OHD) and parathyroid hormone (PTH). Vitamin D intake was assessed by a 2-day food weighing method. RESULTS: Median dietary intake of vitamin D was 4.1 μg/day, and the median concentrations of serum 25OHD and PTH were 7.7 and 49.9 pg/ml, respectively. In 76% of the patients, serum 25OHD level was lower than 10 ng/ml, indicating vitamin D deficiency. Vitamin D intake and serum 25OHD level were significantly lower in patients under enteral nutrition (EN) than those with oral intake (OI). Multivariate analyses revealed that EN was a significant predictor of decreased serum 25OHD level (β coefficient = − 0.59, P = 0.03). CONCLUSIONS: Vitamin D deficiency is highly prevalent in XP-A patients, and supplementation should be considered to avoid unfavorable skeletal consequences in these patients. In addition, determination of dietary vitamin D requirement has been a difficult work issue in the decision of dietary reference intakes (DRIs) because of its cutaneous production. Data from XP patients would yield useful information for the determination of DRIs for vitamin D. European Journal of Clinical Nutrition (2015) 69, 693–696; doi:10.1038/ejcn.2015.1; published online 11 February 2015

INTRODUCTION Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by defective repair of ultraviolet (UV) irradiation-induced DNA damage.1 The prevalence of XP is 1:1 000 000 in the United States and Europe, and 1:22 000 in Japan.2 As patients with XP have 410 000-fold higher risk to develop sunlight-induced skin cancer,3 they need photoprotection through various ways such as minimization of daytime outdoor activity and constant sunscreen use. XP has seven complementation groups (A–G) and one variant, each associated with distinct gene mutation and different level of the repair defect. Most strict photoprotection is required in patients with XP-A, in which clinical features including the involvement of skin and nervous system are most severe. Vitamin D has an essential role in maintaining the calcium and phosphate homeostatis. Its unique feature is that significant amount is produced in the skin through the action of UV-B.4,5 Under the ordinary living conditions, UV-mediated cutaneous vitamin D production has been reported to contribute to as much as 90% of the total vitamin D requirement, with dietary intake making only the residual 10% contribution.5 Then, it is quite natural to imagine that XP patients would be associated with vitamin D deficiency. As some recent epidemiologic studies have shown that higher level of vitamin D is associated with reduced risk of melanoma and improved the survival of skin cancer patients,6 improving the vitamin D status would be further beneficial for patients with XP. Reports have been scarce, however, on the vitamin D status of patients with XP.

Then in this paper, we have studied the vitamin D status in XP-A patients under most strict photoprotection.

MATERIALS AND METHODS Subjects The study participants were 21 outpatients with XP-A (male, 12; female, 9; aged 6–25) attending the Dermatology Clinic at Kobe University Hospital or Osaka Medical College. Exclusion criteria were routine use of medication or supplementation possibly affecting the vitamin D status. Detailed information about this study was given and written consent was obtained from the subject or the proxy. The study protocol was approved by the ethical committee in Kobe University and Osaka Medical College.

Laboratory data Blood was obtained after overnight fasting. After centrifugation, serum was kept frozen at –30 °C until analysis. Serum concentration of 25OHD was measured by using a chemiluminescent immunoassay (CLIA) technology (LIAISON 25 OH Vitamin D TOTAL Assay). Circulating level of intact parathyroid hormone (PTH) was measured by using a chemiluminescent immunoassay (CLIA) (LIAISON N-TACT PTH II Assay).

Energy and nutrients intake estimation Semi-weighted, 2-day household dietary records with food photographs were obtained. Nutrient intake was estimated based on the Standard Tables of Food Composition in Japan 2010.7

1 Department of Health and Nutrition, Osaka Shoin Women’s University, Higashiosaka-shi, Osaka, Japan; 2Department of Hygienic Sciences, Kobe Pharmaceutical University, Kobe, Japan; 3Department of Food and Nutrition, Kyoto Women’s University, Kyoto, Japan; 4Department of Dermatology, Clinical Molecular Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan and 5Department of Dermatology, Osaka Medical College, Osaka, Japan. Correspondence: Dr A Kuwabara, Department of Health and Nutrition, Osaka Shoin Women’s University, 4-2-26 Hishiyanishi, Higashiosaka-shi 577-8550, Osaka, Japan. E-mail: [email protected] Received 20 June 2014; revised 9 December 2014; accepted 21 December 2014; published online 11 February 2015

Vitamin D deficiency in xeroderma pigmetosum patients A Kuwabara et al

694 Statistical analysis Data were expressed as mean ± s.d. where normally distributed, and by median and interquartile range for those with skewed distribution. Association between vitamin D intake and serum 25OHD was analyzed by Spearman’s correlation coefficient. Comparison between the two independent groups was made by Student’s t-test or Mann–Whitney U-test depending on normality. Contingency table was analyzed by χ2-test in complex sample analysis. Multiple regression analysis was employed to determine the significant predictor(s) for serum 25OHD level. All statistical analyses were carried out using SPSS for Windows (version 19.0; SPSS Inc, Tokyo, Japan). Statistical significance was defined as a two-tailed P o0.05 for all analyses.

