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Serum 25-hydroxy vitamin D levels in age-related macular degeneration

Serum 25-hydroxy vitamin D levels in age-related macular degeneration Background: The aim of this study was to determine the 25‑hydroxy vitamin D (25(OH)D) levels in age ‑related macu‑ lar degeneration (AMD) patients. Methods: Age‑related macular degeneration (AMD) patients were classified into four groups: early AMD (N = 10), intermediate AMD (N = 12), advanced atrophic AMD (N = 19) and advanced neovascular AMD (N = 52) after undergo‑ ing fundus photography. Serum 25(OH)D levels of all subjects were evaluated. From a random control group of 326 patients whose 25(OH)D levels had been measured, a group of 93 were selected to match the age range of the AMD group. We measured 25(OH)D levels during the same period to rule out seasonal variation. Results: A total of 93 AMD patients (36 males and 57 females) and 93 healthy individuals (39 males and 54 females) were enrolled in this study with the mean age of 78.96 ± 8.46 vs. 78.80 ± 8.35, respectively. The patients affected by AMD had statistically significant lower 25(OH)D levels (15 ± 10 ng/mL) than the healthy subjects control group (21 ± 14 ng/mL) (p = 0.004). However, the median 25(OH)D levels in early AMD, intermediate AMD, advanced atrophic AMD and advanced neovascular AMD (12.5 ± 7.3; 15 ± 11; 15 ± 8 and 17 ± 11.5, respectively) were not statistically significant (p = 0.442). Conclusion: This study shows that patients affected by AMD had lower vitamin D levels compared to healthy sub ‑ jects. Further research is necessary to investigate the possible association between 25(OH)D levels and AMD. Keywords: Vitamin D, Age‑related macular degeneration, 25‑hydroxy vitamin D, Vitamin D deficiency, 25(OH)D Background potential to rise due to the increase in the life expectancy Age-related macular degeneration (AMD) is a complex of the population [2, 3]. disease associated with a high risk of complications that AMD has historically been classified into 2 types: dry affect vision. It develops mainly in people over 50  years or non-exudative AMD (dAMD) and wet, exudative, or of age and a key characteristic is the accumulation of a neovascular AMD (nAMD), dAMD forms the major- series of extracellular deposits in the macula, mainly ity of diagnosed cases and nAMD is responsible for the drusen [1]. It is the main cause of irreversible blindness in majority of severe vision loss. Although AMD is the subjects over 55 years of age in developed countries with major cause of severe vision loss, the geographic atrophy millions of affected patients and, in addition, with high produced by dAMD can also cause significant vision loss [4]. More recently, AMD has been classified according to 3 clinical stages: early AMD, intermediate AMD and advanced AMD divided into atrophic or neovascular *Correspondence: antoniopese@hotmail.com 1 AMD [5]. Department of Ophthalmology, Hospital General La Mancha Centro, Ciudad Real, Alcázar de San Juan, Spain Vitamin D could play a role in the pathophysiology Full list of author information is available at the end of the article of AMD. Vitamin D is known to be implicated as being © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pérez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 2 of 7 a protective factor in certain diseases such as cancer, From a group of 326 randomly selected patients whose cardiovascular diseases, bone diseases, kidney disease, 25 (OH)D level had been measured, we chose 93 to act as and other diseases [6]. Most vitamin D is produced by a control group to match the AMD group. the skin in the form of vitamin D3 due to the ultravio- We measured 25(OH)D in the serum of all patients let rays from sun exposure, and as such, due to confine - during the same period to rule out seasonal variation of ment, these levels may have been affected [7 ]. The main 25(OH)D levels. 25(OH)D was determined by electro- function of vitamin D is the absorption of calcium and chemiluminiscence immunoassay (ECLIA) (Roche cobas phosphorus from the diet, thereby contributing to the e 801). mineralization of bone. Osteoporosis, a disease with a The optimal vitamin D status is defined in different deficit in bone mass density, would be a clear example ways [14, 15]. Plasma 25(OH)D concentrations were of its association with vitamin D deficiency [8 ]. assessed from blood samples and categorized as severe Oxidative stress and inflammation lead to photore - deficiency (< 10 ng/mL), deficiency (10–19 ng/mL), insuf - ceptor degeneration and appear to be involved in the ficiency (20–29 ng/mL), or sufficiency (≥ 30 ng/mL). pathophysiology of AMD [9]. Vitamin D appears to increase the expression of antioxidant genes and there- Secondary outcome measures fore has the ability to reduce oxidative damage that For all AMD patients the best corrected visual acuity leads to photoreceptors degeneration [10]. In fact, the (BCVA), intraocular pressure (IOP), refraction, state of vitamin D receptor (VDR) is detected in retinal pig- the lens and central foveal thickness (CFT) were meas- ment epithelium and retinal photoreceptor cells [11, ured. The use of AREDS2 supplementation and smok - 12]. Vitamin D could play a role in reducing chronic ing status were also checked. BCVA was measured with oxidative stress, inhibiting amyloid protein deposits, Snellen charts (Topcon cc-100 hw3.0) and converted into inhibiting chronic inflammation and therefore also logMAR for statistical analysis purposes. The