Vitamin D References

By- Chintan Chavda

1. Vitamin D3 in Infection

“Subclinical vitamin D deficiency and nonexclusive breastfeeding in the first 4 months of life were significant risk factors for severe ALRI (acute lower respiratory infection) in Indian children”.

Wayse V, Yousafzai A, Mogale K, Filteau S, Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y: Eur J Clin Nutr. 2004 Apr;58(4):563-7.

“We found a high rate of vitamin D deficiency in critically ill children”

Madden K, Feldman HA, Smith EM, Gordon CM, Keisling SM, Sullivan RM, Hollis BW, Agan AA, Randolph AG, Vitamin D Deficiency in Critically Ill Children; Pediatrics. 2012 Aug 6.

“We conclude that a large bolus dose of vitamin D is associated with reductions in two inflammatory cytokines, IL-6 and TNF-α. This study supports the concept that vitamin D may help regulate inflammation in CF”

Grossmann RE, Zughaier SM, Liu S, Lyles RH, Tangpricha V, Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation; Eur J Clin Nutr. 2012 Jul 18. doi: 10.1038/ejcn.2012.82

“This suggests that vitamin D(3) may down regulate the recruitment and activation of T-cells through CXC chemokines at the site of infection and may act as a potential anti-inflammatory agent”.

Selvaraj P, Harishankar M, Singh B, Banurekha VV, Jawahar MS. Effect of vitamin D(3) on chemokine expression in pulmonary tuberculosis; Cytokine. 2012 Jul 14.

“A truncated isoform of vitamin D binding protein (VDBP) is present at significantly reduced levels in the SF of oligoarticular patients at risk of disease extension, relative to other subgroups (p<0.05). Furthermore, sialylated forms of immunopurified synovial VDBP were significantly reduced in extended oligoarticular patients (p<0.005).Reduced conversion of VDBP to a macrophage activation factor may be used to stratify patients to determine risk of disease extension in JIA patients”.Gibson DS, Newell K, Evans AN, Finnegan S, Manning G, Scaife C, McAllister C, Pennington SR, Duncan MW, Moore TL, Rooney ME, Vitamin D binding protein isoforms as candidate predictors of disease extension in childhood arthritis. J Proteomics. 2012 Jul 6.

“This study opens up the issue of recognising severe vitamin D deficiency ( < 25 nmol/l) as a possible risk factor for diabetic foot infections and the need for vitamin D supplementation in such patients for a better clinical outcome”.

Tiwari S, Pratyush DD, Gupta B, Dwivedi A, Chaudhary S, Rayicherla RK, Gupta SK, Singh SK. Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. Br J Nutr. 2012 Apr 3:1-4.

“25-hydroxycholecalciferol deficiency was associated with active tuberculosis (odds ratio 2·9 [95% Cl 1·3—6·5], p=0·008), and undetectable serum 25-hydroxycholecalciferol (<7 nmol/L) carried a higher risk of tuberculosis (9·9 [1·3—76·2], p=0·009). 25-hydroxycholecalciferol deficiency may contribute to the high occurrence of tuberculosis in this population. Polymorphisms in theVDR gene also contribute to susceptibility when considered in combination with 25-hydroxycholecalciferol deficiency”Robert J Wilkinson PhD a b, Martin Llewelyn MRCP b, Zahra Toossi MD a, Punita Patel MSc b, Geoffrey Pasvol DPhil b, Ajit LalvaniMRCP c, Dennis Wright PhD b, Mohammed Latif MRCP b, Dr Robert N Davidson MD b. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study; The Lancet, Volume 355, Issue 9204, Pages 618 - 621, 19 February 2000

“We report here that TLRactivation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D1–hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility”.Toll-Like Receptor Triggering of a Vitamin D–Mediated Human Antimicrobial Response; www.sciencexpress.org / 23 February 2006 / Page 1/ 10.1126/science.1123933

“Observational studies have demonstrated important links between rickets or vitamin D deficiency and higher rates of infectious diseases that have significant burden of disease, such as pneumonia and tuberculosis.

