|
 
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| EDITORIAL |
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| Year : 2023 | Volume
: 3
| Issue : 2 | Page : 43-46 |
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The sunshine vitamin
Kiran Vishnu Narayan
Department of Pulmonary Medicine, Government Medical College, Thiruvananthapuram, Kerala, India
| Date of Submission | 26-Mar-2023 |
| Date of Acceptance | 05-Apr-2023 |
| Date of Web Publication | 02-May-2023 |
Correspondence Address:
Dr. Kiran Vishnu Narayan
Department of Pulmonary Medicine, Government Medical College, Thiruvananthapuram, Kerala
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jalh.jalh_6_23
How to cite this article:
Narayan KV. The sunshine vitamin. J Adv Lung Health 2023;3:43-6 |
Vitamin D, the “Sunshine Vitamin” produced under the skin using sunlight, is required for normal calcium homeostasis. Recent studies show an association between Vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and depression, although some are conflicting reports.[1],[2]
Vitamin D deficiency is highly prevalent with 47% of African–American and 56% of Caucasian infants having it in the United States. More than 90% of infants studied in India, Iran, and Turkey also had Vitamin D deficiency. The same scenario is identifiable in adults with 35% of the adult population in the United States having Vitamin D deficiency. In countries such as India, Bangladesh, and Pakistan, the proportion was over 80%.[3]
Vitamin D is obtained through the diet and produced in the skin under the influence of sunlight. A 20-min exposure of at least 40% of the skin is necessary to prevent deficiency. Ultraviolet (UV)-B rays convert 7-dehydrocholesterol in the skin to pre-Vitamin D, and this pre-Vitamin D undergoes heat isomerization to Vitamin D. It is then metabolized in the liver to 25-hydroxyvitamin D (25[OH]D) and further in the kidneys to the biologically active form 1, 25-hydroxyvitamin D (1,25[OH]D). The 1-hydroxylation of Vitamin D in the kidneys is parathyroid hormone (PTH) dependent, and PTH secretion, in turn, is magnesium dependent. The active form of Vitamin D binds to a Vitamin D receptor in the nucleus and causes gene transcription. The proteins transcribed cause a three-fold increase in the intestinal absorption of calcium and phosphorus and increased reabsorption of calcium by the kidneys. Vitamin D is further needed for the mineralization of collagen matrix in bones. Vitamin D deficiency causes calcium and phosphorus deficiency, thereby causing secondary hyperparathyroidism, which results in osteomalacia, muscle weakness, and body pains.
Skin color determines the amount of Vitamin D produced from the skin. Increased melanin seen in dark-skinned individuals absorbs the UV rays and prevents the conversion of 7-dehydrocholesterol to Vitamin D. Applying sunscreens also absorbs UV rays and decreases the cutaneous production of Vitamin D. Vitamin D, being fat-soluble, gets absorbed in fat, especially in obese. Hence, a higher dose of Vitamin D is needed as a replacement. Reduced sunlight exposure due to occupations, prolonged hospitalization, staying in indoor environments, physical inactivity, reduced play, and recreational activities even in children has resulted in a widespread prevalence of Vitamin D deficiency. Disorders such as nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, alcoholic liver disease, celiac disease, cystic fibrosis, inflammatory bowel disease, and chronic pancreatitis affect the absorption of ergocalciferol and cholecalciferol. Chronic liver disease affects the initial conversion of these dietary sources into 25OHD. Drugs that induce cytochrome P450 enzymes such as rifampicin, phenytoin, and phenobarbitone can increase the metabolism of Vitamin D3. Hypomagnesemia, renal failure, 1-hydroxylase deficiency, and hyperparathyroidism can affect the final stage of Vitamin D production. A good lifestyle with a balanced diet throughout the year is important for preventing Vitamin D deficiency.[4],[5],[6]
