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Vitamin d monograph

The document discusses the critical roles and history of vitamin D (cholecalciferol) in human health, including its synthesis, metabolism, and various physiological functions. It highlights the clinical significance of vitamin D in relation to conditions such as cardiovascular disease, diabetes, autoimmune diseases, and cancer prevention. Additionally, it addresses the prevalence of vitamin D deficiency in different populations and outlines the benefits of maintaining optimal vitamin D levels.

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REVEALING CHOLECALCIFEROL
CONTENTS 1. Milestones in the history of Vitamin D 2. Introduction 3. More About of Vitamin D Synthesis Metabolism & Physiological funtions Non Calcemic functions Normal Levels of Vitamin D in Blood Benefits of Optimal Levels of Vitamin D Prevalence of Vitamin D Deficiency 4. Clinical Significance of Vitamin D Cardiovascular Disease; Hypertension; Diabetes Osteoarthritis; Multiple Sclerosis; Type 1 Diabetes Depression; Epilepsy; Migraine PCOS; Musculoskeletal Pain Critical Illnesses Cancer Prevention and Treatment 5. Vitamin D in Cardiovascular Diseases (CVD) Clinical studies in CVD 6. Vitamin D in Hypertension Clinical studies in Hypertension 7. Vitamin D in Diabetes Clinical studies in Diabetes 8. Vitamin D in Auto-Immune Disease and Pains Vitamin D deficiency in Spine Surgery Vitamin D and Spinal Cord Disease Vitamin D and BMD in premenopausal Women
CONTENTS Vitamin D and Rheumatology 9. Vitamin D and Cancers Colorectal Cancers Breast Cancers Prostate Cancers Pancreatic Cancers Rare Cancers Skin Cancers Modifying Cancer Risk 10. Vitamin D in Pregnancy 11. Vitamin D in Children 12.Gist of Clinical Studies Cardiovascular Disease Hypertension Diabetes Pains Auto-Immune Diseases Cancer Falls in Elderly Longevity 13.Dosing 14.References
MILESTONES IN THE HISTORY OF VITAMIN D 1645-Whistlerwrotethefirstscientificdescriptionofrickets. 1865 - In his textbook on clinical medicine, Trousseau recommended cod liver oil as treatment for rickets. He also recognized the importance of sunlightandidentifiedosteomalaciaastheadultformofrickets. 1919 - Mellanby proposed that rickets is due to the absence of a fat- solubledietaryfactor. 1922 - McCollum and coworkers established the distinction between vitaminAandtheantirachiticfactor. 1925 - McCollum and coworkers named the antirachitic factor vitamin D. Hess and Weinstock show that a factor with antirachitic activity is producedintheskinbyultravioletirradiation. 1936-WindausidentifiedthestructureofvitaminDincodliveroil. 1937 - Schenck obtained crystallized vitamin D3 by activation of 7- dehydro-cholesterol. 1968 - Haussler and colleagues reported the presence of an active metaboliteofvitaminDintheintestinalmucosaofchicks. 1969 - Haussler and Norman discovered calcitriol receptors in chick intestine. 1970 - Fraser and Kodicek discovered that calcitriol is produced in the kidney. 1971-Normanandcoworkersidentifiedthestructureofcalcitriol. 1973-Fraserandassociatesdiscoveredthepresenceofaninbornerrorof
vitamin D metabolism that produces rickets resistant to vitamin D therapy. 1978 - De Luca's group discovered a second form of vitamin D-resistant rickets(TypeII). 1981 - Abe and colleagues in Japan demonstrated that calcitriol is involvedinthedifferentiationofbone-marrowcells. 1983 - Provvedini and colleagues demonstrated the presence of calcitriol receptorsinhumanleukocytes. 1984 - The same group presented the evidence that calcitriol has a regulatoryroleinimmunefunction. 1986 - Morimoto and associates suggested that calcitriol may be useful in thetreatmentofpsoriasis. 1989 - Baker and associates showed that the vitamin D receptor belongs tothesteroid-receptorgenefamily. 1994 - The U.S. Food and Drug Administration approved a vitamin D- basedtopicaltreatmentforpsoriasis,calledcalcipotriol. 2003 - A prospective study from Feskanich and coworkers among 72,000 postmenopausal women in the U.S. over 18 years indicated that women consuming at least 600 IU vitamin D/day from food plus supplements had a37%lowerriskofhipfracture. 2006 - Researchers from Harvard School of Public Health examined cancer incidence and vitamin D exposure in over 47,000 men in the Health Professionals Follow-Up Study. They found that a high level of vitamin D (~1500 IU daily) was associated with a 17% reduction in all cancerincidencesanda29%reductionintotalcancermortalitywitheven strongereffectsfordigestive-systemcancers. Reference: Whistler, D. Morbo puerili Anglorum, quem patrio idiomate indigenae vocant The Rickets. Lugduni Batavorum 1-13 (1645).; Glisson, F. De Rachitide sive morbo puerili, qui vulgoThe Rickets diciteur, London 1-416 (1650).; Glisson, F. A treatise of the rickets being a disease common to children. London 1-373 (1668).; Mellanby, E. and Cantag, M.D. Experimental investigation on rickets. Lancet 196:407-412 (1919).; Mellanby, E. Experimental rickets. Medical Research (G.B.), Special Report Series SRS-61:1-78 (1921).; Hess, A. Influence of light on the prevention of rickets. Lancet 2:1222 (1922).; Steenbock, H. The induction of growth promoting and calcifying properties in a ration by exposure to light. Science 60:224-225 (1924).; Windaus, A., Linsert, O. Luttringhaus, A. and Weidlinch, G. Uber das krystallistierte Vitamin D2. Justis. Liebigs. Ann. Chem. 492:226-231 (1932).; Brockmann, H. Die Isolierung des antirachitischen Vitamins aus Thunfischleberol. H.-S.Zeit. Physiol. Chem. 241:104-115 (1936).; Crowfoot-Hodgkin, D., Webster, M.S. and Dunitz, J.D. Structure of calciferol. Chem. Industry1148-1149(1957).;Solecki,R.S.Shanidar:TheHumanityofNeanderthalMan,NewYork:Knopf.pp.1-252(1971).