RESULTS Background profiles and data of the study subjects The background profiles and blood data are shown in Table 1. All patients were under rigorous photoprotection by minimization of the daytime outdoor activity and utilization of measures such as sun-protective clothing and constant use of sunscreen with sun protection factor (SPF) of at least 30. Most of the present subjects were ambulant. Underweight was defined as body mass index (BMI) o 18.5 kg/m2 for adult, Rohrer index o 100 for school age children and Kaup index o 16 for infant. On the basis of such definition, 18% of patients were considered to be underweight. The median concentrations of serum 25OHD and PTH were 7.7 and 49.9 pg/ml, respectively. There is a general consensus that serum 25OH-D concentration o 20 ng/ml indicates hypovitaminosis D.8,9 Serum 25OH-D concentration was o 10 ng/ml, 10–20 ng/ml and ⩾ 20 ng/ml in 76, 24% and none of the patients, respectively. Three patients had serum PTH level above the upper reference range value (reference range; 17.3–72.9 pg/ml). Nutritional intake in the study subjects Of the 21 subjects, complete 2-day dietary records without any missing information were obtained from 14 patients (Table 2). Ten patients could be managed by oral intake (OI), whereas the remaining four subjects were enterally fed. Enteral nutrition (EN) was indicated for those with dysphagia, which was caused by the neurological abnormalities often found in XP-A patients.10,11 Macronutrients intake such as protein, fat and carbohydrates appeared appropriate for their age and sex. In 64% of the patients, calcium intake was below the estimated average requirement in dietary reference intakes (DRIs).12 The adequate intakes (AI) for vitamin D in Japan ranged from 3.0 to 5.5 μg/day depending on the age and gender.12 In the present study, median dietary vitamin D intake was 4.1 μg/day, and in 57% of the subjects vitamin D intake was below AI. Serum 25OHD level was not correlated with vitamin D intake or serum PTH level (data not shown). Table 1.

Comparison of the vitamin D status between OI and EN subjects EN patients were significantly older and had significantly lower intakes for energy and vitamin D than OI patients (Table 3). Underweight was significantly more prevalent in EN patients compared with OI patients. Serum 25OHD level was significantly lower in patients under EN than those with OI. Multiple regression analysis for the determination of independent factor for circulating vitamin D concentration In a single regression analysis, type of feeding (OI/EN) was a significant contributing factor for the serum 25OHD concentration (r = − 0.59, P = 0.03), and vitamin D intake was not significantly associated with serum 25OHD concentration (data not shown; Table 4). Next, we have done multiple regression analysis for serum 25OHD level. Serum 25OHD concentration was entered as a dependent variable, and type of feeding (OI/EN), presence of underweight (yes/no) and vitamin D per body weight (μg/BW kg/day) as covariates for the analysis of multiple regression analysis with the stepwise method. EN was a significant predictor of decreased serum 25OHD level. DISCUSSION In this study, we have studied the vitamin D status in Japanese patients with XP-A. The serum 25OHD level was as low as 7.7 ng/ml as the median and o 20 ng/ml in all the study subjects. It was even o10 ng/ml in 76% of the subjects. Thus, the current study subjects were considered to have severe hypovitaminosis D. Few studies have previously examined the circulating vitamin D level in XP patients. One report was apparently inconsistent with ours. Sollito et al.13 reported that XP patients under strict photoprotection had normal level of serum 25OHD over a 6-year study period. The serum 25OHD level in their study was 17.8 ng/ml as the average and o 20 ng/ml in practically all subjects. While their subjects were supplied with sunscreens with SPF of at least 15, our XP-A patients used one with more than 30 of SPF. As difference in SPF could influence the efficacy of photoprotection, their photoprotection might be milder than ours and have resulted in normal serum 25OHD level. Indeed, they reported that there was a small increase in mean serum 25OHD level in the summer months. Moreover, average vitamin D intake of their subjects was 7.7 μg/day, which was higher than ours. Their study, however, showed no correlation between vitamin D intake and its serum concentration. In contrast, another report was apparently consistent with our result. Hosel et al.14 have reported that serum 25OHD was 9.2 ng/ml as an average and decreased in 67% of the patients (10 out of 15). Their study subjects, however, were not limited to XP-A, but included other groups: XP-C, XP-D, XP-F and XP-V. Table 2.