SEMIRA MANASEKI, Vitamin D for Childhood Pneumonia, INDIAN PEDIATRICS; VOLUME 49__JUNE 16, 2012

“Increased production of 1,25- dihydroxyvitamin D3 result in synthesis of cathelicidin, a peptide capable of destroying M. tuberculosis as well as other infectious agents. When serum levels of 25-hydroxyvitamin D fall below 20 ng per milliliter (50 nmol per liter), the monocyte or macrophage is prevented from initiating this innate immune response, which may explain why black Americans, who are often vitamin D–deficient, are more prone to contracting tuberculosis than are whites, and tend to have a more aggressive form of the disease”.

2. Vitamin D3 in Immunity System

“Vitamin D(3) affects both the innate as well as adaptive immune responses. Epidemiological studies have established that vitamin D(3) deficiency plays an important role in tuberculosis (TB) and viral influenza prevalence as well as susceptibility to active disease in TB. Vitamin D(3) status has been associated with the clinical course of HIV infection and drug interaction with anti-retroviral therapy”.

Khoo AL, Chai L, Koenen H, Joosten I, Netea M, van der Ven A. Radboud University Nijmegen Medical Center, Department of Laboratory Medicine, Laboratory Medical Immunology , Nijmegen , Netherlands. Translating the role of vitamin D(3) in infectious diseases; Review of infectious diseases vitamin D trials – Feb 2012

“An efficient immune response against the intracellular pathogen Mycobacterium tuberculosis is critically dependent on rapid detection of the invader by the innate immune response and the activation of the adaptive immune response. Toll-like receptors (TLRs) contribute to innate immunity by the detection of Mycobacteria-associated molecular patterns and mediating the secretion of antibacterial effector molecules. TLRs influence the adaptive immune response by upregulation of immunomodulatory molecules supporting the development of a Th1-biased T cell response. In this manner, activation of TLRs contributes to defense against microbial infection.”

Stenger S, Modlin RL, Control of Mycobacterium tuberculosis through mammalian Toll-like receptors; Curr Opin Immunol. 2002 Aug;14(4):452-7.

“The net effect of the vitamin D system on the immune response is an enhancement of innate immunity coupled with multifaceted regulation of adaptive immunity. Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of several autoimmune diseases, and clarification of the physiological role of endogenous VDR agonists in the regulation of autoimmune responses will guide the development of pharmacological VDR agonists for use in the clinic. The antiproliferative, prodifferentiative, antibacterial, immunomodulatory and anti-inflammatory properties of synthetic VDR agonists could be exploited to treat a variety of autoimmune diseases, from rheumatoid arthritis to systemic lupus erythematosus, and possibly also multiple sclerosis, type 1 diabetes, inflammatory bowel diseases, and autoimmune prostatitis.”

Nat Clin Pract Rheumatol. 2008 Aug;4(8):404-12. Epub 2008 Jul 1. Control of autoimmune diseases by the vitamin D endocrine system. Adorini L, Penna G.

“As the vitamin D receptor is expressed on immune cells (B cells, T cells, and antigen-presenting cells), and these immunologic cells are all capable of synthesizing the active vitamin D metabolite, vitamin D has the capability of acting in an autocrine manner in a local immunologic milieu. Vitamin D can modulate the innate and adaptive immune responses. Deficiency in vitamin D is associated with increased autoimmunity and an increased susceptibility to infection. As immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D-deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis”.

Aranow C., Vitamin D and the immune system; J Investig Med. 2011 Aug;59(6):881-6.

“Vitamin D3 has wide-ranging effects on the immune system. Due to its actions on both Th1 and Th2 mediated immune responses, vitamin D

deficiency has been purported as a potential unifying factor in the rise of the prevalence of both Th1 disorders (autoimmunity) and Th2 disorders (allergies) over a similar time span. Vitamin D may be of particularly critical importance at early stages of development to ensure proper immune function later in life”.

ADVANCES in orthomolecular research, Volume 3 Issue 5 page 25-27

“Vitamin D has been linked to immune system and lung development in utero, and our epidemiologic studies show that higher vitamin D intake by pregnant mothers reduces asthma risk by as much as 40% in children 3 to 5 years old”

Augusto A. Litonjua, MD, MPH, and Scott T. Weiss, MD, MS, Boston, Mass, Is vitamin D deficiency to blame for the asthma epidemic?; J ALLERGY CLIN IMMUNOL NOVEMBER 2007.