INTRODUCTION VitaminDbelongstothegroupoffat-solublevitamins.Thetwoimportant forms of Vitamin D are vitamin D2 or ergocalciferol - the plant source of vitamin D - and vitamin D3 also referred as cholecalciferol. Vitamin D3 is produced in the skin when the skin is exposed to the sun - when the light energy is absorbed by it. If an individual is exposed adequately to sunlight thereisnofurtherneedforVitaminDintheformofsupplements.Natural food sources might not typically have the sufficient amount of Vitamin D and so a conscious consumption of Vitamin D rich foods and deliberate exposure of the skin to sunlight is required to prevent possible deficiencies. The World Health Organization has responsibility for defining the "International Unit" of vitamin D3. Their most recent definition, provided states that "the International Unit of vitamin D recommended for adoption is the vitamin D activity of 0.025 micrograms of the internationalstandardpreparationofcrystallinevitaminD3".Thus,1.0IU ofvitaminD3is0.025micrograms,whichisequivalentto65.0pmoles. In today’s world ultraviolet light from the sun may be blocked by air pollution. The tendency to wear clothes, to live in cities where tall buildings block adequate sunlight from reaching the ground, to live indoors, to use synthetic sun-screens that block ultraviolet rays, and to live in geographical regions of the world that do not receive adequate sunlight, all contribute to the inability of the skin to biosynthesize sufficient amounts of vitamin D3. Under these conditions vitamin D becomes a true vitamin in that it must be supplied in the diet on a regular basis. Animal products constitute the bulk source of vitamin D. Salt water fish such as herring, salmon, sardines, and fish liver oils are good sources of vitamin D3. Small quantities of vitamin D3 are also derived from eggs, veal, beef, butter, and vegetable oils while plants, fruits, and nuts are extremelypoorsourcesofvitaminD.
The structures of vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are presented below. Vitamin D is a generic term and indicatesamoleculeofthegeneralstructureshownforringsA,B,C,andD with differing side chain structures. The A, B, C, and D ring structure is derived from the cyclopentanoperhydrophenanthrene ring structure for steroids. Technically vitamin D is classified as a seco-steroid. Seco- steroids are those in which one of the rings has been broken; in vitamin D, the 9,10 carbon-carbon bond of ring B is broken, and it is indicated by the inclusionof"9,10-seco"intheofficialnomenclature. Reference: Utiger, R.D. The need for more vitamin D. N. Engl. J. Med. 228:828-829 (1998).; Holick, M.F. Vitamin D and bone health. J. Nutr. 126 Suppl. 159S-1164S (1996).; Collins, E.D. and Norman, A.W. Vitamin D. In: Handbook of vitamins, edited by Machlin, L.J. New York: Marcel Dekker, pp. 59-98 (1990).; Subcommittee on the Tenth Edition of the RDAs, Food & Nutrition Board, Commission on Life Sciences and National Research Council.Recommendeddietaryallowances,Washington,D.C.:NationalAcademyPress.Ed.10thpp.1-285(1989).
MORE ABOUT VITAMIN D
SYNTHESIS OF VITAMIN D 7-Dehydrocholesterol Cholecalciferol (Vitamin D3) Dietary Intake Liver Kidney 25 Hydroxy Vitamin D3 1, 25 Dihydroxy Vitamin D3 Vitamin D3 (fish & meat) Vitamin D2 (Supplements) SKIN Reference:ClinicalLaboratoryNews,December2007:Volume33,Number12
METABOLISM OF VITAMIN D Intestinal absorption of calcium PTH mediated bone resorption Renal Ca++ and phosphate excretion UV Light 7-dehydrocholesterol 7-dehydrocholesterol Liver Kidney Cholecalciferol Vitamin D3 Calcitriol 1,25 dihydroxy Vitamin D 24,25 dihydroxy Vitamin D Ergocalciferol Vitamin D2 Calcidiol 25-hydroxy Vitamin D Reference:Literaturereview,ZalmanSAgus,MDEmeritusProfessorofMedicineandPhysiology;AssociateDean,CMEPerelmanSchoolofMedicineattheUniversityofPennsylvania
NON CALCEMIC FUNCTIONS OF 1,25-DIHYDROXY VITAMIN D Vitamin D Decreased Renin Adaptive Immune Modulation VDR-RXR VDR-RXR Decreased 25 (OH)D 1-OHase 1-OHase Increased 1-OHase p21, p27 etc 25 (OH) D2 1,25 (OH) D2 Activated T & B Lymphocytes Pancreas Increased Insulin Secretion Increased 25 (OH) D2 Innate Immune Modulation Cytokines Macrophage Increased VDR mRNA, 1-OHase mRNA M.Tuberculosis Death LPS TLR Solar UV Radiation Dietary Sources Liver Maintenance of normal cell proliferation in prostate, colon, breast etc Increased CD Reference: Hewison M, et al. Molecular and Cellular Endocrinology 2004; 215: 31-38.; Helming L, et al. Blood 2005; 106: 4351-4358; Abu-Amer Y, Bar-Shavit Z. Cellular Immunology 1993; 151: 356-368. Cohen MS, et al. JournalofImmunology1986;136:1049-1053.;WangTT,etal.JournalofImmunology2004;173:2909-2912.;OrvHetil.2011Aug14;152(33):1312-9.;Immunology.2011Oct;134(2):123-39
NORMAL LEVELS OF CIRCULATING 25 (OH)D Severely deficient Deficient Insufficient Sufficient Optimal <8ng/ml 8 - 19ng/ml 20 - 29ng/ml 30 - 49ng/ml 50 - 99ng/ml 25 Hydroxy Vitamin D (ng/ml) PTH Levels 6-10 11-15 16-20 21-25 26-30 >30 Serum 25 (OH)D (nmol/L) AbsorptionFraction Calcium Absorption 0.0 20 40 60 80 100 120 140 0.1 0.2 0.3 0.4 0.5 Reference:EndocrineSociety’s ClinicalGuideline2011 ParaThyroidHormone(pg/ml) 20 0-5 30 40 50 60 70 80 90 100
BENEFITS WITH OPTIMAL LEVELS OF VITAMIN D SKELETAL-MUSCULAR STRONG MUSCLES AND BONES INFECTIONS PREVENT INFLUENZA, TREAT TUBERCULOSIS CANCER PREVENT BREAST, COLON, AND PROSTATE CANCER AUTOIMMUNE DISEASES PREVENT MULTIPLE SCLEROSIS AND TYPE 1 DIABETES CARDIOVASCULAR DISEASE SLOW PROGRESSION OF ATHEROSCLEROSIS TREAT HYPERTENSION AND CONGESTIVE HEART FAILURE NEUROPSYCHIATRIC DISORDERS PREVENT SCHIZOPHRENIA AND RELIEVE DEPRESSION