Energy and nutrients intake in relation to vitamin D intake All (n = 14)

Subjects’ background profiles All patients (n = 21)

M/F 12/9 Age (years) 13 ± 6 (min-max: 6–25) Physical activity ambulant/mild ambulant (n) 6/15 Body height (cm) 133 ± 14 Body weight (kg) 30.0 ± 8.8 Underweight (n) 4 (19%) Serum 25OHD level (ng/ml) 7.7 (6.2,10.2) Serum PTH level (pg/ml) 49.9 (34.6,72.8) Abbreviations: F, female; M, male; PTH, parathyroid hormone; 25OHD,25hydroxy-vitamin D. Data are expressed as mean ± s.d. or as median (Q1,Q3) depending on normality.

European Journal of Clinical Nutrition (2015) 693 – 696

Oral intake/Enteral nutrition Energy (kcal/day) Protein (g/day) Total fat (g/day) Carbohydrates (g/day) Calcium (mg/day) Vitamin D (μg/day) Vitamin D per body weight (μg/BW kg/day) Vitamin D per 1000 kcal (μg/1000kcal/day) Number of subject with taking vitamin D under the adequate intake of DRI (n)

10/4 1370 ± 440 50.6 ± 14.1 37.3 (21.3, 57.6) 195.8 ± 51.6 463 (312, 808) 4.1 (2.7, 6.9) 0.2 ± 0.2 2.9 (2.6, 5.0) 8 (57%)

Abbreviation: DRI, dietary reference intake. Data are expressed as mean ± s.d. or as median (Q1,Q3) depending on normality.

© 2015 Macmillan Publishers Limited

Vitamin D deficiency in xeroderma pigmetosum patients A Kuwabara et al

695 Table 3.

Comparison of the vitamin D status between subjects based on their type of feeding

M/F Age (y) Underweight (n) Serum 25OHD level (ng/ml) Serum PTH level (pg/ml) Vitamin D deficiency (n) Energy intake (kcal) Vitamin D intake (μg) Vitamin D per body weight (μg/BW kg/day) Vitamin D intake (μg/1000kcal) Calcium (mg/day) Number of subject with taking vitamin D under the adequate intake of DRI (n) Number of subject with taking calcium under the estimated average intake of DRI (n)

OI (n = 10)

EN (n = 4)

P value

7/3 10 ± 3 0 (0%) 9.0 (7.3, 13.1) 49.9 (35.1,69.6) 6 (60%) 1470 (1300, 1890) 5.3 (3.5, 9.8) 0.3 ± 0.1 3.5 (2.5, 6.2) 565 (312, 1083) 4 (40%) 5 (50%)

2/2 22 ± 2 3 (75%) 5.6 (5.1, 6.1) 75.2 (only one person) 4 (100%) 930 (870, 1020) 2.7 (2.3, 3.2) 0.1 ± 0.0 2.9 (2.6, 3.2) 402 (323, 452) 4 (100%) 4 (100%)

0.58 0.02 0.01 0.02 − 0.25 0.02 0.04 o0.01 0.73 0.24 0.09 0.22

Abbreviations: DRI, dietary reference intake; EI, enteral nutrition; F, female; M, male; OI, oral intake; PTH, parathyroid hormone; 25OHD, 25-hydroxy-vitamin D. Data are expressed as mean ± s.d. with the values in parentheses showing the median. Comparison of indices between OI group and EN group were done by unpaired t-test or Mann–Whitney U-test depending on normality.

Table 4.

Multiple regression analysis for the determination of independent factor for circulating vitamin D concentration Variable Type of feeding (OI/EN, ref; OI)

β-coefficient

P-value

−0.59

0.03

Abbreviations: EN, enteral nutrition; OI, oral intake. R = 0.292, P = 0.027. Only significant predictors are shown. The independent predictor for serum 25OH-D level was analyzed by multivariate analysis with the stepwise regression. Prevalence of underweignt (yes/no), their type of feeding (OI/EN) and vitamin D per body weight (μg/BW kg/day) were included in all analyses. OI was used as reference. 2