3. Vitamin D3 in Respiratory System

“In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency’.Ann Chen Wu1,2,3, Kelan Tantisira3,4,5, Lingling Li1,3, Anne L. Fuhlbrigge3,4, Scott T. Weiss3,4,5, Augusto Litonjua3,4,5 and for the Childhood Asthma Management Program Research Group. Effect of Vitamin D and Inhaled Corticosteroid Treatment on Lung Function in Children Am. J. Respir. Crit. Care Med. September 15, 2012 vol. 186 no. 6 508-513

“Vitamin D deficiency causes deficits in lung function that are primarily explained by differences in lung volume. This study is the first to provide direct mechanistic evidence linking vitamin D deficiency and lung development, which may explain the association between obstructive lung disease and vitamin D status”.Graeme R. Zosky1,2, Luke J. Berry1,2, John G. Elliot3, Alan L. James3, Shelley Gorman1,2 and Prue H. Hart, Vitamin D Deficiency Causes Deficits in Lung Function and Alters Lung Structure; Am. J. Respir. Crit. Care Med.May 15, 2011 vol. 183 no. 10 1336-1343

4. Vitamin D3 in Digestive System

“Vitamin D receptors (VDRs) and vitamin D metabolic enzymes have been identified in many other tissues aside from bone and the intestine, suggesting involvement in the metabolism and function of many cell types. Specifically, VDR is expressed in cells of the immune system, such as T cells,activated B cells, and dendritic cells”.

Augusto A. Litonjua, MD, MPH, and Scott T. Weiss, MD, MS, Boston, Mass, Is vitamin D deficiency to blame for the asthma epidemic?; J ALLERGY CLIN IMMUNOL NOVEMBER 2007.

“The reviewed data for vitamin D and its oxygen analogue OCT indicate genomic effects on multiple target tissues of the digestive system that involve cell proliferation and differentiation, endo- and exocrine secretion,

digestion and absorption for maintaining optimal functions, with potentials for health prophylaxis and therapies.”Eur J Drug Metab Pharmacokinet. 2008 Apr-Jun;33(2):85-100. Vitamin D and the digestive system. Stumpf WE.

“we have considered the importance of vitamin D as a real hormone responsible for both muscle and bone strength. With aging there is a significant reduction in the genomic and non-genomic effect of vitamin D which has been associated with increasing incidence of falls and fractures”.

Manuel Montero-Odasso, Gustavo Duque. Vitamin D in the aging musculoskeletal system: An authentic strength preserving hormone; Molecular Aspects of Medicine 26 (2005) 203–219

5. Vitamin D3 in nervous system & Brain development

“The relationship of many of these diseases and aging related changes in physiology show a U-shaped response curve to serum calcidiol concentrations. Clinical data suggest that vitamin D3 insufficiency is associated with an increased risk of several CNS diseases, including multiple sclerosis, Alzheimer’s and Parkinson’s disease, seasonal affective disorder and schizophrenia. In line with this, recent animal and human studies suggest that vitamin D insufficiency is associated with abnormal development and functioning of the CNS. Overall, imbalances in the calcipherol system appear to cause abnormal function, including premature aging, of the CNS”.

P. Tuohimaa, T. Keisala, A. Minasyan, J. Cachat, A. Kalueff, Vitamin D, nervous system and aging; 26 March 2009; received in revised form 4 July 2009; accepted 6 July 2009.

“Experimental data suggest that cerebral white matter is vitamin D responsive and oligodendrocytes in the brain and spinal cord and express vitamin D receptors. It is possible that differentiation and axonal adhesion of oligodendrocytes are influenced by vitamin D level during brain development and a relative lack of vitamin D may increase oligodendroglial apoptosis”

Abhijit Chaudhuri, Department of Neurology, Institute of Neurological Sciences, 1345 Govan Road, Glasgow G51 4TF, UK, Why we should offer routine vitamin D supplementation in pregnancy and childhood to prevent multiple sclerosis; 14 June 2004; accepted 24 June 2004

“The widespread distribution of 1a-OHase and the VDR suggests that Vitamin D may have autocrine/paracrine properties in the human brain.”