PREVALENCE OF VITAMIN D DEFICIENCY 67% of healthy Indians from Lucknow has serum 25(OH)D levels < 15 ng/ml -Arya V, Osteoporosis Int 2004 Vitamin D deficiency (25 (OH)D<20ng/dl) reported in 83% of healthy adults in Kashmir - Zargar et al Postgraduate Medical Journal 2007 85% of healthy Indian adult men could not achieve normal serum 25(OH)D levels despite adequate outdoor activities and sun exposure - Marwaha RK & Tandon N et al Journal of Clinical Densitometry 2009 Prevalence of vitamin D deficiency in Indian lactating women and infants (<20 ng/ml) is 93.8% - Seth A and Marwaha RK et al;JPEM 2009 Studies on bone mineral health from different parts of India indicate wide prevalence of vitamin D deficiency (VDD) in all age groups including neonates, infants, school children, pregnant / lactating women and adult males and females residing in rural and urban India- Marwaha RK et al No. of Patients History of Cancer 25-hydroxyvitamin D3 Level (ng/ml) 7 (9.6 %) 1 (colon) < 8 (severely deficient) 41 (56.2%) 6 8-19.9 (deficient) 9 (12.3%) 0 20-29.9 (insufficient) 13 (17.8%) 0 30-49.9 (sufficient) 3 (4.1%) 0 50-100 (optimal) PREOP VITAMIN D3 LEVELS IN 73 VETERANS UNDERGOING HEART SURGERY AT THE SEATTLE VA HOSPITAL
CLINICAL SIGNIFICANCE OF VITAMIN D REFERENCE: THE CLINICAL IMPORTANCE OF VITAMIN D (CHOLECALCIFEROL): A PARADIGM SHIFT WITH IMPLICATIONS FOR ALL HEALTHCARE PROVIDERS; Alex Vasquez, DC, ND, Gilbert Manso, MD, John Cannell, MD; ALTERNATIVETHERAPIES,sept/oct2004,VOL.10,NO.5
CLINICAL SIGNIFICANCE OF VITAMIN D CARDIOVASCULAR DISEASE Deaths from cardiovascular disease are more common in the winter, more common at higher latitudes and more common at lower altitudes, observations that are consistent with vitamin D insufficiency. The risk of heart attack is twice as high for those with 25(OH)D levels less than 34 ng/ml (85 nmol/L) than for those with vitamin D status above this level. Patients with congestive heart failure were recently found to have markedlylowerlevelsofvitaminDthancontrols,andvitaminDdeficiency as a cause of heart failure has been documented in numerous case reports. HYPERTENSION It has long been known that blood pressure is higher in the winter than the summer, increases at greater distances from the equator and is affected by skin pigmentation—all observations consistent with a role for vitamin D in regulating blood pressure. When patients with hypertension were treated with ultraviolet light three times a week for six weeks their vitamin D levels increased by 162%, and their blood pressure fell significantly. Even small amounts of oral cholecalciferol (800 IU) for eight weeksloweredbothbloodpressureandheartrate. Type2Diabetes Hypovitaminosis D is associated with insulin resistance and beta-cell dysfunction in diabetics and young adults who are apparently healthy. Healthy adults with higher serum 25(OH)D levels had significantly lower 60 min, 90 min and 129 min postprandial glucose levels and significantly better insulin sensitivity than those who were vitamin D deficient. The authors noted that, compared with metformin, which improves insulin sensitivity by 13%, higher vitamin D status correlated with a 60% improvement in insulin sensitivity. In a recent clinical trial using 1,332 IU/day for only 30 days in 10 women with type 2 diabetes, vitamin D supplementationwasshowntoimproveinsulinsensitivityby21%.
CLINICAL SIGNIFICANCE OF VITAMIN D OSTEOARTHRITIS We know that vitamin D prevents and treat osteoporosis, but few know that the progression of osteoarthritis, the most common arthritis, is lessened by adequate blood levels of vitamin D. Framingham data showed osteoarthritis of the knee progressed more rapidly in those with 25(OH)D levels lower than 36 ng/ml (90 nmol/L). Another study found that osteoarthritis of the hip progressed more rapidly in those with 25(OH)Dlevelslowerthan30ng/ml(75nmol/L). MULTIPLE SCLEROSIS Theautoimmune/inflammatorydiseasemultiplesclerosis(MS)isnotably rare in sunny equatorial regions and becomes increasingly prevalent among people who live farther from the equator and/or who lack adequate sun exposure. In a clinical trial with 10 MS patients, Goldberg, Fleming, and Picard prescribed daily supplementation with approximately 1,000 mg calcium, 600 mg magnesium, and 5,000 IU vitamin D (from 20 g cod liver oil) for up to two years and found a reduction in the number of exacerbations and an absence of adverse effects.Thisisoneofveryfewstudiesinhumansthatemployedsufficient daily doses of vitamin D (5,000 IU) and had sufficient duration (2 years). More recently, Mahon et al gave 800 mg calcium and 1,000 IU vitamin D per day for six months to 39 patients with MS and noted a modest anti- inflammatoryeffect. PREVENTION OF TYPE 1DIABETES Type 1 diabetes is generally caused by autoimmune/inflammatory destruction of the pancreatic beta-cells. Vitamin D supplementation shows significant preventive and ameliorative benefits in type 1 diabetics. In a study with more than 10,000 participants, showed that supplementation in infants and children with 2,000 IU of vitamin D per dayreducedtheincidenceoftype1diabetesbyapproximately80%.
CLINICAL SIGNIFICANCE OF VITAMIN D Depression Seasonal affective disorder (SAD) is a particular subtype of depression characterized by the onset or exacerbation of melancholia during winter months when bright light, sun exposure, and serum 25(OH)D levels are reduced. Recently, a dose of 100,000 IU of vitamin D was found superior to light therapy in the treatment of SAD after one month. Similarly, in a study involving 44 subjects, supplementation with 400 or 800 IU per day was found to significantly improve mood within five days of supplementation. EPILEPSY Seizures can be the presenting manifestation of vitamin D deficiency.39 Hypovitaminosis D decreases the threshold for and increases the incidence of seizures, and several “anticonvulsant” drugs interfere with theformationofcalcitriolinthekidneyandfurtherreducecalcitriollevels via induction of hepatic clearance. Therefore, antiepileptic drugs may lead to iatrogenic seizures by causing iatrogenic hypovitaminosis D. Conversely, supplementation with 4,000–16,000 IU per day of vitamin D2 was shown to significantly reduce seizure frequency in a placebo controlledpilotstudybyChristiansenetal. MIGRAINE HEADACHES Calcium clearly plays a role in the maintenance of vascular tone and coagulation, both of which are altered in patients with migraine. Thys- Jacobs reported two cases showing a reduction in frequency, duration, and severity of menstrual migraine attacks following daily supplementationwith1,200mgofcalciumand 1,200–1,600IUofvitamin DinwomenwithvitaminDdeficiency.
