Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(2):e2024037 1 Correlation Among Serum Calcidiol, Sun Index, and Vitamin D Intake in Individuals With Seborrheic Keratoses Living in Coastal Area Izzah Aulia1, Larisa Paramitha Wibawa1, Lis Surachmiati Suseno1, Nurul Ratna Mutu Manikam2 1 Dermatology and Venereology Department, Faculty of Medicine, Universitas Indonesia – dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia 2 Department of Nutrition, Faculty of Medicine, Universitas Indonesia – dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia Key words: calcidiol, seborrheic keratosis, sun, vitamin D Citation: Aulia I, Wibawa LP, Suseno LS, Manikam NRM. Correlation Among Serum Calcidiol, Sun Index, and Vitamin D Intake in Individuals With Seborrheic Keratoses Living in Coastal Area. Dermatol Pract Concept. 2024;14(2):e2024037. DOI: https://DOI.org/10.5826/dpc.1402a37 Accepted: November 1, 2023; Published: April 2024 Copyright: ©2024 Aulia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Larisa Paramitha Wibawa, MD, Dermatology and Venereology Department, Faculty of Medicine, Universitas Indonesia – dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia. Phone number: +62 821-1311-8480 E-mail: larisa.paramitha@ui.ac.id Introduction: Seborrheic keratoses (SK) are benign epidermal tumors with high sun exposure as a major risk factor. Vitamin D deficiency is also thought to play a role in its pathogenesis. There has been no data regarding SK, calcidiol level, vitamin D intake, and sun index (SI) among people living in coastal areas in Indonesia. Objectives: To assess the correlation between 1) serum calcidiol levels with SI and vitamin D intake and 2) lesion size with SI and serum calcidiol level among SK patients living in a coastal area. Methods: This is a cross-sectional study. We performed interviews using the sun index questionnaire and semiquantitative food frequency questionnaire for vitamin D; physical examination; dermoscopy to determine the largest SK lesion size; and measurement of serum calcidiol levels in participants with SK living in Cilincing District, North Jakarta. Spearman correlation test was used to assess the rela- tionship between variables. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2024;14(2):e2024037 Introduction Seborrheic keratoses (SK) are benign epidermal tumors es- timated to be present in 20% of adults, especially in the el- derly [1,2]. Sun exposure was considered as the main risk factor for SK [1].1 Genetics, mutations of specific genes, hu- man papillomavirus infection, and vitamin D deficiency were also thought to play a role in the pathogenesis of SK [2,3]. Various studies pointed to the association between vitamin D deficiency and SK, especially gene mutation studies and the use of topical vitamin D analogs to treat SK lesions [4,5]. Vitamin D deficiency is fewer in Brazil and England pop- ulations living closer to the sea due to high sun exposure [6,7]. Indonesia is a tropical climate country with many coastal areas. Jakarta, as one of its cities, has a 12-hour du- ration of sun exposure with the highest average ultraviolet (UV) index of 10-12 [8]. Despite the exposure, vitamin D deficiency was common in various populations in Indone- sia [9-11]. In addition to its endogenous synthesis with the aid of sun exposure, 10%–20% of vitamin D in the body is obtained from foods [12,13]. Low vitamin D intake is also a risk factor for vitamin D deficiency [11,14]. Indonesians have darker skin tones from light brown to dark brown (Fitzpatrick skin types 4 and 5). Objectives To our knowledge, data on serum calcidiol levels, sun in- dex, and vitamin D intake among people with SK living in Indonesian coastal communities remains limited. Therefore, we aim to obtain baseline data regarding calcidiol level, sun exposure, and vitamin D intake among people with SK who live in coastal areas in Indonesia. Furthermore, we would explore the correlation between serum calcidiol