IOP in mm reducing angiogenesis [13]. Hg was measured by Goldmann applanation tonometer. The aim of the present study was to determine 25(OH) Refraction was measured by Canon RK-5 and Topcon D levels in AMD patients. Auto kerato-refractometers and was calculated as spheri- cal equivalent. Fundus photography was taken to catego- rize AMD according to Ferris clinical classification and to Methods measure CFT DRI OCT Triton plus (Topcon) and OCT This cross-sectional study was approved by the Hospital 3D OCT-2000 (Topcon) were used. We classified the General la Mancha Centro Ethics Committee (Alcázar state of the lens as phakic or pseudophakic. We excluded de San Juan, Spain) and was carried out in accordance all patients taking AREDS2 supplementation contain- with the Ethical Principles of the Declaration of Helsinki. ing vitamin D. Smoking status was defined as a current All candidates received detailed information about the smoker, ex-smoker, and non-smoker. nature of the investigation, and all provided their writ- Strict classification was used to analyse the affected ten informed consent. This study included patients who eye. Where the degree of severity did not differ, the eye had visited Hospital General la Mancha Centro, Alcázar with worse BCVA was used as the affected eye. de San Juan (Spain) and Hospital General de Tomelloso, Tomelloso (Spain), from February 2021 to April 2021. Sample size We categorized the participants into 4 AMD groups The number of patients needed was estimated based on according to Ferris clinical classification [5] after under - the 25(OH)D levels provided by Kan E et  al. [16]; with going fundus photography as follows: early AMD a statistical power of 90% and an α error of 0.05, 140 (N = 10), intermediate AMD (N = 12), advanced atrophic patients (n = 70 per group) will be needed. AMD (N = 19) and advanced neovascular AMD (N = 52), and those without any macular degeneration (control group). Statistical analysis We excluded patients with osteoporosis, vitamin D Statistical analysis was performed using the Statistical absorption problems, chronic renal failure, liver disease Package for Social Sciences (IBM SPSS Version 24) for or parathyroid disease based on the medical records in Windows. The distribution of numeric data was assessed our hospital. In addition, we excluded patients who were by the Kolmogorov–Smirnov test. Pearson’s chi-squared taking vitamin D supplements. test was employed to examine the differences between We also excluded patients with amblyopia, retinal dys- categorical variables. The Mann–Whitney U test was trophy, pathologic myopia, diabetic retinopathy, retinal used for the comparison the differences between two vein occlusion and retinal artery occlusion. groups. The Kruskal–Wallis H test was used to analyze P érez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 3 of 7 the differences between three or more groups. Values of p < 0.05 was considered as statistically significant. Results A total of 93 AMD patients (36 males and 57 females) and 93 healthy individuals (39 males and 54 females) were enrolled in this study with the mean age of 78.96 ± 8.5 and 78.8 ± 8.4, respectively. There was no significant dif - ference between AMD group and control group in terms of age (p = 0.970) and gender (F/M: 61.3%/38.7% Vs 58.1%/41.9%;p = 0.654). Table  1 shows the main charac- teristics of patients included in our study. Of 93 patients with AMD, 10 subjects had early AMD (10.8%), 12 had intermediate AMD (12.9%), 19 had advanced dAMD (20.4%) and 52 had advanced nAMD (55.9%). The mean BCVA, mean IOP, mean CFT was + 1.11 ± 0.95 logMAR, 15.20 ± 2.99  mm Hg and 61.95 ± 63,61 µm, respectively. Of 93 patients with AMD, 49 (52.7%) were phakic and 44 pseudophakic (47.3%). 34 (36.6%) patients were identified to be taking AREDS2 supplementation and 59 (63.4%) were not taking any AREDS2 supplementation. 6 (6.5%) patients were cur- Fig. 1 Serum 25(OH)D levels in Control versus AMD patients rent smokers, 25 (26.9%) were ex-smokers and 62 (66.7%) were non-smokers. The patients affected by AMD had statistically signifi - cant lower serum 25(OH)D levels (15 ± 10  ng/mL) than The prevalence of vitamin D deficiency was high - healthy subject group (21 ± 14  ng/mL) (p = 0.004). Fig.  1 est in the AMD group vs. control patients (47 (50.5%) and Table 1 vs. 29 (31.2%), respectively, p = 0.007). Rates of vitamin However, the median 25(OH)D levels in early AMD, D severe deficiency were highest in the AMD group vs. intermediate AMD, advanced dAMD and advanced control patients (15 (16.1%) and 11 (11.8%), respectively, nAMD (12.5 ± 7.3, 15 ± 11, 15 ± 8, 17 ± 11.5, respec- p = 0.398). Instead, the prevalence of vitamin D insuffi - tively) were not statistically significant (p = 0.442). Fig. 2. ciency was highest in the control group vs. AMD group (34 (36.6%) vs. 21 (22.6%), respectively, p = 0.037). Rates of vitamin D sufficiency were highest in the control group vs. AMD group 19 (20.4%) vs. 10 (10.8%), respec- Table 1 Main characteristics of patients included in our study tively, p = 0.069). Fig. 3 and Table 1. AMD Group Control Group p Eighty-three (89.2%) AMD patients had abnormal (n = 93) (n = 93) serum 25(OH)D levels (< 30  ng/mL) and 74 (79.6% in healthy patients. Ten (10.8%) AMD patients had normal Age, mean ± SD 78.96 ± 8.5 78.8 ± 8.4 0.970 serum 25(OH)D levels (≥ 30  ng/mL) vs 19 (20.4%) in Gender healthy patients; p = 0.069. Fig. 4. Female 57 (61.3%) 54 (58.1%) 0.654 Finally in AMD group, abnormal serum 25(OH)D lev- Male 36 (38.7%) 39 (41.9%) els (< 30 ng/mL) was not associated with age (p = 0.858), Levels Vit D, median ± IQR 15 ± 10 21 ± 14 0.004 gender (p > 0.999), BCVA (p = 0.274), IOP (p = 0.774), Sufficiency 10 (10.8%) 19 (20.4%) 0.013 refraction (p = 0.542), state of the lens (p = 0.324), CFT Insufficiency 21 (22.6%) 34 (36.6%) (p = 0.673), AREDS2 supplementation (p > 0.999) or Deficiency 47 (50.5%) 29 (31.2%) smoking status (p = 0.544) Table 2. Severe deficiency 15 (16.1%) 11 (11.8%) Normal 10 (10.8%) 19 (20.4%) 0.069 Discussion Pathological 83 (89.2%) 74 (79.6%) There is no consensus on the current status of the rela - Sufficiency + insufficiency 31 (33.3%) 53 (57%) 0.001 tionship between serum 25(OH)D levels and AMD. Two Deficiency + severe defi‑ 62 (66.7%) 40 (43%) ciency different meta-analyses show different results regarding the relationship between vitamin D and AMD [17, 18]. SD standard deviation, IQR interquartile range Pérez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 4 of 7 Fig. 2 Serum 25(OH)D levels according to AMD Ferris clinical classification Fig. 3 Prevalence of vitamin D sufficiency, insufficiency, deficiency and severe deficiency according to group P érez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 5 of 7 Fig. 4 Prevalence of normal serum 25(OH)D levels (≥30 ng/mL) vs. abnormal serum 25(OH)D levels (<30 ng/mL) according to group Table 2 Comparison between AMD patients with abnormal high 25(OH)D concentrations may be protective against serum 25(OH)D levels and AMD patients with normal serum AMD. 25(OH)D levels However, the second meta-analysis [18] shows there is no evidence to indicate an inverse association between Normal Phatological p (n = 10) (n = 83) serum vitamin D levels and any stages and subtypes of AMD risk. Age, mean ± SD 78.5 ± 5.1 79 ± 8.8 0.858 One problem is defining what vitamin D value is nor - Gender mal and which is abnormal. Current guidelines suggest Female 6 (60%) 51 (61.4%) > 0.999 that 25(OH)D concentration values < 12 ng/mL are asso- Male 4 (40%) 32 (38.6%) ciated with an increased risk of osteomalacia, whereas BCVA, median ± IQR 0.5 ± 1.05 1 ± 1.7 0.274 25(OH)D levels between 20 and 50  ng/mL appear to be IOP, median ± IQR 14.5 ± 4 15 ± 4 0.774 safe and sufficient for skeletal health in the healthy gen - State of lens eral population [14]. It is not clear how or whether these Pseudophakic 3 (30%) 41 (49.4%) 0.324 guidelines should be considered with regard to individu- Phakic 7 (70%) 42 (50.6%) als who have metabolic bone diseases, such as osteoporo- CFT, Median ± IQR 251.5 ± 45 252 ± 63 0.673 sis or primary hyperparathyroidism. AREDS suppl 4 (40%) 30 (36.1%) > 0.899 Different agencies and countries interpret 25(OH)D Smoking status concentration levels in a different way. We chose recom - Current smoker 0 6 (7.2%) 0.544 mendations for interpreting serum levels from the Inter- Former smoker 2 (20%) 23 (27.7%) national Osteoporosis Foundation [15]. Non smoker 10 (80%) 54 (65.1%) Itty et  al. [19] defined vitamin D insufficiency, defi - SD standard deviation, IQR interquartile range ciency, and severe deficiency according to non-neovascu - lar AMD (NNVAMD), neovascular AMD (NVAMD) and control group. The prevalence of vitamin D insufficiency, The first meta-analysis [17] supports the idea that age- deficiency, and severe deficiency were all highest in the related decrease in 25(OH)D concentration may expose NVAMD vs. NNVAMD and control patients. to AMD onset and worsening and provides evidence that Day et  al. [20] concluded that associations between vitamin D deficiency and a first diagnosis of NNVAMD Pérez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 6 of 7 Acknowledgements and NVAMD were not statistically significant (p = 0.62 We thank Ángel Arias for statistical support and Aileen Gilhooly for english in NNVAMD group and p = 0.82 in NVAMD group). manuscript revision. Moreover, our study did not show statistically signifi - Authors’ contributions cant differences between the different stages of AMD. Material preparation, data collection, and analysis were performed by APS. In a Korean population Kim et al. [21] showed that a All authors were involved in the literature search, drafting, revising, and final high level of blood 25(OH)D was inversely associated approval of the paper. All authors read and approved the final manuscript. with late AMD in men but not women. In another piece Funding of Korean research Cho et  al. [22] indicated that per 1 The authors received no financial support for the research, authorship, and/or unit ng/mL increase in 25(OH)D the OR was 1.01 (95% publication of this article. CI 1–1.03, p = 0.179) in any AMD and 0.98 (95% CI Availability of data and materials 0.94–1.03, p = 0.501) in late AMD. Access to SPSS data file may be provided at any point of time during the Golan et  al. [23] in a study population comprised of submission process. 1,045 members diagnosed as having AMD, and 8,124 as non-AMD the mean ± SD level of 25(OH)D was Declarations 24.1 ± 9.41 ng/ml (range 0.8–120) for the AMD patients Ethics approval and consent to participate and 24.13 ± 9.50 ng/ml (range 0.0–120) for the controls, The study was approved by the Hospital General la Mancha Centro Ethics not statistically significant. They found no evidence for Committee (Alcázar de San Juan, Spain) and was carried out in accordance with the Ethical Principles of the Declaration of Helsinki. Data was analyzed inverse association between 25(OH)D and AMD. anonymously. The serum 25(OH)D levels in our study are lower in the AMD and the control group, (17.12 ± 7.73  ng/ Informed consent Informed consent was obtained from all individual participants included in mL and 21.51 ± 10.61  ng/mL, respectively). We found the study. it difficult and inaccurate to compare the results of the different studies due to the different methods of Consent for publication All authors agree with the publication. measuring vitamin D, the differences between the study designs, and the different latitudes of the study Competing interests populations. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Cutaneous vitamin D3 synthesis is diminished or absent at relatively high latitudes (> 35°N/S, particularly Author details during the winter) by ecological factors that reduce ultra- Department of Ophthalmology, Hospital General La Mancha Centro, Ciudad Real, Alcázar de San Juan, Spain. Department of Ophthalmology, Hospital violet B (UVB) penetration and by individual factors that Universitario Juan Ramón Jiménez, Ronda Exterior Norte s/n, 21005 Huelva, limit cutaneous exposure to UVB, such as dark skin pig- 3 Spain. Department of General Medicine, Centro de Salud Trigueros, Trigueros, 4 5 mentation, sun avoidant lifestyles, conservative clothing Huelva, Spain. Universidad Castilla‑La Mancha, Albacete, Spain. Depar tment of Ophthalmology, Hospital Universitario Puerta de Hierro‑Majadahonda, habits, and liberal use of sunscreen [24]. Madrid, Spain. Our study is located in a region 39º north latitude in Spain, thus in a risk zone for vitamin D deficiency and the Received: 28 January 2022 Accepted: 20 February 2022 study was completed during the Covid-19 pandemic, so people could have had less cutaneous exposure to UVB and been able to synthesize less vitamin D although this References would equally affect both of the studied groups. 1. Spaide RF, Jaffe GJ, Sarraf D, et al. Consensus nomenclature for reporting Our study had some limitations. Firstly, the weaknesses neovascular age‑related macular degeneration data. Ophthalmology. of cross-sectional studies include the inability to make 2020;127:616–36. https:// doi. org/ 10. 1016/j. ophtha. 2019. 11. 004. 2. Garcia‑Layana A, Cabrera‑López F, García‑Arumí J, et al. Early and interme ‑ a causal inference. Secondly, the size of the samples in diate age‑related macular degeneration: update and clinical review. Clin some groups was relatively small. Therefore, it was diffi - Interv Aging. 2017;12:1579–87. https:// doi. org/ 10. 2147/ CIA. S1426 85. cult to determine the exact correlation between vitamin 3. Pennington KL, DeAngelis MM. Epidemiology of age‑related macular degeneration (AMD): associations with cardiovascular disease phe‑ D deficiency and AMD severity. notypes and lipid factors. Eye Vis. 2016;3:34. https:// doi. org/ 10. 1186/ s40662‑ 016‑ 0063‑5. 4. Gheorghe A, Mahdi L, Musat O. Age‑related macular degeneration. Rom J Ophthalmol. 2015;59(2):74–7. Conclusion 5. Ferris FL, Wilkinson CP, Bird A, et al. Clinical classification of age ‑related In conclusion, this study shows that patients affected macular degeneration. Ophthalmology. 2013;120:844–51. https:// doi. org/ by AMD have lower vitamin D levels in comparison to 10. 1016/j. ophtha. 2012. 10. 036. 6. Kaarniranta K, Pawlowska E, Szczepanska J, et al. Can vitamin D protect healthy subjects. Further research is necessary to inves- against age‑related macular degeneration or slow its progression? Acta tigate the possible association between 25(OH)D levels Biochim Pol. 2019. https:// doi. org/ 10. 18388/ abp. 2018_ 2810. and AMD. P érez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 7 of 7 7. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease1–4. Am J Clin Nutr. 2018;80:11. https:// doi. org/ 10. 1093/ ajcn/ 80.6. 1678s. 8. Gallagher JC. Vitamin D and aging. Endocrinol Metab Clin North Am. 2013;42:319–32. https:// doi. org/ 10. 1016/j. ecl. 2013. 02. 004. 9. Abokyi S, To C‑H, Lam TT, Tse DY. Central role of oxidative stress in age ‑ related macular degeneration: evidence from a review of the molecular mechanisms and animal models. Oxid Med Cell Longev. 2020;2020:1–19. https:// doi. org/ 10. 1155/ 2020/ 79012 70. 10. Tohari AM, Zhou X, Shu X. Protection against oxidative stress by vitamin D in cone cells. Cell Biochem Funct. 2016;34:13. https:// doi. org/ 10. 1002/ cbf. 11. Morrison MA, Silveira AC, Huynh N, et al. Systems biology‑based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age‑related macular degeneration. Syst Biol. 2011;5:31. https:// doi. org/ 10. 1186/ 1479‑ 7364‑5‑ 6‑ 538. 12. Reins RY, McDermott AM. Vitamin D: implications for ocular disease and therapeutic potential. Exp Eye Res. 2015;134:101–10. https:// doi. org/ 10. 1016/j. exer. 2015. 02. 019. 13. Layana A, Minnella A, Garhöfer G, et al. Vitamin D and age‑related macu‑ lar degeneration. Nutrients. 2017;9:1120. https:// doi. org/ 10. 3390/ nu910 14. Giustina A, Adler RA, Binkley N, et al. Controversies in vitamin D: summary statement from an international conference. J Clin Endocrinol Metab. 2019;104:234–40. https:// doi. org/ 10. 1210/ jc. 2018‑ 01414. 15. Bouillon R. Comparative analysis of nutritional guidelines for vitamin D. Nat Rev Endocrinol. 2017;13:466–79. https:// doi. org/ 10. 1038/ nrendo. 2017. 31. 16. Kan E, Kan EK, Yücel ÖE. The possible link between vitamin D levels and exudative age‑related macular degeneration. Oman Med J. 2020;35:e83– e83. https:// doi. org/ 10. 5001/ omj. 2020. 01. 17. Annweiler C, Drouet M, Duval GT, et al. Circulating vitamin D concen‑ tration and age‑related macular degeneration: systematic review and meta‑analysis. Maturitas. 