CLINICAL SIGNIFICANCE OF VITAMIN D POLYCYSTIC OVARY SYNDROME Polycystic ovary syndrome (PCOS) is a disease seen only in humans and is classically characterized by polycystic ovaries, amenorrhea, hirsuitism, insulin resistance, and obesity. Animal studies have shown that calcium is essential for oocyte activation and maturation. Vitamin D deficiency was highly prevalent among 13 women with PCOS, and supplementation with 1,500 mg of calcium per day and vitamin D normalized menstruation and/or fertility in nine of nine women with PCOS-related menstrual irregularitieswithinthreemonthsoftreatment. MUSCULOSKELETAL PAIN Patients with non-traumatic, persistent musculoskeletal pain show an impressively high prevalence of overt vitamin D deficiency. Plotnikoff and Quigley recently showed that 93% of their 150 patients with persistent, nonspecific musculoskeletal pain were overtly deficient in vitamin D. Masood et al found a high prevalence of vitamin D deficiency in children with limb pain, and vitamin D supplementation ameliorated pain within threemonths. AlFaraj and AlMutairifound vitaminD deficiencyin83%of their 299 patients with low-back pain, and supplementation with 5,000–10,000 IU of vitamin D per day lead to pain reduction in nearly 100%ofpatientsafterthreemonths.
CLINICAL SIGNIFICANCE OF VITAMIN D CRITICAL ILLNESS AND AUTOIMMUNE/INFLAMMATORY CONDITIONS Deficiency of vitamin D is common among patients with inflammatory and autoimmune disorders and those with prolonged critical illness. In addition to the previously mentioned epidemic of vitamin D insufficiency in patients with MS, we also see evidence of vitamin D insufficiency in a largepercentageofpatientswithGrave’sdisease,ankylosingspondylitis, systemic lupus erythematosus, and rheumatoid arthritis. Clinical trials with proper dosing and duration need to be performed in these patient groups. C-reactive protein was reduced by 23% and matrix metalloproteinase-9 was reduced by 68% in healthy adults following bolusinjectionsofvitaminDthatresultedinanaveragedoseof547IUper day for 2.5 years. A recent trial of vitamin D supplementation in patients withprolongedcriticalillnessshowedasignificantanddose-dependent “anti-inflammatory effect” evidenced by reductions in IL-6 and CRP. However, the insufficient dose of only 400 IU per day (administered intravenously) for only ten days precluded more meaningful and beneficialresults,andwepresentguidelinesforfuturestudieslaterinthis paper.
CLINICAL SIGNIFICANCE OF VITAMIN D CANCER PREVENTION AND TREATMENT The inverse relationship between sunlight exposure and cancer mortality was documented by Apperly in 1941. Vitamin D has anti-cancer effects mediated by anti-proliferative and proapoptotic mechanisms which are augmented by modulation of nuclear receptor function and enzyme action, and limited research shows that synthetic vitamin D analogs may have a role in the treatment of human cancers. Grant has shown that inadequate exposure to sunlight, and hence hypovitaminosis D, is associated with an increased risk of cancer mortality for several malignancies, namely those of the breast, colon, ovary, prostate, bladder, esophagus, kidney, lung, pancreas, rectum, stomach, uterus, and non- Hodgkin lymphoma. He proposes that adequate exposure to ultraviolet light and/or supplementation with vitamin D could save more than 23,000 American lives per year from a reduction in cancer mortality alone. The aforementioned clinical trials using vitamin D in a wide range of health conditions have helped to expand our concept of vitamin D and to appreciate its manifold benefits. However, in light of new research showing that the physiologic requirement is 3,000–5,000 IU/day for adults and that serum levels plateau only after 3-4 months of daily supplementation, we must conclude that studies using lower doses and/or shorter durations have underestimated the clinical efficacy of vitaminD.
VITAMIN D IN CARDIO VASCULAR DISEASES
VITAMIN D - BENEFITS IN CARDIOVASCULAR DISEASES Inhibitionofvascularsmoothmuscleproliferation The hormonal metabolite of vitamin D, 1,25-dihyroxyvitamin D inhibits endothelin (ET)-dependent DNA synthesis and cell proliferation by suppressing ET-induced activation of cyclin-dependent kinase 2 (Cdk2), a key 1 cellcyclekinase . Suppressionofvascularcalcification Medial calcification is associated with proliferation of vascular smooth 2 muscle cells . Vascular calcification can be affected by vitamin D receptors (VDRs), which affect gene activation. When 25(OH)D levels are low, not enough VDRs can be activated to inhibit calcification. The benefit of vitamin D is likely due to its activation of the VDR in vasculature and cardiac 3 myocytes . One of the effects of calcitriol is to act upon osteoclast precursor cells and suppresses their differentiation in addition to intestinal and renal 4 regulationofcalciumandphosphorus . Vitamin D suppresses vascular calcification primarily by regulating parathyroid hormone (PTH). High PTH causes mineral and skeletal abnormalities predisposing to ectopic calcifications and increased 4 mortality . PTH levels decline fairly rapidly with increasing serum 25(OH)D 5,6 levels to about 75 nmol/L, with little change thereafter . There are various lines of evidence that elevated PTH levels are linked to increased risk of vascularproblemsanddementia. Reductionofinflammation An observational study in England found a statistically significant inverse correlation between serum 25(OH)D and tissue plasminogen activator (tPA) 7 antigen, with tPA levels peaking in August . (tPA is a protein involved in the breakdown of blood clots. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat only embolic or thrombotic stroke.) tPA antigen was found to be 8 associatedwithincidenceofcoronaryheartdisease .