The Endocrine Society, the National and International Osteoporosis Foundation, and the American Geriatrics Society define Vitamin D deficiency when 25OHD levels are <30 ng/mL. As the active form of Vitamin D (1, 25OHD) has a half-life of only 4 h, it should not be used for the assay. 25OHD has a half-life of 2 weeks, and it can be used for Vitamin D3 assay. The normal range of Vitamin D also is not standardized across ethnicities and races. Hence, it has also been noted that the cutoff values for deficiency and insufficiency of Vitamin D are not uniform across the world. The National Institute of Health labels Vitamin D values as deficient when the 25OHD levels are <12 ng/mL and 12–20 ng/mL as insufficient. If we consider this as a cutoff in the Indian population, most of the individuals in this part of the state would then have low values of Vitamin D. Vitamin D is difficult to acquire from food sources. Hence, the only other source is sunlight. From an evolutionary standpoint, it is then a paradox that in places where there was more sunlight, the skin was more dark, thus preventing the production of Vitamin D. The Endocrine Society recommends maintaining 40–60 ng/mL as the normal range. Therefore, an intake of 400–1000 International Units (IUs) daily for infants <1 year, 600–1000 IU for ages 1–18 years, and 1500–2000 IU for all adults is recommended.[7]
The estimated average requirement of Vitamin D is the intake that meets the need of 50% of the population, i.e., the most likely requirement (median value in a Gaussian distribution). The recommended daily allowance (RDA) is, in fact, a cutoff that indicates the estimated requirement for people at the highest end of the distribution. The RDA is synonymous with the upper end of the spectrum of human needs. Almost everyone in the population (at least 97.5%, or within 2 standard deviation of the median) will need Vitamin D below the RDA to keep a normal range of around 20 ng/mL. Many published literature, however, term “inadequacy” using the RDA value as a cutoff. This misclassifies most people as deficient in spite of their nutrient requirements being met, thus paradoxically creating a “pandemic of Vitamin D deficiency.”[8]
A high level of Vitamin D deficiency has been documented in chronic respiratory diseases, including allergic rhinitis and asthma. Since Vitamin D deficiency is universal, it is unknown whether it is an innocent bystander in these conditions.[9] In this edition, a retrospective study has been conducted in North Kerala to evaluate the Vitamin D levels among children aged 5–18 years with asthma and allergic rhinitis. Thirty percent of children in the study group had Vitamin D deficiency, 56% had insufficient values, and 14% had normal values as per the definition of Vitamin D insufficiency and deficiency. Most of the children with low Vitamin D levels had raised values for immunoglobulin E (IgE) and absolute eosinophil count (AEC); however, the association as seen in the study was not statistically significant. The author also notes that IgE and AECs have been used as surrogates for allergic diseases.[10],[11] Many studies have documented low Vitamin D levels in allergic rhinitis and asthma, and Vitamin D supplementation in Vitamin D-deficient individuals has been found to improve glucocorticoid response by increasing glucocorticoid receptor expression and reducing asthma-specific cytokines such as interleukin (IL)-17 and IL-4.[12],[13],[14],[15]
Vitamin D receptors are widely distributed in respiratory epithelial cells and immune cells (B-cell, T-cell, macrophages, and monocytes), and the active form of Vitamin D (1, 25OHD) exerts its physiological effects by binding to Vitamin D receptors. The 1-hydroxylase enzyme, which is found in the kidney, respiratory epithelial cells, brain, prostate, colon, and breast, causes the conversion of 25(OH) Vitamin D to 1,25(OH) Vitamin D3. This, then, binds to Vitamin D receptors which regulate the transcription of many genes related to immunomodulation and inflammation. Vitamin D supplementation was found to decrease phospholipase A2 production and reduce mast cell activation and eosinophilic inflammation in asthmatics as evidenced by a lower eosinophil count and IgE levels. It also acts to reduce inflammation by increasing IL-10 levels, especially in severe asthmatics. This occurs by blocking Th1 and Th2 and shifting Th17 effector cells, toward a Treg phenotype, thus reducing the levels of IL-4, 5, 13, and 17 and pro-inflammatory mediators. Active Vitamin D3, in addition, inhibits p65, a key transcription factor, which aids in the differentiation of CD4+ T-helper cells to the Th17 lineage. It also has a role in preventing airway remodeling by reducing the proliferation of airway smooth muscles and matrix metalloproteinases.[16]