Darryl W. Eyles, Steven Smith, Robert Kinobe, Martin Hewison, John J. McGrath, Distribution of the Vitamin D receptor and 1a-hydroxylase in human brain; Journal of Chemical Neuroanatomy 29 (2005) 21–30

“The VDR is expressed in the neurons and glial cells, and induces nerve growth factor – exerting a potent inhibitory effect upon mitosis and promoting cell differentiation”.

Brown J, Bianco JI, McGrath JJ, Eyles DW. 1,25-Dihydroxyvitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons. Neurosci Lett 2003;343:139–143.

“Vitamin D could play a significant role in the brain in a way analogous to the neuroactive steroids, modulating neuron excitability and the production of specific neurotropins and nervous tissue growth factors in neurons and glial cells, inducing the production of calcium-binding proteins, and acting through the nitric oxide system”.

FAUSTINO R. PE´ REZ-LO´ PEZ, Vitamin D: The secosteroid hormone and human reproduction, Department of Obstetrics and Gynecology, Zaragoza Gynecological Institute, Zaragoza, Spain. 24 September 2006; accepted 1 October 2006.

“In a cross-section of older adults, vitamin D deficiency was associated with low mood and with impairment on two of four measures of cognitive performance”.

Consuelo H. Wilkins, M.D., Yvette I. Sheline, M.D., Catherine M. Roe, Ph.D., Stanley J. Birge, M.D., John C. Morris, M.D. Vitamin D Deficiency Is Associated With Low Mood and Worse Cognitive Performance in Older Adults. Am J Geriatr Psychiatry 14:12, December 2006.

6. Vitamin D in Cardiovascular System

“Vitamin D may potentially affect the treatment and prevention of hypertensive vascular disease, coronary artery disease, cardiac arrhythmias, peripheral vascular disease, lipid metabolism, and diabetes mellitus. Accumulating epidemiologic evidence suggests that hypovitaminosis D may be associated with an increased risk of cardiovascular events and experimental data generally support the hypothesis that vitamin D has a protective role in cardiovascular health”.

Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol 2009 Sep;4 (9):1515-22.

Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol 2008 Dec 9;52(24):1949-56.

Levin A, Li YC. Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease? Kidney Int 2005 Nov; 68 (5):1973-81.

Wu-Wong JR, Nakane M, Ma J, Ruan X, Kroeger PE. Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis 2006 May;186(1):20-8.

“Hypovitaminosis D is associated with disturbed glucose metabolism and pancreatic cell dysfunction, lipoprotein alterations, hypertension, overweight and obesity. The evidence highlights the importance of improving vitamin Dstatus in the general population for the prevention of adverse long-term health risks, including cardiovascular health”

Faustino R. Pérez-López, Vitamin D metabolism and cardiovascular risk factors in postmenopausal women, department of Obstetrics and Gynaecology, University of Zaragoza, Faculty of Medicine, Hospital Clínico Universitario de Zaragoza, Domingo Miral s/n, Zaragoza 50009, Spain; Maturitas 62 (2009) 248–262.

“Vitamin D deficiency is prevalent in neonates with congenital cardiac defects, regardless of race. Second, 25(OH)D levels are not altered by CPB. Third, higher 24 hour postoperative 25(OH)D levels are associated with areduction in inotropic requirement in neonates undergoing cardiac operations with CPB. These findings provide support that vitamin D may play a role in myocardial injury and postoperative recovery”.

VITAMIN D STATUS IN NEONATES UNDERGOING CARDIAC OPERATIONS: RELATIONSHIP TO CARDIOPULMONARY BYPASS AND OUTCOMES, March 24, 2012.

“Diastolic dysfunction is likely related to vitamin D deficiency as well since secondary hyperparathyroidism in these patients is induced by chronic vitamin D deficiency. The cardiovascular changes observed are not easily reversible, hence early preventive therapy with vitamin D supplementation before the onset of vitamin D deficiency is advocated”.

Amit Patange; Rudolph Valentini; Wei Du; Michael Pettersen, VITAMIN D DEFICIENCY IS ASSOCIATED WITH DIASTOLIC DYSFUNCTION IN CHILDREN WITH CHRONIC KIDNEY DISEASE, J Am Coll Cardiol. 2012;59(13s1):E2147-E2147. doi:10.1016/S0735-1097(12)62148-2