In a study of the effects of calcitriol on synthesis of mitochondrial RNAs encoding interleukin-6 (IL-6), interferon-gamma (IFN-gamma) in trophoblasts challenged with TNF-alpha found calcitriol inhibited the expression profile of inflammatory cytokine genes in a dose-response 9 manner (P<0.05) . Further findings regarding calcitriol and TNF-alpha are 6 giveninDussoetal . Another way 25(OH)D reduces risk of CVD is through reduction in matrix 10 metalloproteinases (MMPs) such as MMP9 . MMPs are a class of enzymes that can break down proteins, such as collagen and gelatin, and, thus, damagetissuesinthevascularsystem. MMP-2,MMP-9,TIMP-1,andTIMP-2 plasma levels were higher in diabetic, ACS, and DACS patients, which may reflect abnormal extracellular matrix metabolism in diabetes and in acute 11 coronary syndrome . Serum MMP-9 has a modest association with incident CHD in the general population, which is not independent of cigarette smoking exposure and circulating markers of generalized inflammation. MMP-9 is unlikely to be a clinically useful biomarker of CHD risk, but may still 12 play a role in the pathogenesis of CHD . MMP-8 also plays a role in 13,14 atherosclerosis . Reductionofbloodpressure Hypertension is a risk factor for CVD. See the document on hypertension for evidencethatvitaminDreducestheriskofhypertension. Musclefunction 15 Muscle wasting is a characteristic of congestive heart failure . There is 16 growing evidence that vitamin D helps maintain muscle mass and strength 17 and avoid sarcopenia (lack of muscle mass) . The mechanism seems to be 18 avoidanceofhypophosphatemiarelatedtovitaminDdeficiency . VitaminD also protects the myocardium, which protect against heart failure or 19 arrhythmias . VITAMIN D - BENEFITS IN CARDIOVASCULAR DISEASES
CLINICAL STUDIES OF VITAMIN D IN CARDIO VASCULAR DISEASES
Short-term vitamin D3 supplementation lowers plasma renin activity in patientswithstablechronicheartfailure:anopen-label,blindedendpoint, randomizedprospectivetrial(VitD-CHFtrial). 2013Aug;166(2):357-364.e2. BACKGROUND:Manychronicheartfailure(CHF)patientshavelowvitaminD (VitD) and high plasma renin activity (PRA), which are both associated with poor prognosis. Vitamin D may inhibit renin transcription and lower PRA. We investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF patients. METHODS AND RESULTS: We conducted a single-center, open-label, blinded end point trial in 101 stable CHF patients with reduced left ventricular ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3 daily or control. At baseline, mean age was 64 ± 10 years, 93% male, left ventricular ejection fraction 35% ± 8%, and 56% had VitD deficiency. The geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L (43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the control group (P < .001). The primary outcome PRA decreased from 6.5 ng/mL per hour (3.8-11.2) to 5.2 ng/mL per hour (2.9-9.5) in the VitD3 treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3 ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled by a larger decrease in plasma renin concentration in the VitD3 treatment group compared to control (P = .020). No significant changes were observed in secondary outcome parameters, including N-terminal pro-B-type natriureticpeptidenatriureticpeptideandfibrosismarkers. CONCLUSIONS: Most CHF patients had VitD deficiency and high PRA levels. Six weeks of supplementation with 2,000 IU VitD3 increased 25- hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration. AmHeartJ.
VITAMIN D DEFICIENCY AND SUPPLEMENTATION AND RELATION TO CARDIOVASCULAR HEALTH. AmericanJournalofCardiology2012Feb1;109(3):359-63. Recent evidence supports an association between vitamin D deficiency and hypertension, peripheral vascular disease, diabetes mellitus, metabolic syndrome, coronary artery disease, and heart failure. The effect of vitamin D supplementation, however, has not been well studied. We examined the associations between vitamin D deficiency, vitamin D supplementation, and patient outcomes in a large cohort. Serum vitamin D measurements for 5 years and 8 months from a large academic institution were matched to patientdemographic,physiologic,anddiseasevariables.ThevitaminDlevels were analyzed as a continuous variable and as normal (≥ 30 ng/ml) or deficient (<30 ng/ml). Descriptive statistics, univariate analysis, multivariate analysis, survival analysis, and Cox proportional hazard modeling were performed. Of 10,899 patients, the mean age was 58 ± 15 years, 71% were women(n=7,758),andtheaveragebodymassindexwas30±8kg/m(2).The mean serum vitamin D level was 24.1 ± 13.6 ng/ml. Of the 10,899 patients, 3,294 (29.7%) were in the normal vitamin D range and 7,665 (70.3%) were deficient. In conclusion, vitamin D deficiency was associated with a significant risk of cardiovascular disease and reduced survival. Vitamin D supplementation was significantly associated with better survival, specificallyinpatientswithdocumenteddeficiency. Vitamin D deficiency was associated with several cardiovascular- related diseases, including hypertension, coronary artery disease, cardiomyopathy, and diabetes (all p <0.05). Vitamin D deficiency was a strong independent predictor of all-cause death (odds ratios 2.64, 95% confidence interval 1.901 to 3.662, p <0.0001) after adjusting for multiple clinical variables. Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p <0.0001).
PREVALENCE OF VITAMIN D DEFICIENCY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION. AmericanJournalofCardiology2011Jun1;107(11):1636-8. Deficiencyin25-hydroxyvitaminD(25[OH]D)isatreatableconditionthathas been associated with coronary artery disease and many of its risk factors. A practicaltimetoassessfor25(OH)Ddeficiency,andtoinitiatetreatment,isat the time of an acute myocardial infarction. The prevalence of 25(OH)D deficiency and the characteristics associated with it in patients with acute myocardial infarction are unknown. In this study, 25(OH)D was assessed in 239 subjects enrolled in a 20-hospital prospective myocardial infarction registry. Patients enrolled from June 1 to December 31, 2008, had serum samples sent to a centralized laboratory for analysis using the DiaSorin 25(OH)D assay. Normal 25(OH)D levels are ≥ 30 ng/ml, and patients with levels <30 and >20 ng/ml were classified as insufficient and those with levels ≤ 20 ng/ml as deficient. Vitamin D levels and other baseline characteristics were analyzed with the linear or Mantel-Haenszel trend test. Of the 239 enrolled patients, 179 (75%) were 25(OH)D deficient and 50 (21%) were insufficient, for a total of 96% of patients with abnormally low 25(OH)D levels. No significant heterogeneity was observed among age or gender subgroups, but 25(OH)D deficiency was more commonly seen in non- Caucasian patients and those with lower social support, no insurance, diabetes, and lower activity levels. Higher parathyroid hormone levels (45.3 vs 32.7 pg/ml, p = 0.029) and body mass indexes (31.2 vs 29.0 kg/m(2), p = 0.025) were also observed in 25(OH)D-deficient subjects. In conclusion, vitamin D deficiency is present in almost all patients with acute myocardial infarctioninamulticenterUnitedStatescohort. VitaminDdeficiencyispresentinalmost(96%)ofpatientswithacuteMI
VITAMIN D, PARATHYROID HORMONE, AND SUDDEN CARDIAC DEATH: RESULTS FROM THE CARDIOVASCULAR HEALTH STUDY. Hypertension.2011Dec;58(6):1021-8. Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25- OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 eventsper1000forPTH<65pg/mLand4eventsper1000forPTH≥65pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25- OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovasculardisease. Lower 25-OHD and higher PTH concentrations appears to increases sudden cardiacarrestriskby>2fold.