Vitamin D, as an anti-asthma therapy adjuvant, helps by reducing airway smooth muscle proliferation and also enhancing steroid responsiveness. This is done by increasing mitogen-activated protein kinase 1 and by downregulation of corticosteroid pathways. A lack of Vitamin D can promote infections by modulating the production of antimicrobial peptides. 1, 25OHD is related to an antimicrobial peptide called cathelicidin, and this protein can colocalize inside phagosomes. It is active against viruses, bacteria, mycobacteria, and fungi. Hence, in the absence of a normal Vitamin D level, asthmatics may be prone to infection, poorer lung function, and more severe asthma exacerbations.[17]
In a meta-analysis conducted by Martineau et al. (25 randomized controlled trials [RCTs], 11,321 participants, aged from 0 to 95 years), Vitamin D supplementation was shown to reduce the risk of acute respiratory infections by 12% (adjusted odds ratio [aOR]: 0.88, 95% confidence interval [CI]: 0.81–0.96). The subgroup analysis showed that protective effects were seen only when the population received daily or weekly Vitamin D doses rather than high bolus doses like 6 lakh units. In fact, stronger protection was obtained if the baseline 25OHD levels were lower than 10 ng/mL (aOR: 0.30, 95% CI: 0.17–0.53). Hence, supplementing Vitamin D doses weekly in atopic asthmatics when having Vitamin D levels below 10 ng/mL seems effective in reducing respiratory tract infections.[18]
Jolliffe et al. showed that Vitamin D reduced the rate of asthma exacerbations only if the Vitamin D levels were low or insufficient. This is presumed to be due to its immunomodulatory effects and its antiviral and antibacterial effects.[19]
A meta-analysis of 27 studies by Liu et al. assessed the relation between lung function and asthma control in both children and adults with deficient, insufficient, and normal Vitamin D levels. The analysis included 290 adults and 545 children. It showed that asthma patients with low Vitamin D levels had lower forced expiratory volume in 1 s (FEV1) (mean difference [MD] = −0.05, 95% CI = −0.06 to −0.05, P < 0.01; I2 = 87%, P < 0.01), FEV1% (MD = −7.11, 95% CI = −13.23 to −0.98, P = 0.02; I2 = 78%, P < 0.01), and FEV1/forced vital capacity (MD = −5.14,95% CI = −5.48 to −4.80, P < 0.01; I2 = 80%, P < 0.01) than those with sufficient Vitamin D levels. In addition, an inverse relation was seen between the serum IgE levels and the Vitamin D value both in the pediatric and adult groups. The limitation of the study included large heterogeneity of the population studies. The authors concluded by saying that an optimal cutoff dose of Vitamin D for assessing asthma control and lung function could not be determined from the available meta-analyses.[20],[21],[22]
However, not every trial on Vitamin D and asthma symptoms and control is positive. In a study by Chen et al., Vitamin D did not improve the Asthma Control Test score or lung function among asthmatics who were already on optimum corticosteroids.[23] A meta-analysis on Vitamin D supplementation and asthma treatment, which included 10 randomized control trials with 1349 patients, demonstrated that supplementation did not affect the Asthma Control Test scores, FEV1, and fractional exhaled nitric oxide, but reduced the rate of asthma exacerbations (Risk ratio = 0.69, 95% CI = 0.41–0.88, P < 0.01), especially in subgroups of children and a follow-up time <6 months. There are wide sources of literature that links Vitamin D deficiency with the progression and exacerbation of asthma, but many inconsistencies are noted in these clinical studies. The authors report that there is high heterogeneity among the trials in terms of the dose of Vitamin D supplemented and standard asthma treatment given.[24]
The prevalence of Vitamin D deficiency has been increasing in the general population in recent decades. This high prevalence of Vitamin D deficiency has been attributed to the avoidance of sun exposure, indoor lifestyle, use of sunscreen or occlusive clothing, and decreased intake of Vitamin D-containing foods. In fact, Vitamin D deficiency is an indicator of subclinical and clinical malnutrition, which is widely prevalent even in developed countries. Since Vitamin D is sequestered in adipose tissue, the increasing prevalence of obesity can also explain the higher prevalence of Vitamin D deficiency.