2016;88:101–12. https:// doi. org/ 10. 1016/j. matur itas. 2016. 04. 002. 18. Wu W, Weng Y, Guo X, et al. The association between serum vitamin D levels and age‑ related macular degeneration: a systematic meta‑analytic review. Invest Ophthalmol Vis Sci. 2016;57(4):2168–77. https:// doi. org/ 10. 1167/ iovs. 15‑ 18218. 19. Itty S, Day S, Lyles KW, et al. Vitamin D deficiency in neovascular versus nonneovascular age‑related macular degeneration. Retina. 2014;34:1779–86. https:// doi. org/ 10. 1097/ IAE. 00000 00000 000178. 20. Day S, Acquah K, Platt A, et al. Association of vitamin D deficiency and age‑related macular degeneration in medicare beneficiaries. Arch Oph‑ thalmol. 2012;130:1070. https:// doi. org/ 10. 1001/ archo phtha lmol. 2012. 21. Kim EC, Han K, Jee D. Inverse relationship between high blood 25‑hydroxyvitamin D and late stage of age ‑related macular degenera‑ tion in a representative Korean population. Investig Opthalmol Vis Sci. 2014;55:4823. https:// doi. org/ 10. 1167/ iovs. 14‑ 14763. 22. Cho B‑ J, Heo JW, Kim TW, et al. Prevalence and risk factors of age‑related macular degeneration in Korea: the Korea national health and nutrition examination survey 2010–2011. Investig Opthalmol Vis Sci. 2014;55:1101. https:// doi. org/ 10. 1167/ iovs. 13‑ 13096. 23. Golan S, Shalev V, Treister G, et al. Reconsidering the connection between vitamin D levels and age‑related macular degeneration. Eye. 2011;25:1122–9. https:// doi. org/ 10. 1038/ eye. 2011. 174. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 24. Roth DE, Abrams SA, Aloia J, et al. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low‑ and middle ‑income fast, convenient online submission countries. Ann N Y Acad Sci. 2018;1430:44–79. https:// doi. org/ 10. 1111/ thorough peer review by experienced researchers in your field nyas. 13968. rapid publication on acceptance support for research data, including large and complex data types Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ • gold Open Access which fosters wider collaboration and increased citations lished maps and institutional affiliations. maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. 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Abstract

Background: The aim of this study was to determine the 25‑hydroxy vitamin D (25(OH)D) levels in age ‑related macu‑ lar degeneration (AMD) patients. Methods: Age‑related macular degeneration (AMD) patients were classified into four groups: early AMD (N = 10), intermediate AMD (N = 12), advanced atrophic AMD (N = 19) and advanced neovascular AMD (N = 52) after undergo‑ ing fundus photography. Serum 25(OH)D levels of all subjects were evaluated. From a random control group of 326 patients whose 25(OH)D levels had been measured, a group of 93 were selected to match the age range of the AMD group. We measured 25(OH)D levels during the same period to rule out seasonal variation. Results: A total of 93 AMD patients (36 males and 57 females) and 93 healthy individuals (39 males and 54 females) were enrolled in this study with the mean age of 78.96 ± 8.46 vs. 78.80 ± 8.35, respectively. The patients affected by AMD had statistically significant lower 25(OH)D levels (15 ± 10 ng/mL) than the healthy subjects control group (21 ± 14 ng/mL) (p = 0.004). However, the median 25(OH)D levels in early AMD, intermediate AMD, advanced atrophic AMD and advanced neovascular AMD (12.5 ± 7.3; 15 ± 11; 15 ± 8 and 17 ± 11.5, respectively) were not statistically significant (p = 0.442). Conclusion: This study shows that patients affected by AMD had lower vitamin D levels compared to healthy sub ‑ jects. Further research is necessary to investigate the possible association between 25(OH)D levels and AMD. Keywords: Vitamin D, Age‑related macular degeneration, 25‑hydroxy vitamin D, Vitamin D deficiency, 25(OH)D Background potential to rise due to the increase in the life expectancy Age-related macular degeneration (AMD) is a complex of the population [2, 3]. disease associated with a high risk of complications that AMD has historically been classified into 2 types: dry affect vision. It develops mainly in people over 50  years or non-exudative AMD (dAMD) and wet, exudative, or of age and a key characteristic is the accumulation of a neovascular AMD (nAMD), dAMD forms the major- series of extracellular deposits in the macula, mainly ity of diagnosed cases and nAMD is responsible for the drusen [1]. It is the main cause of irreversible blindness in majority of severe vision loss. Although AMD is the subjects over 55 years of age in developed countries with major cause of severe vision loss, the geographic atrophy millions of affected patients and, in addition, with high produced by dAMD can also cause significant vision loss [4]. More recently, AMD has been classified according to 3 clinical stages: early AMD, intermediate AMD and advanced AMD divided into atrophic or neovascular *Correspondence: antoniopese@hotmail.com 1 AMD [5]. Department of Ophthalmology, Hospital General La Mancha Centro, Ciudad Real, Alcázar de San Juan, Spain Vitamin D could play a role in the pathophysiology Full list of author information is available at the end of the article of AMD. Vitamin D is known to be implicated as being © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pérez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 2 of 7 a protective factor in certain diseases such as cancer, From a group of 326 randomly selected patients whose cardiovascular diseases, bone diseases, kidney disease, 25 (OH)D level had been measured, we chose 93 to act as and other diseases [6]. Most vitamin D is produced by a control group to match the AMD group. the skin in the form of vitamin D3 due to the ultravio- We measured 25(OH)D in the serum of all patients let rays from sun exposure, and as such, due to confine - during the same period to rule out seasonal variation of ment, these levels may have been affected [7 ]. The main 25(OH)D levels. 