VITAMIN D STATUS IS ASSOCIATED WITH ARTERIAL STIFFNESS AND VASCULAR DYSFUNCTION IN HEALTHY HUMANS. JournaloftheAmericanCollegeofCardiology2011Jul5;58(2):186-92. OBJECTIVES: The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25- hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascularfunctioninhealthyadults. BACKGROUND: Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function inhumans,withthehypothesisthatvitaminDinsufficiencywillbeassociated withincreasedarterialstiffnessandabnormalvascularfunction. METHODS: We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assessarterialstiffness. RESULTS: Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independentlyassociatedwithflow-mediatedvasodilation(β=0.1,p=0.03), reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = -0.09, p = 0.04), augmentation index (β = -0.11, p = 0.03), and subendocardial viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactivehyperemiaindex(0.38±0.14,p=0.009)andsubendocardialviability
VITAMIN D STATUS IS ASSOCIATED WITH ARTERIAL STIFFNESS AND VASCULAR DYSFUNCTION IN HEALTHY HUMANS. ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mmHg,p=0.02). CONCLUSIONS: Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovasculardisease. 25-OH D remained independently associated with flow-mediated vasodilation (p = 0.03), reactive hyperemia index (p < 0.001), pulse wave velocity (p = 0.04), augmentation index (p = 0.03), and subendocardial viabilityratio(p=0.001).
VITAMIN D STATUS AND OUTCOMES IN HEART FAILURE PATIENTS. EuropeanJournalofHeartFailure2011Jun;13(6):619-25. AIMS: Vitamin D status has been implicated in the pathophysiology of heart failure (HF). The aims of this study were to determine whether a low vitamin D status is associated with prognosis in HF and whether activation of the renin-angiotensin system (RAS) and inflammatory markers could explain this potentialassociation. METHODS AND RESULTS: We measured 25-hydroxy-vitamin D (25(OH)D), plasma renin activity(PRA), interleukin-6(IL-6), C-reactive protein (CRP), and the incidence of death or HF rehospitalization in 548 patients with HF. Median age was 74 (64-80) years, left ventricular ejection fraction was 30% (23-42), and mean follow-up was 18 months. Low 25(OH)D levels were associated with female gender (P< 0.001), higher age (P= 0.002), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P< 0.001). Multivariable linear regression analysis showed that PRA (P= 0.048), and CRP levels (P= 0.006) were independent predictors of 25(OH)D levels. During follow-up, 155 patients died and 142 patients were rehospitalized. Kaplan- Meier analysis showed that After adjustment in a multivariable Cox regression analysis, low 25(OH)D concentration remained independently associated with an increased risk for the combined endpoint [hazard ratio (HR) 1.09 per 10 nmol/L decrease; 95% confidence interval (CI) 1.00-1.16; P= 0.040] and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI 1.00- 1.22;P=0.049). CONCLUSION: A low 25(OH)D concentration is associated with a poor prognosis in HF patients. Activation of the RAS and inflammation may confer theadverseeffectsoflowvitaminDlevels. lower 25(OH)D concentration was associated with an increased risk for the combined endpoint (all-cause mortality and HF rehospitalization; log rank test P= 0.045) and increased risk for all-cause mortality (log rank test P= 0.014).
VITAMIN D IN HYPERTENSION
VITAMIN D - BENEFITS IN HYPERTENSION Vitamin D lowers blood pressure by affecting the renin angiotensin 1 2 3 aldosterone system by suppressing renin . Renin is a proteolytic enzyme secreted by the kidneys, which catalyzes the production of angiotensin, which, in turn, mediates extracellularfluid volume (blood plasma, lymph and 4 interstitialfluid)andarterialvasoconstriction . 5 Parathyroid hormone (PTH) is associated with increased blood pressure , 6 with a larger effect on diastolic pressure . PTH decreases with increasing serum 25(OH)D until about 30 ng/ml, after which there is little additional 7 change . 8 Vitamin D also increases insulin sensitivity . Insulin resistance is a risk factor 910 forhypertension . Arterial calcification increases blood pressure by stiffening the arterial 11 walls . Serum 25(OH)D levels are inversely correlated with arterial 12 calcifications for those on hemodialysis . Related to arterial stiffening is endothelial dysfunction. (The epithelium is the thin layer of cells that lines 13 the interior surface of blood vessels.) Too little 25(OH)D and much calcium in the blood leads to endothelial dysfunction, which also contributes to 14 increased blood pressure . The paper by Rostand has a figure outlining his modelforelevatedbloodpressureamongAfrican-Americans.
CLINICAL STUDIES OF VITAMIN D IN HYPERTENSION
BLOOD 25-HYDROXYVITAMIN D CONCENTRATION AND HYPERTENSION: A META-ANALYSIS. JournalofHypertension2011Apr;29(4):636-45. OBJECTIVES: Increasing evidence indicates that vitamin D may influence the risk of hypertension, which is a major risk factor for cardiovascular disease. We conducted a meta-analysis to quantitatively review and summarize the results on the association between blood 25-hydroxyvitamin D concentrationsandhypertension. METHODS: Relevant studies were identified by a search of PubMed and EMBASE databases until November 2010. We also reviewed the references of retrieved articles. We included prospective and cross-sectional studies with blood 25-hydroxyvitamin D concentrations as the exposure and hypertension as the outcome. Studies had to report results as a relative risk oranoddsratio.Weusedrandom-effectsmodel. RESULTS: Of the 18 studies included in the meta-analysis, 4 were prospective studies and 14 were cross-sectional studies. The pooled odds ratio of hypertension was 0.73 [95% confidence interval (CI) 0.63-0.84] for the highest versus the lowest category of blood 25-hydroxyvitamin D concentration. In a dose-response meta-analysis, the odds ratio for a 40 nmol/l (16 ng/ml) (approximately 2 SDs) increment in blood 25- hydroxyvitaminDconcentrationwas0.84(95%CI0.78-0.90). CONCLUSION: Findings from this meta-analysis indicate that blood 25- hydroxyvitaminDconcentrationisinverselyassociatedwithhypertension.