Such differences could be related to that they did not observe any significant association between the duration of sun protection and 25OHD level, and argued against the causal relationship of stringent photoprotective measures and serum vitamin D level. Although all subjects in our study had vitamin D deficiency, most of them had normal PTH concentration. In a recent study including large number of subjects, unignorable percentage of subjects with normal PTH levels ( o65 pg/ml) had frank vitamin D deficiency.15 As an explanation for such apparently paradoxical observation, they postulated magnesium deficiency as the underlying cause, since magnesium deficiency is known to be associated with impaired PTH secretion.16 In any case, median dietary vitamin D intake was below the AI in the Japanese DRIs in 57% of the subjects. Vitamin D intake was 5.3 and 2.7 μg/day in OI and EN patients, respectively, and type of feeding was a significant predictor for serum 25OHD level by multiple regression analysis. Delong et al.17 have studied the vitamin D status in patients with skin cancer and those at higher risk for skin cancer including patients with XP. Those with oral vitamin D supplementation had higher serum 25OHD level than those without it. According to their multivariate analysis, serum 25OHD level was significantly contributed by vitamin D supplementation, but not by dietary vitamin D intake. In their study, 94% of the subjects had daily vitamin D intake o 10 μg/day. Their results could be interpreted as that co-existence of multiple factors associated with vitamin D deficiency, including sun protection, low-dietary vitamin D intake and lack of vitamin D supplementation, had rendered the subjects at even higher risk for vitamin D deficiency. Our results that EN was a significant predictor of decreased serum 25OHD level could be interpreted similarly. Thus, low vitamin D supply in patients with EN can more strongly contribute to vitamin D deficiency under the strict photoprotection. Therefore, vitamin D © 2015 Macmillan Publishers Limited

supplementation should be considered to avoid vitamin D deficiency in XP patients with strict photoprotection. With regard to the dose required, the report by Garland et al.18 would be informative. According to their intervention study, expected incremental serum 25OHD level after daily supplementation with every 25 μg/day vitamin D3 was dependent on the basal serum 25OHD level and was 11 ng/ml per 25 μg/day at a starting value of 10 ng/ml. Then it follows that at least of 25 μg/day vitamin D would be the required intake for XP-A subjects Apart from such clinical aspects, our finding would have another implication related to the DRIs. Determination of dietary vitamin D requirement has been an annoying issue in the decision of DRIs because of its cutaneous production. Recently published DRIs for calcium and vitamin D in 2011 from the Institute of Medicine adopted the comparison of serum 25OHD level and dietary vitamin D intake in subjects from the arctic region, based on the consideration that the assumption of minimal sun exposure and all of the vitamin D acquired from the diet is mandatory to set the reference values.19 This is an interesting study approach, which, however, is not applicable to other countries like Japan where data from arctic area are unavailable. Japanese AI is based on the median intake of apparently healthy subjects;12 however, the current AI for vitamin D in Japanese DRIs might be insufficient for maintaining the appropriate level of 25OHD.20 The AI for vitamin D in the current Japanese DRIs is rather different from that in the DRIs of United States and Canada. For example, AI for adult is 5.5 μg/day in the Japanese DRIs, which is much lower than the recommended dietary allowance (RDA) of 15 μg/day in the United States. Finally, the relationship between skin type and serum 25OHD level need to be considered. A number of studies have shown an association between skin lightness and 25OHD levels,21–25 most comparing individuals from different ethnicities. Recent study also indicated that vitamin D production could not meet the RDA level (15 μg/day) in indoor-working adult subjects, especially in those with skin type III–VI.26 As skin type of Japanese may correspond to the skin type II–IV of the Fitzpatrick’s classification,27 the current AI for vitamin D in Japanese DRIs may not be satisfactory. Therefore, studies on the vitamin D status of XP patients including the dietary intake evaluation and blood 25OHD measurement would be a quite suitable model to study the dietary vitamin D requirement and yield useful information for determining Japanese DRIs. The limitation of our paper is its cross-sectional study design. An intervention study of vitamin D supplementation is required to confirm the vitamin D intake requirement for all subjects including European Journal of Clinical Nutrition (2015) 693 – 696

Vitamin D deficiency in xeroderma pigmetosum patients A Kuwabara et al

696 subjects with minimal sun exposure. In a general context, our study had no control, and the number of the study subjects of 21 would be judged to be small and considered to be another methodological limitation. Considering the low prevalence of XP-A, however, we believe that our study is rather a large-scale one for this disorder. In conclusion, we have found that vitamin D deficiency is highly prevalent in XP-A patients under strict sunlight deprivation. Our data would be of value in the clinical management of these patients and also for the determination of DRIs for vitamin D. CONFLICT OF INTEREST The authors declare no conflict of interest.

ACKNOWLEDGEMENTS This work was supported by JSPS KAKENHI Grant Number 25750061 and 25350157.

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High prevalence of vitamin D deficiency in patients with xeroderma pigmetosum-A under strict sun protection.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by defective repair of ultraviolet (UV) irradiation-induced DNA damage ...
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