25(OH)D was determined by electro- function of vitamin D is the absorption of calcium and chemiluminiscence immunoassay (ECLIA) (Roche cobas phosphorus from the diet, thereby contributing to the e 801). mineralization of bone. Osteoporosis, a disease with a The optimal vitamin D status is defined in different deficit in bone mass density, would be a clear example ways [14, 15]. Plasma 25(OH)D concentrations were of its association with vitamin D deficiency [8 ]. assessed from blood samples and categorized as severe Oxidative stress and inflammation lead to photore - deficiency (< 10 ng/mL), deficiency (10–19 ng/mL), insuf - ceptor degeneration and appear to be involved in the ficiency (20–29 ng/mL), or sufficiency (≥ 30 ng/mL). pathophysiology of AMD [9]. Vitamin D appears to increase the expression of antioxidant genes and there- Secondary outcome measures fore has the ability to reduce oxidative damage that For all AMD patients the best corrected visual acuity leads to photoreceptors degeneration [10]. In fact, the (BCVA), intraocular pressure (IOP), refraction, state of vitamin D receptor (VDR) is detected in retinal pig- the lens and central foveal thickness (CFT) were meas- ment epithelium and retinal photoreceptor cells [11, ured. The use of AREDS2 supplementation and smok - 12]. Vitamin D could play a role in reducing chronic ing status were also checked. BCVA was measured with oxidative stress, inhibiting amyloid protein deposits, Snellen charts (Topcon cc-100 hw3.0) and converted into inhibiting chronic inflammation and therefore also logMAR for statistical analysis purposes. The IOP in mm reducing angiogenesis [13]. Hg was measured by Goldmann applanation tonometer. The aim of the present study was to determine 25(OH) Refraction was measured by Canon RK-5 and Topcon D levels in AMD patients. Auto kerato-refractometers and was calculated as spheri- cal equivalent. Fundus photography was taken to catego- rize AMD according to Ferris clinical classification and to Methods measure CFT DRI OCT Triton plus (Topcon) and OCT This cross-sectional study was approved by the Hospital 3D OCT-2000 (Topcon) were used. We classified the General la Mancha Centro Ethics Committee (Alcázar state of the lens as phakic or pseudophakic. We excluded de San Juan, Spain) and was carried out in accordance all patients taking AREDS2 supplementation contain- with the Ethical Principles of the Declaration of Helsinki. ing vitamin D. Smoking status was defined as a current All candidates received detailed information about the smoker, ex-smoker, and non-smoker. nature of the investigation, and all provided their writ- Strict classification was used to analyse the affected ten informed consent. This study included patients who eye. Where the degree of severity did not differ, the eye had visited Hospital General la Mancha Centro, Alcázar with worse BCVA was used as the affected eye. de San Juan (Spain) and Hospital General de Tomelloso, Tomelloso (Spain), from February 2021 to April 2021. Sample size We categorized the participants into 4 AMD groups The number of patients needed was estimated based on according to Ferris clinical classification [5] after under - the 25(OH)D levels provided by Kan E et  al. [16]; with going fundus photography as follows: early AMD a statistical power of 90% and an α error of 0.05, 140 (N = 10), intermediate AMD (N = 12), advanced atrophic patients (n = 70 per group) will be needed. AMD (N = 19) and advanced neovascular AMD (N = 52), and those without any macular degeneration (control group). Statistical analysis We excluded patients with osteoporosis, vitamin D Statistical analysis was performed using the Statistical absorption problems, chronic renal failure, liver disease Package for Social Sciences (IBM SPSS Version 24) for or parathyroid disease based on the medical records in Windows. The distribution of numeric data was assessed our hospital. In addition, we excluded patients who were by the Kolmogorov–Smirnov test. Pearson’s chi-squared taking vitamin D supplements. test was employed to examine the differences between We also excluded patients with amblyopia, retinal dys- categorical variables. The Mann–Whitney U test was trophy, pathologic myopia, diabetic retinopathy, retinal used for the comparison the differences between two vein occlusion and retinal artery occlusion. groups. The Kruskal–Wallis H test was used to analyze P érez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 3 of 7 the differences between three or more groups. Values of p < 0.05 was considered as statistically significant. Results A total of 93 AMD patients (36 males and 57 females) and 93 healthy individuals (39 males and 54 females) were enrolled in this study with the mean age of 78.96 ± 8.5 and 78.8 ± 8.4, respectively. There was no significant dif - ference between AMD group and control group in terms of age (p = 0.970) and gender (F/M: 61.3%/38.7% Vs 58.1%/41.9%;p = 0.654). Table  1 shows the main charac- teristics of patients included in our study. Of 93 patients with AMD, 10 subjects had early AMD (10.8%), 12 had intermediate AMD (12.9%), 19 had advanced dAMD (20.4%) and 52 had advanced nAMD (55.9%). The mean BCVA, mean IOP, mean CFT was + 1.11 ± 0.95 logMAR, 15.20 ± 2.99  mm Hg and 61.95 ± 63,61 µm, respectively. Of 93 patients with AMD, 49 (52.7%) were phakic and 44 pseudophakic (47.3%). 