RENIN-ANGIOTENSIN SYSTEM ACTIVITY IN VITAMIN D DEFICIENT, OBESE INDIVIDUALS WITH HYPERTENSION: AN URBAN INDIAN STUDY. Indian Journal of Endocrinology and Metabolism 2011 Oct;15 Suppl 4:S395- 401. BACKGROUND: Elevated renin-angiotensin-aldosterone system (RAAS) activity is an important mechanism in the development of hypertension. Both obesity and 25-hydroxy vitamin D [25(OH)D] deficiency have been associated with hypertension and augmented renin-angiotensin system (RAS) activity. We tried to test the hypothesis that vitamin D deficiency and obesity are associated with increased RAS activity in Indian patients with hypertension. MATERIALSANDMETHODS:Fiftynewlydetectedhypertensivepatientswere screened. Patients with secondary hypertension, chronic kidney disease, or coronaryarterydiseasewereexcluded.Patientsunderwentmeasurementof vitamin D and plasma renin and plasma aldosterone concentrations. They were divided into three groups according to their baseline body mass index (BMI; normal <25 kg/m(2), overweight 25-29.9 kg/m(2) and obese ≥ 30 kg/m(2)) and 25(OH)D levels (deficient <20 ng/ml, insufficient 20-29 ng/ml andoptimal≥30ng/ml). RESULTS: A total of 50 (male:female - 32:18) patients were included, with a mean age of 49.5 ± 7.8 years, mean BMI of 28.3 ± 3.4 kg/m(2) and a mean 25(OH)D concentration of 18.5 ± 6.4 ng/ml. Mean systolic blood pressure (SBP) was 162.4 ± 20.2 mm Hg and mean diastolic blood pressure (DBP) was 100.2 ± 11.2 mm Hg. Though all the three blood pressure parameters (SBP, DBP and MAP) were higher among individuals with higher BMIs, they were not achieving statistical significance. Increasing trends in PRAandPACwerenoticedwithlower25(OH)DandhigherBMIlevels. All the three blood pressure parameters [SBP, DBP and mean arterial pressure (MAP)] were significantly higher among individuals with lower 25(OH)D levels. The P values for trends in SBP, DBP and MAP were 0.009, 0.01 and 0.007, respectively.
RENIN-ANGIOTENSIN SYSTEM ACTIVITY IN VITAMIN D DEFICIENT, OBESE INDIVIDUALS WITH HYPERTENSION: AN URBAN INDIAN STUDY. Indian Journal of Endocrinology and Metabolism 2011 Oct;15 Suppl 4:S395- 401. CONCLUSION: Vitamin D deficiency and obesity are associated with stimulation of RAAS activity. Vitamin D supplementation along with weight loss may be studied as a therapeutic strategy to reduce tissue RAS activity in individualswithVitaminDdeficiencyandobesity.
SERUM 25-HYDROXYVITAMIN D LEVELS AND ALL-CAUSE AND CARDIOVASCULAR DISEASE MORTALITY AMONG US ADULTS WITH HYPERTENSION: THE NHANES LINKED MORTALITY STUDY. JournalofHypertension2012Feb;30(2):284-9. OBJECTIVES: Research suggests that serum concentrations of 25- hydroxyvitamin D [25(OH)D] are inversely associated with hypertension incidence. This study examined whether concentrations of 25(OH)D are inverselyassociatedwithmortalityriskamongUSadultswithhypertension. METHODS: We analyzed data from the 2001-2004 National Health and Nutrition Examination Survey with mortality data obtained through 2006. Hazard ratios with 95% confidence intervals (CIs) for all-cause and cardiovascular disease (CVD) mortality were estimated using Cox proportionalhazardmodels. RESULTS:Of2609participantswithhypertension,191died(including68CVD deaths) during an average of 3.7-year follow-up. Compared with participants with 25(OH)D concentrations in the highest quartile (≥29ng/ml), the hazard ratios for all-cause mortality were 1.93 (95% CI 1.06-3.49), 1.32 (95% CI 0.85- 2.04), and 1.36 (95% CI 0.84-2.22), respectively (P for trend <0.05), and the hazard ratios for CVD mortality were 3.21 (95% CI 1.14-8.99), 2.42 (95% CI 0.85-6.90), and 2.33 (95% CI 0.88-6.12), respectively (P for trend <0.05), in the first (<17ng/ml), second (17-<23ng/ml) and third (23-<29ng/ml) quartiles of 25(OH)D after adjustment for potential confounding variables. Additionally, concentrations of 25(OH)D as a continuous variable were linearly and inversely associated with the risk of mortality from all causes (P=0.012) and from CVD (P=0.010). These relationships were not affected muchbyadjustmentforbaselinebloodpressureanduseofantihypertension medications. CONCLUSION: Concentrations of 25(OH)D were inversely associated with all- cause and CVD mortality among adults with hypertension in the US. Enhancing vitamin D intake may contribute to a lower risk for premature death.
PREDIABETES AND PREHYPERTENSION IN HEALTHY ADULTS ARE ASSOCIATED WITH LOW VITAMIN D LEVELS. DiabetesCare.2011Mar;34(3):658-60. OBJECTIVE: To determine whether modest elevations of fasting serum glucose(FSG)andrestingbloodpressure(BP)inhealthyadultsareassociated withdifferentialserumvitaminDconcentrations. RESEARCH DESIGN AND METHODS: Disease-free adults in the National Health and Nutrition Examination Survey 2001-2006 were assessed. Prediabetes (PreDM) and prehypertension (PreHTN) were diagnosed using American Diabetes Association and Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure criteria: FSG 100-125 mg/dL and systolic BP 120-139 mmHg and/or diastolic BP 80-89 mmHg. Logistic regression was used to assess the effects of low vitamin D levels on the odds for PreDM and PreHTN in asymptomatic adults (n=1,711). RESULTS: The odds ratio for comorbid PreDM and PreHTN in Caucasian men (n = 898) and women (n = 813) was 2.41 (P < 0.0001) with vitamin D levels ≤ 76.3versus>76.3nmol/Lafteradjustingforage,sex,andBMI. CONCLUSIONS: This study strengthens the plausibility that low serum vitamin D levels elevate the risk for early-stage diabetes (PreDM) and hypertension(PreHTN).