levels with sun exposure and vitamin D intake among this population. Methods This cross-sectional study was conducted in the Cilincing district, North Jakarta, Indonesia on 10–12 November 2020. During the study, we implemented protocols for Coronavirus Disease 2019. We reported this study following the STROBE checklist for cross-sectional studies. Subjects aged 18–59 years with SK lesions based on clin- ical examination and dermoscopy were enrolled consecu- tively in this study [15-17]. Impaired vitamin D absorption and metabolism were often found in geriatrics, so this age group was not included in this study [11]. Furthermore, through interview, we excluded subjects who took vitamin D supplements; received therapy for SK in the past month; had routine sunscreen use; had impaired renal or liver function; had a history of malabsorption diagnosis; were pregnant or breastfeeding during the recruitment period; or were grade II or morbid obesity according to the WHO Category for Asia-Pacific Region [18]. The primary outcome measure of this study was the cor- relation of serum calcidiol level with vitamin D intake and sun index. Furthermore, we would explore the correlation of the largest lesion size with calcidiol level and sun index. We recorded baseline characteristics such as age, sex, and occupation. We also collected basic anthropometric data, food intake, sun index, SK clinical characteristics, and serum calcidiol levels. Anthropometric data was measured by using a digital scale and microtoise Trained nutritionists assessed macro- nutrient intake with the 24-hour food recall and vitamin D intake with a semiquantitative food frequency question- naire (FFQ) under supervision of clinical nutrition specialist (N.R.M.M.). One researcher (I.A.) did the interview to mea- sure sun exposure with the sun index questionnaire. The sun index (SI) is an index for objective sun exposure measure- ment by multiplying the fraction of body surface area (BSA) by the duration of exposure on weekdays and weekends/ holidays [19]. Another researcher who was blinded to the sun index and vitamin D assessment recorded the physical and dermoscopic examination by using a standard cam- era. Two board-certified dermatolovenereologists (L.P.W. and L.S.S.) oversaw the examination. We measured the SK largest diameter, specified its region, and categorized the le- sions based on whether they were sun-exposed or partially exposed. The sun-exposed area was defined as the neck and V-neck area, outer forearms, or back of hands, whereas the Results: Thirty-nine participants with SK aged 19–59 years were analyzed. The median of the SK largest diameter, SI, serum calcidiol, and vitamin D intake was 2 (1–10) mm, 3.95 (1.1–23.52), 14.3 (5.25–35.30) ng/ml, and 4.3 (0.1–30.1) mcg/day, respectively. SI and vitamin D intake were not signifi- cantly correlated with calcidiol levels. Similarly, SI and calcidiol levels were not significantly correlated with the largest SK lesion size. Conclusions: We found low calcidiol levels and vitamin D intake in this coastal population. The SI and vitamin D intake had no correlations with calcidiol levels. Furthermore, calcidiol levels and SI had no correlations with the lesion largest diameter. Original Article | Dermatol Pract Concept. 2024;14(2):e2024037 3 partially exposed area included the trunk, upper arms, flexor forearms, legs, and V-neck area. Serum calcidiol levels were measured by using LIAISON® analyzer (DiaSorin) and clas- sified according to the Endocrine Society Classification [20]. Ethics Statement This study was conducted following the Declaration of Hel- sinki and approved by the Health Research Ethics Commit- tee Faculty of Medicine Universitas Indonesia (no. KET1003/ UN2.F1/ETIK/PPM.00.02/2020). Written informed consent was obtained for all subjects before study enrollment. Statistical Analysis We calculated the minimum sample size to detect an r of 0.45 with an α error rate of 5% and 80% power to be 36 