We must also be aware of unregulated Vitamin D supplementation. There are no long-term studies on Vitamin D excess and the effects they can produce and insufficient data on the maximum safe upper limit of serum 25OHD. Vitamin D, the proposed magic cure for a wide variety of diseases, is one of the most abused medicines in the recent decade. From asthma to cancer, the drug forms an arsenal of many of the prescriptions irrespective of the specialty involved. Vitamin D intoxication occurs when unregulated Vitamin D is given, and the Vitamin D levels are more than 100–150 ng/mL. This will occur only from excess oral intake and not due to excessive sunlight exposure. The dominant finding is hypercalcemia as manifested by polyuria, polydipsia, constipation, and confusion.[25]
However, the controversy on benefits still exists because trials are contradictory. There is a definite anti-inflammatory and antioxidant effect, and there is probably an overall benefit of Vitamin D3 in improving outcomes among respiratory diseases in general. Rather than giving a blanket treatment of Vitamin D, it would be prudent to assess patients who are at high risk of deficiency or who have a disorder related to calcium metabolism. Targeting these groups with Vitamin D supplementation at levels above the RDA is logical. However, overscreening and unnecessary prescription of Vitamin D remain important until results from well-conducted RCTs with strict inclusion and exclusion criteria applied are available. More importantly, providing a balanced healthy diet and exposure to adequate sunlight in favor of high-dose Vitamin D supplementation seem the way forward.[6]
| References | |  |
| 1. | Nair R, Maseeh A. Vitamin D: The “sunshine” vitamin. J Pharmacol Pharmacother 2012;3:118-26.  [ PUBMED] [Full text] |
| 2. | Holick MF. Vitamin D: Important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J 2005;98:1024-7. |
| 3. | Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol 2014;144 Pt A:138-45. |
| 4. | Maurya VK, Aggarwal M. Factors influencing the absorption of vitamin D in GIT: An overview. J Food Sci Technol 2017;54:3753-65. |
| 5. | Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777-83. |
| 6. | Sasidharan PK. Vitamin D deficiency, causes and solutions. J Fam Med Forecast 2018;1:1008. |
| 7. | Bouillon R. Comparative analysis of nutritional guidelines for vitamin D. Nat Rev Endocrinol 2017;13:466-79. |
| 8. | Manson JE, Brannon PM, Rosen CJ, Taylor CL. Vitamin D deficiency – Is there really a pandemic? N Engl J Med 2016;375:1817-20. |
| 9. | Maes K, Serré J, Mathyssen C, Janssens W, Gayan-Ramirez G. Targeting vitamin D deficiency to limit exacerbations in respiratory diseases: Utopia or strategy with potential? Calcif Tissue Int 2020;106:76-87. |
| 10. | Chakkamadathil JK, Nair S, Chetambath R. Vitamin D levels in children with allergic rhinitis and asthma in South India: A cross-sectional study. J Adv Lung Health 2023;XX:XX-XX. |
| 11. | Vijayakumar M, Bhatia V, George B. Vitamin D status of children in Kerala, Southern India. Public Health Nutr 2020;23:1179-83. |
| 12. | Mulrennan S, Knuiman M, Walsh JP, Hui J, Hunter M, Divitini M, et al. Vitamin D and respiratory health in the Busselton healthy ageing study. Respirology 2018;23:576-82. |
| 13. | Cherrie MP, Sarran C, Osborne NJ. Association between serum 25-hydroxy Vitamin D levels and the prevalence of adult-onset asthma. Int J Environ Res Public Health 2018;15:1103. |
| 14. | Han YY, Forno E, Celedón JC. Vitamin D insufficiency and asthma in a US nationwide study. J Allergy Clin Immunol Pract 2017;5:790-6.e1. |
| 15. | Niruban SJ, Alagiakrishnan K, Beach J, Senthilselvan A. Association between vitamin D and respiratory outcomes in Canadian adolescents and adults. J Asthma 2015;52:653-61. |
| 16. | Hall SC, Agrawal DK. Vitamin D and bronchial asthma: An overview of data from the past 5 years. Clin Ther 2017;39:917-29. |
| 17. | Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J Cyst Fibros 2007;6:403-10. |
| 18. | Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis. Health Technol Assess 2019;23:1-44. |
| 19. | Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA Jr., Kerley CP, et al. Vitamin D supplementation to prevent asthma exacerbations: A systematic review and meta-analysis of individual participant data. Lancet Respir Med 2017;5:881-90. |
| 20. | Liu J, Dong YQ, Yin J, Yao J, Shen J, Sheng GJ, et al. Meta-analysis of vitamin D and lung function in patients with asthma. Respir Res. 2019;20:161. doi: 10.1186/s12931-019-1072-4. |
| 21. | Pfeffer PE. Targeting the exposome: Does correcting vitamin D deficiency have potential to treat and prevent asthma? Expert Rev Clin Immunol 2018;14:241-3. |
| 22. | Davidson BL, Alansari K. Vitamin D deficiency can impair respiratory health. Respirology 2018;23:554-5. |
| 23. | Chen Z, Peng C, Mei J, Zhu L, Kong H. Vitamin D can safely reduce asthma exacerbations among corticosteroid-using children and adults with asthma: A systematic review and meta-analysis of randomized controlled trials. Nutr Res 2021;92:49-61. |
| 24. | Liu M, Wang J, Sun X. A meta-analysis on vitamin D supplementation and asthma treatment. Front Nutr 2022;9:860628. |
| 25. | Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, Jones G. Vitamin D toxicity-a clinical perspective. Front Endocrinol (Lausanne) 2018;9:550. |
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