34 (36.6%) patients were identified to be taking AREDS2 supplementation and 59 (63.4%) were not taking any AREDS2 supplementation. 6 (6.5%) patients were cur- Fig. 1 Serum 25(OH)D levels in Control versus AMD patients rent smokers, 25 (26.9%) were ex-smokers and 62 (66.7%) were non-smokers. The patients affected by AMD had statistically signifi - cant lower serum 25(OH)D levels (15 ± 10  ng/mL) than The prevalence of vitamin D deficiency was high - healthy subject group (21 ± 14  ng/mL) (p = 0.004). Fig.  1 est in the AMD group vs. control patients (47 (50.5%) and Table 1 vs. 29 (31.2%), respectively, p = 0.007). Rates of vitamin However, the median 25(OH)D levels in early AMD, D severe deficiency were highest in the AMD group vs. intermediate AMD, advanced dAMD and advanced control patients (15 (16.1%) and 11 (11.8%), respectively, nAMD (12.5 ± 7.3, 15 ± 11, 15 ± 8, 17 ± 11.5, respec- p = 0.398). Instead, the prevalence of vitamin D insuffi - tively) were not statistically significant (p = 0.442). Fig. 2. ciency was highest in the control group vs. AMD group (34 (36.6%) vs. 21 (22.6%), respectively, p = 0.037). Rates of vitamin D sufficiency were highest in the control group vs. AMD group 19 (20.4%) vs. 10 (10.8%), respec- Table 1 Main characteristics of patients included in our study tively, p = 0.069). Fig. 3 and Table 1. AMD Group Control Group p Eighty-three (89.2%) AMD patients had abnormal (n = 93) (n = 93) serum 25(OH)D levels (< 30  ng/mL) and 74 (79.6% in healthy patients. Ten (10.8%) AMD patients had normal Age, mean ± SD 78.96 ± 8.5 78.8 ± 8.4 0.970 serum 25(OH)D levels (≥ 30  ng/mL) vs 19 (20.4%) in Gender healthy patients; p = 0.069. Fig. 4. Female 57 (61.3%) 54 (58.1%) 0.654 Finally in AMD group, abnormal serum 25(OH)D lev- Male 36 (38.7%) 39 (41.9%) els (< 30 ng/mL) was not associated with age (p = 0.858), Levels Vit D, median ± IQR 15 ± 10 21 ± 14 0.004 gender (p > 0.999), BCVA (p = 0.274), IOP (p = 0.774), Sufficiency 10 (10.8%) 19 (20.4%) 0.013 refraction (p = 0.542), state of the lens (p = 0.324), CFT Insufficiency 21 (22.6%) 34 (36.6%) (p = 0.673), AREDS2 supplementation (p > 0.999) or Deficiency 47 (50.5%) 29 (31.2%) smoking status (p = 0.544) Table 2. Severe deficiency 15 (16.1%) 11 (11.8%) Normal 10 (10.8%) 19 (20.4%) 0.069 Discussion Pathological 83 (89.2%) 74 (79.6%) There is no consensus on the current status of the rela - Sufficiency + insufficiency 31 (33.3%) 53 (57%) 0.001 tionship between serum 25(OH)D levels and AMD. Two Deficiency + severe defi‑ 62 (66.7%) 40 (43%) ciency different meta-analyses show different results regarding the relationship between vitamin D and AMD [17, 18]. SD standard deviation, IQR interquartile range Pérez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 4 of 7 Fig. 2 Serum 25(OH)D levels according to AMD Ferris clinical classification Fig. 3 Prevalence of vitamin D sufficiency, insufficiency, deficiency and severe deficiency according to group P érez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 5 of 7 Fig. 4 Prevalence of normal serum 25(OH)D levels (≥30 ng/mL) vs. abnormal serum 25(OH)D levels (<30 ng/mL) according to group Table 2 Comparison between AMD patients with abnormal high 25(OH)D concentrations may be protective against serum 25(OH)D levels and AMD patients with normal serum AMD. 25(OH)D levels However, the second meta-analysis [18] shows there is no evidence to indicate an inverse association between Normal Phatological p (n = 10) (n = 83) serum vitamin D levels and any stages and subtypes of AMD risk. Age, mean ± SD 78.5 ± 5.1 79 ± 8.8 0.858 One problem is defining what vitamin D value is nor - Gender mal and which is abnormal. Current guidelines suggest Female 6 (60%) 51 (61.4%) > 0.999 that 25(OH)D concentration values < 12 ng/mL are asso- Male 4 (40%) 32 (38.6%) ciated with an increased risk of osteomalacia, whereas BCVA, median ± IQR 0.5 ± 1.05 1 ± 1.7 0.274 25(OH)D levels between 20 and 50  ng/mL appear to be IOP, median ± IQR 14.5 ± 4 15 ± 4 0.774 safe and sufficient for skeletal health in the healthy gen - State of lens eral population [14]. It is not clear how or whether these Pseudophakic 3 (30%) 41 (49.4%) 0.324 guidelines should be considered with regard to individu- Phakic 7 (70%) 42 (50.6%) als who have metabolic bone diseases, such as osteoporo- CFT, Median ± IQR 251.5 ± 45 252 ± 63 0.673 sis or primary hyperparathyroidism. AREDS suppl 4 (40%) 30 (36.1%) > 0.899 Different agencies and countries interpret 25(OH)D Smoking status concentration levels in a different way. We chose recom - Current smoker 0 6 (7.2%) 0.544 mendations for interpreting serum levels from the Inter- Former smoker 2 (20%) 23 (27.7%) national Osteoporosis Foundation [15]. Non smoker 10 (80%) 54 (65.1%) Itty et  al. [19] defined vitamin D insufficiency, defi - SD standard deviation, IQR interquartile range ciency, and severe deficiency according to non-neovascu - lar AMD (NNVAMD), neovascular AMD (NVAMD) and control group. The prevalence of vitamin D insufficiency, The first meta-analysis [17] supports the idea that age- deficiency, and severe deficiency were all highest in the related decrease in 25(OH)D concentration may expose NVAMD vs. NNVAMD and control patients. to AMD onset