subjects. All data were analyzed using SPSS® IBM® ver.20 (IBM Corporation). Subjects with missing outcome data were dropped out from the final analysis. Data distribution was determined using the normality test. Pearson or Spearman correlation test was performed to assess the correlation of serum calcidiol with the sun index and vitamin D intake. Furthermore, we also assess the cor- relation of the largest lesion size with the serum calcidiol and sun index. The correlation value was defined using the r correlation coefficient: 0.7–1.0 as a strong correlation, 0.3–0.69 as a moderate correlation, and 0–0.29 as a weak correlation. A P value less than 0.05 was considered statisti- cally significant. Results Among 80 assessed for eligibility, 40 subjects were eligible and consecutively enrolled. The blood sample of one subject was lysed, so he was dropped out of the analysis. A  total of 39 subjects were included in the final analysis (Figure 1). Most of the subjects were women. The median age was 40.5 (21–59) years. The median BMI was 25.7 (15.81–29.06) kg/m2. More than half of the subjects were formal employees. The complete sociodemographic and clinical characteristics are described in Table 1. Most patients (97.4%) had the largest lesion in the sun-exposed areas; only one subject had it on the trunk. There was a significant difference in the largest lesion di- ameter among age groups: 1 (1–3) mm at the 19–29 years, 2 (1–4) at the 30–39 years, 3 (1–10) mm at the 40–49 years, and 3 (1–7) mm at the 50–59 years group (P = 0.016). There was no significant difference in lesion diameter among sub- jects with low SI (<4) compared to high SI (>4) (2.00 [1–10] mm versus 2 [1–9] mm, P = 0.815). The mean size of lesions in the vitamin D deficient, insufficient, and normal groups was 2 (1–10) mm, 2 (1–9) mm, and 3 (1–5) mm, respectively (P = 0.995). The mean number of calcidiol levels were similar across all age groups, with the absolute values in the 19-29, 30–39, 40–49, and 50–59 years of age were 14.83 (6.82), 17.33 (9.43), 17.40 (10.03), and 14.08 (4.05) ng/ml, respectively (P = 0.686). Most of the subjects (71.8%) had vitamin D de- ficiency. However, vitamin D deficiency was more commonly found among the older age group than the younger age group (80% versus 63.2%, P = 0.209). The serum calcidiol had an increasing trend according to the sun exposure duration in- crement. In the group with sun exposure <14 hours/week, 14-28 hours/week, and >28 hours/week, the serum calcidiol level was 11.3 [10.2–18.7], 14.3 [7.25–26.20], and 15.1 [5.25–35.30] ng/ml, respectively (P = 0.569) ( Figure 2). The value of SI in the vitamin D deficient was lower compared than in the insufficient or normal group (3.82 [1.1 –17.64] versus 6.83 [2.21–23.52], P = 0.177) (Figure 3). Figure 1. Patient flowchart. SK = seborrheic keratoses. 4 Original Article | Dermatol Pract Concept. 2024;14(2):e2024037 Table 1. Sociodemographic and clinical characteristics Variables Values Gender, N (%) Men Women 17 (43.6) 22 (56.4) Age (year), median (min-max) 19-29, N (%) 30-39, N (%) 40-49, N (%) 50-59, n (%) 40.5 (21–59) 11 (28.2) 8 (20.5) 8 (20.5) 12 (30.8) BMI category, N (%) Underweight Normal Overweight Grade 1 obesity 2 (5.1) 7 (17.9) 6 (15.4) 25 (61.5) BMI (kg/m2), median (min-max) 24.82 (3.59) Occupation, N (%) Fishermen Fishmongers Laborers Employees Others (housewives, students, etc.) 2 (5.1) 4 (10.3) 1 (2.6) 22 (56.4) 10 (25.6) Sun index Sun exposure per week (hour), median (min-max) Fraction of BSA exposed to sunlight, median (min-max) Sun indexa median (min-max) 24.8 (5.25–84) 0.20 (0.05–0.45) 3.95 (1.1–23.52) Seborrheic keratoses Largest lesion diameter (mm), median (min-max) 2 (1–10) Region, N (%) Sun-exposed Partially exposed 38 (97.4) 1 (2.6) Calcidiol Calcidiol level (ng/ml), median (min-max) 14.3 (5.25–35.3) Categoryb N (%) Deficient (<20 ng/ml) Insufficient (20–29 ng/ml) Normal (30–100 ng/ml) Toxic (>100 ng/ml) 28 (71.8) 9 (23.1) 2 (5.1) 0 (0) BMI = body mass index; BSA = body surface area. aHours of sun exposure per week × fraction of BSA exposed to sunlight bAccording to Endocrine Society [37]37 Figure 2. Serum calcidiol levels according to sun exposure duration group. Figure 3. Sun index according to calcidiol category group. Table 2 describes the profile of energy, carbohydrate, fat, protein, and vitamin D intake among study participants. The vitamin D intake in the vitamin D deficient, insufficient, and normal group was 4.2 (0.10–30.10), 4.3 (2.0–28.80), and 15.55 (10.30–20.80) mcg/day (P = 0.226), respectively. Pro- tein intake in subjects with insufficient and normal calcidiol levels was higher than in those with deficient calcidiol levels (54.25 [16.96] versus 48.28 [20.82], P = 0.234). The daily protein intake of subjects with deficient, insufficient, and nor- mal calcidiol levels was 54.0 (12.10–89.0), 51.40 (26.0–76.0), and 67.25 (54.5–80.0) grams/day, respectively (P = 0.440). Finally, we found that there was no significant correla- tion between the largest lesion diameter and SI (r = -0.057, P = 0.731) nor serum calcidiol (r = 0.108, P = 0.513). Explor- atory analysis showed a weak negative correlation between lesion size and calcidiol level in the 19–39 years age group (r = -0.270, P = 0.250), and a significant positive correlation in the 40–59 years age group (r = 0.523, P = 0.018). There was also no significant correlation between calcidiol level and SI (r = 0.188, P = 0.253), vitamin D intake (r = 0.042, P = 0.801), or daily protein intake (r=0.113, p=0.495). Original Article | Dermatol Pract Concept. 2024;14(2):e2024037 5 Table 2. Profile of energy, carbohydrate, fat, protein, and vitamin D intake Variable Value Daily needs Energy (kcal/day), median (min-max) Carbohydrate (%), mean (SD) Fat (%), median (min-max) 1189 (267–2357) 53.14 (11.11) 31.57 (3.13–50.4) 1800–2650 kcal/daya 45–65%b 20–30%b Protein (grams/day), median (min-max) 54 (12.10–89) 60–65 grams/daya Vitamin D (mcg/day), median (min-max) 4.3 (0.1–30.1) 15 mcg/daya Vitamin D intake category, N (%) Deficient Sufficient 34 (87.2) 5 (12.8) SD = standard deviation. aAccording to Indonesian Recommended Dietary Allowance 2019 bAccording to Indonesian Balanced Nutrition Guidelines Conclusions This study is among the first to describe the demographic and clinical characteristics of people living with SK in coastal areas of Indonesia and explore their SI, vitamin D intake, and serum calcidiol levels. Among this coastal population, we found no correlations between SI, calcidiol levels, and the size of the largest SK lesion. We also did not find any cor- relations between SI, vitamin D intake, and calcidiol levels. Among our population, the median SI was greater than a similar study in Malaysia which found a median SI of 0.72 (0.26–1.28) in the urban population and 0.89 (0.42–1.83) in the rural population [20]. Nevertheless, despite the high SI, most of the subjects (71.8%) had vitamin D deficiency. This figure is within the reported prevalence of vitamin D deficiency in Southeast Asia, which ranges from 22%–87% [21-23]. We found that people with vitamin D deficiency were older and had higher BMIs. Older age is associated with decreased vitamin D metabolism due to decreased he- patic and kidney function [24], whereas in young age, vi- tamin D level is associated with higher vitamin D binding protein (DBP) levels, resulting in higher vitamin D levels [25]. Among overweight and obese individuals, vitamin D distri- bution into the fat tissue will reduce its total half-life and lower its serum level [26,27]. We originally hypothesized that lesion diameter would be associated with SI and calcidiol level. However, we found that there was no correlation between SI and SK largest di- ameter. The lesion size significantly increased along with the increment in age decades, as also found in the Korean population study. This finding might be caused by increased cumulative UV exposure in people with older age [28]. We also found no correlation between lesion diameter and cal- cidiol level. Vitamin D was found to play a role in the patho- genesis of SK in mice studies, including research on FGFR3, PIK3CA, and EGFR mutations. The topical administration of vitamin D analogs i.e. calcipotriol and tacalcitol, has been shown to reduce lesion size [29,30]. However, in the 19–39 years age group, there was a negative weak correla- tion between serum calcidiol level and the largest diameter, although this correlation was not significant. The opposite result was shown in individuals aged over 40 years, wherein we found a significant positive correlation between calcidiol levels and the largest diameter of SK. In this group, the higher the calcidiol, the larger the lesion size. We suspected that even though high sun exposure might cause higher cal- cidiol levels, it also increased the risk of SK, which was also a sign of photodamage. We found that calcidiol level had no correlations with SI, even though the mean SI in subjects with insufficient and normal calcidiol was greater than in the deficient one. More- over, there was an increment in calcidiol levels according to the increase in sun exposure duration. High sun exposure in the coastal community is among the many factors causing higher vitamin D levels in this community compared to the urban community. This finding is also similar to the study in England, which found that the average calcidiol levels of the population living closer to the coast were higher than in the people living within a radius of 40 km of the coastal area.7 But still, the high sun exposure (median 24.8 [5.25– 84]) hours per week) in the area with high UV index, did not prove to be adequate to increase calcidiol levels in this population. A study on a population of pregnant women in West Sumatra, Indonesia, also found that there was no relationship between outdoor activity and vitamin D defi- ciency, with an odds ratio of 0.986 (95% confidence inter- val: 0.972–1.001) [13]. There are also other factors affecting vitamin D produc- tion with the help of sunlight, including the amount of UV exposure, the use of sunscreen and protective clothing, and Fitzpatrick skin type [20]. Although food is not the primary source of vitamin D, the lack of vitamin D intake from food is one of several factors causing vitamin D deficiency in In- donesia [11,13]. The lack of vitamin D intake in subjects is 6 Original Article | Dermatol Pract Concept. 2024;14(2):e2024037 3. Mostafa WZ, Hegazy RA. Vitamin D and the skin: Focus on a complex relationship: A review. J Adv Res. 2015;6(6):793-804. DOI: 10.1016/j.jare.2014.01.011. PMID: 26644915. PMCID: PMC4642156. 4. Lu’o’ng K, Nguyễn LT. The roles of vitamin D in seborrhoeic keratosis: Possible genetic and cellular signalling mechanisms. Int J Cosmet Sci. 2013;35(6):525-531. DOI: 10.1111/ics.12080. PMID: 23859137. 5. Hafner C, Di Martino E, Pitt E, et al. Fgfr3 mutation affects cell growth, apoptosis and attachment in keratinocytes. Exp Cell Res. 2010;316(12):2008-2016. DOI: 10.1016/j.yexcr.2010.04.021. PMID: 20420824. 6. Coutinho RCS, Santos AFD, Costa JGD, Vanderlei AD. Sun exposure, skin lesions and vitamin D production: Evaluation in a population of fishermen. An Bras Dermatol. 2019;94(3):279-286. DOI: 10.1590/abd1806-4841.20197201. PMID: 31365655. PMCID: PMC6668935. 7. Cherrie MP, Wheeler BW, White MP, Sarran CE, Osborne NJ. Coastal climate is associated with elevated solar irradiance and higher 25(OH)D level. Environ Int. 2015;77:76-84. DOI: 10.1016/j.envint.2015.01.005. PMID: 25660687. 8. Badan Meteorologi Klimatologi dan Geofisika. Indeks sinar ultraviolet 2023 [Internet]. Accessed on 14-02-2023. Available from: https://www.bmkg.go.id/kualitas-udara/indeks-uv.bmkg. 9. Green TJ, Skeaff CM, Rockell JE, et al. Vitamin D status and its association with parathyroid hormone concentrations in women of child-bearing age living in Jakarta and Kuala Lumpur. Eur J Clin Nutr. 2008;62(3):373-378. DOI: 10.1038/sj.ejcn.1602696. PMID: 17342165. 