and worsening and provides evidence that Day et  al. [20] concluded that associations between vitamin D deficiency and a first diagnosis of NNVAMD Pérez Serena et al. International Journal of Retina and Vitreous (2022) 8:17 Page 6 of 7 Acknowledgements and NVAMD were not statistically significant (p = 0.62 We thank Ángel Arias for statistical support and Aileen Gilhooly for english in NNVAMD group and p = 0.82 in NVAMD group). manuscript revision. Moreover, our study did not show statistically signifi - Authors’ contributions cant differences between the different stages of AMD. Material preparation, data collection, and analysis were performed by APS. In a Korean population Kim et al. [21] showed that a All authors were involved in the literature search, drafting, revising, and final high level of blood 25(OH)D was inversely associated approval of the paper. All authors read and approved the final manuscript. with late AMD in men but not women. In another piece Funding of Korean research Cho et  al. [22] indicated that per 1 The authors received no financial support for the research, authorship, and/or unit ng/mL increase in 25(OH)D the OR was 1.01 (95% publication of this article. CI 1–1.03, p = 0.179) in any AMD and 0.98 (95% CI Availability of data and materials 0.94–1.03, p = 0.501) in late AMD. Access to SPSS data file may be provided at any point of time during the Golan et  al. [23] in a study population comprised of submission process. 1,045 members diagnosed as having AMD, and 8,124 as non-AMD the mean ± SD level of 25(OH)D was Declarations 24.1 ± 9.41 ng/ml (range 0.8–120) for the AMD patients Ethics approval and consent to participate and 24.13 ± 9.50 ng/ml (range 0.0–120) for the controls, The study was approved by the Hospital General la Mancha Centro Ethics not statistically significant. They found no evidence for Committee (Alcázar de San Juan, Spain) and was carried out in accordance with the Ethical Principles of the Declaration of Helsinki. Data was analyzed inverse association between 25(OH)D and AMD. anonymously. The serum 25(OH)D levels in our study are lower in the AMD and the control group, (17.12 ± 7.73  ng/ Informed consent Informed consent was obtained from all individual participants included in mL and 21.51 ± 10.61  ng/mL, respectively). We found the study. it difficult and inaccurate to compare the results of the different studies due to the different methods of Consent for publication All authors agree with the publication. measuring vitamin D, the differences between the study designs, and the different latitudes of the study Competing interests populations. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Cutaneous vitamin D3 synthesis is diminished or absent at relatively high latitudes (> 35°N/S, particularly Author details during the winter) by ecological factors that reduce ultra- Department of Ophthalmology, Hospital General La Mancha Centro, Ciudad Real, Alcázar de San Juan, Spain. Department of Ophthalmology, Hospital violet B (UVB) penetration and by individual factors that Universitario Juan Ramón Jiménez, Ronda Exterior Norte s/n, 21005 Huelva, limit cutaneous exposure to UVB, such as dark skin pig- 3 Spain. Department of General Medicine, Centro de Salud Trigueros, Trigueros, 4 5 mentation, sun avoidant lifestyles, conservative clothing Huelva, Spain. Universidad Castilla‑La Mancha, Albacete, Spain. Depar tment of Ophthalmology, Hospital Universitario Puerta de Hierro‑Majadahonda, habits, and liberal use of sunscreen [24]. Madrid, Spain. Our study is located in a region 39º north latitude in Spain, thus in a risk zone for vitamin D deficiency and the Received: 28 January 2022 Accepted: 20 February 2022 study was completed during the Covid-19 pandemic, so people could have had less cutaneous exposure to UVB and been able to synthesize less vitamin D although this References would equally affect both of the studied groups. 1. Spaide RF, Jaffe GJ, Sarraf D, et al. Consensus nomenclature for reporting Our study had some limitations. Firstly, the weaknesses neovascular age‑related macular degeneration data. Ophthalmology. of cross-sectional studies include the inability to make 2020;127:616–36. https:// doi. org/ 10. 1016/j. ophtha. 2019. 11. 004. 2. Garcia‑Layana A, Cabrera‑López F, García‑Arumí J, et al. Early and interme ‑ a causal inference. Secondly, the size of the samples in diate age‑related macular degeneration: update and clinical review. Clin some groups was relatively small. 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Eye. 2011;25:1122–9. https:// doi. org/ 10. 1038/ eye. 2011. 174. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 24. Roth DE, Abrams SA, Aloia J, et al. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low‑ and middle ‑income fast, convenient online submission countries. Ann N Y Acad Sci. 2018;1430:44–79. https:// doi. org/ 10. 1111/ thorough peer review by experienced researchers in your field nyas. 13968. rapid publication on acceptance support for research data, including large and complex data types Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ • gold Open Access which fosters wider collaboration and increased citations lished maps and institutional affiliations. maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

International Journal of Retina and VitreousSpringer Journals

Published: Mar 7, 2022

Keywords: Vitamin D; Age-related macular degeneration; 25-hydroxy vitamin D; Vitamin D deficiency; 25(OH)D

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