10. Yosephin B, Khomsan A, Briawan D, Rimbawan R. Peranan ul- traviolet B sinar matahari terhadap status vitamin D dan tekanan darah pada wanita usia subur. National Public Health Journal. 2014;8(6):5. DOI: 10.21109/kesmas.v0i0.377. 11. Setiati S. Vitamin D status among indonesian elderly women living in institutionalized care units. Acta Med Indones. 2008;40(2):78-83. PMID: 19054885. 12. Jeon SM, Shin EA. Exploring vitamin D metabolism and func- tion in cancer. Exp Mol Med. 2018;50(4):1-14. J DOI: 10.1038 /s12276-018-0038-9. PMID: 29657326. PMCID: PMC5938036. 13. Aji AS, Erwinda E, Yusrawati Y, Malik SG, Lipoeto NI. Vita- min D deficiency status and its related risk factors during early pregnancy: A cross-sectional study of pregnant Minangkabau women, Indonesia. BMC Pregnancy Childbirth. 2019;19(1):183. DOI: 10.1186/s12884-019-2341-4. PMID: 31117971. PMCID: PMC6532131. 14. Bukhary NBI, Isa ZM, Shamsuddin K, et al. Risk factors for antenatal hypovitaminosis D in an urban district in Malaysia. BMC Pregnancy Childbirth. 2016;16(1):156. DOI: 10.1186 /s12884-016-0939-3. PMID: 27411716. PMCID: PMC4944244. 15. Wang SQ, Rabinovitz HS, Oliviero MC, Marghoob AA. Solar lentigines, seborrheic keratoses, and lichen planus-like kerato- sis. In: Marghoob AA, Malvehy J, Braun RP, editors. Atlas of dermoscopy. 2nd Edition ed. New York: Informa Healthcare 2012:58-69. 16. Lin J, Han S, Cui L, et al. Evaluation of dermoscopic algorithm for seborrhoeic keratosis: A prospective study in 412 patients. J Eur Acad Dermatol Venereol. 2014;28(7):957-962. DOI: 10.1111/jdv.12241. PMID: 23980820. 17. Braun RP, Rabinovitz HS, Krischer J, et al. Dermoscopy of pigmented seborrheic keratosis: A morphological study. Arch caused by the lack of food containing vitamin D consump- tion, including fish, shrimp, crab, milk, and dairy products. In our study, the mean vitamin D intake in the deficient group was lower than in the insufficient and normal levels groups. However, we found no correlation between vita- min D intake and calcidiol levels. Calcidiol levels are influ- enced by metabolizing enzymes and the polymorphisms of DBP-regulating genes and vitamin D receptor genes, which were beyond the scope of this study [24,31]. The VDR poly- morphisms were found in a group of healthy women with vitamin D deficiency and insufficiency in North Sumatra, Indonesia [32]. In addition, the median intake of daily energy, carbohy- drates, and protein was below the nutrient requirement. Pro- tein intake, as one of the main nutrients, is thought to play a role in vitamin D deficiency. DBP is a protein derivative that transports 85%–88% of vitamin D in the blood [25,33]. To our knowledge, there is no known research subjecting pro- tein intake to DBP formation and the influence of protein intake on vitamin D deficiency. In this study, the median pro- tein intake was below the Indonesian 2019 recommended daily allowance. Protein intake in subjects with insufficient and normal vitamin D levels was higher than in deficient ones, but no correlation was found between protein intake and calcidiol levels. Our study has several limitations. Firstly, this study did not compare subjects with SK and without SK in the coastal area. We also did not include the calculation of lesion num- ber to shorten the examination time during the COVID-19 pandemic. Furthermore, our study utilized a 24-hour food questionnaire, which might be prone to recall bias and flat- slope syndrome [34,36]. Flat-slope syndrome is the reduc- tion in food intake reported by overweight individuals or the increase in food portions reported by underweight ones [37]. Further study with a larger sample size may be conducted to provide external validity for our result. In conclusion, we found low levels of serum calcidiol and vitamin D intake among people with SK living in the coastal area of Indonesia. 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