LOW 25(OH)D3 LEVELS ARE ASSOCIATED WITH TOTAL ADIPOSITY, METABOLIC SYNDROME, AND HYPERTENSION IN CAUCASIAN CHILDREN AND ADOLESCENTS. EuropeanJournalofEndocrinology2011Oct;165(4):603-11. OBJECTIVES: Evidence of the association between vitamin D and cardiovascular risk factors in the young is limited. We therefore assessed the relationships between circulating 25-hydroxyvitamin D(3) (25(OH)D(3)) and metabolic syndrome (MetS), its components, and early atherosclerotic changes in 452 (304 overweight/obese and 148 healthy, normal weight) Caucasianchildren. METHODS: We determined serum 25(OH)D(3) concentrations in relation to MetS, its components (central obesity, hypertension, low high-density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, glucose impairment, and/or insulin resistance (IR)), and impairment of flow-mediated vasodilatation (FMD) and increased carotid intima-media thickness (cIMT) - twomarkersofsubclinicalatherosclerosis. RESULTS: Higher 25(OH)D(3) was significantly associated with a reduced presence of MetS. Obesity, central obesity, hypertension, hypertriglyceridemia, low HDL-cholesterol, IR, and MetS were all associated with increased odds of having low 25(OH)D(3) levels, after adjustment for age, sex, and Tanner stage. After additional adjustment for SDS-body mass index, elevated blood pressure (BP) and MetS remained significantly associated with low vitamin D status. The adjusted odds ratio (95% confidence interval) for those in the lowest (<17 ng/ml) compared with the highest tertile (>27 ng/ml) of 25(OH)D(3) for hypertension was 1.72 (1.02- 2.92), and for MetS, it was 2.30 (1.20-4.40). A similar pattern of association between 25(OH)D(3), high BP, and MetS was observed when models were adjusted for waist circumference. No correlation was found between 25(OH)D(3)concentrationsandeitherFMDorcIMT. CONCLUSIONS: Low 25(OH)D(3) levels in Caucasian children are inversely relatedtototaladiposity,MetS,andhypertension.
VITAMIN D IN DIABETES
TocontrolType2diabetes: Regulatesinsulinsynthesisandsecretionbyregulatingcalciumlevelsin theblood Directlyaffectfunctionofthepancreas(theorganthanmakesinsulin) Affectgenesassociatedwithglucosetolerance Reducesinsulinresistance Type1Diabetes: VitaminDreducestheriskofautoimmunediseasebystrengthening theimmunesystem. VitaminDsupplementsimprovespoorbloodsugarcontrol.Based ontheavailableinformation,theriskofType1diabetesmaybe reducedif: MaternalvitaminDlevelsareabove30–40ng/mL(75–100 nmol/L)duringpregnancy. Infantsobtain1000-2000IU(25–50mcg)/dayofvitaminD3from supplementsormother’smilk. InfantsmaintainvitaminDbloodlevelsabove30ng/mL(75 nmol/L). VITAMIN D - BENEFITS IN DIABETES
CLINICAL STUDIES OF VITAMIN D IN DIABETES
Effects of vitamin D supplementation on glucose metabolism, lipid concentrations, inflammation, and oxidative stress in gestational diabetes: adouble-blindrandomizedcontrolledclinicaltrial. OBJECTIVE: This study was designed to assess the effects of vitamin D supplementation on metabolic profiles, high-sensitivity C-reactive protein, andbiomarkersofoxidativestressinpregnantwomenwithGDM. DESIGN: This randomized, double-blind, placebo-controlled clinical trial was conducted in 54 women with GDM. Subjects were randomly assigned to receiveeithervitamin D supplements or placebo.Individuals in the vitamin D group (n = 27) received capsules containing 50,000 IU vitamin D3 2 times during the study (at baseline and at day 21 of the intervention) and those in the placebo group (n = 27) received 2 placebos at the same times. Fasting blood samples were collected at baseline and after 6 wk of the intervention toquantifyrelevantvariables. RESULTS: Cholecalciferol supplementation resulted in increased serum 25- hydroxyvitamin D concentrations compared with placebo (+18.5 ± 20.4 comparedwith+0.5±6.1ng/mL;P<0.001).Furthermore,intakeofvitaminD supplements led to a significant decrease in concentrations of fasting plasma glucose (-17.1 ± 14.8 compared with -0.9 ± 16.6 mg/dL; P < 0.001) and serum insulin (-3.08 ± 6.62 compared with +1.34 ± 6.51 μIU/mL; P = 0.01) and homeostasis model of assessment-insulin resistance (-1.28 ± 1.41 compared with +0.34 ± 1.79; P < 0.001) and a significant increase in the Quantitative Insulin Sensitivity Check Index (+0.03 ± 0.03 compared with -0.001 ± 0.02; P = 0.003) compared with placebo. A significant reduction in concentrations of total (-11.0 ± 23.5 compared with +9.5 ± 36.5 mg/dL; P = 0.01) and low- densitylipoprotein(LDL)(-10.8±22.4comparedwith+10.4±28.0mg/dL;P= 0.003)cholesterolwasalsoseenaftervitaminDsupplementation. CONCLUSIONS: Vitamin D supplementation in pregnant women with GDM had beneficial effects on glycemia and total and LDL-cholesterol concentrationsbutdidnotaffectinflammationandoxidativestress. AmJClinNutr.2013Dec;98(6):1425-32.
Improvement in Pancreatic β Cell Function with Vitamin D and Calcium SupplementationinVitaminDDeficientNon-DiabeticSubjects. 2013Sep6:1-33. OBJECTIVE: There are varied reports on the effect of vitamin D supplementation on beta cell function and plasma glucose levels. To study the effect of vitamin D and calcium supplementation on β cell function and plasmaglucoselevelsinsubjectswithvitaminDdeficiency. METHODS: Non-diabetic subjects(n=48) were screened for their serum vitamin D(25 OHD) status along with serum albumin, creatinine, calcium, phosphorus, alkaline phosphatase, and intact parathyroid hormone status(PTH). Subjects with vitamin D deficiency underwent two hour oral glucose tolerance test. Cholecalciferol (9570 IU/day)(upper tolerable level intake 10,000 IU/day-Endocrine Society guidelines for vitamin D supplementation)andcalciumof1gram/daywassupplemented. RESULTS: Thirty seven patients with vitamin D deficiency participated in the study. The baseline, post vitamin D and calcium supplementation, and(the difference) in serum calcium(corrected)(mg/dl) was 9±0.33and 8.33±1.09(- 0.66±1.11); 25 OHD(ng/ml) 8.75 ±4.75 and 36.83±18.68(28.00±18.33); PTH(pg/ml) 57.90±29.30 and 36.33±22.48(-20.25±22.45); Fasting plasma glucose(mg/dl) 78.23±7.60 and 73.47± 9.82(-4.88±10.65) and; HOMA 2-%B- C Peptide 183.17±88.74 and 194.67±54.71(11.38±94.27). There was significant difference in baseline and post vitamin D and calcium supplementation serum levels of corrected calcium(Z - 3.751;P<0.0001); 25 OHD levels(Z -4.9;P<0.0001);intact PTH(Z-4.04;P<0.0001);fasting plasma glucose(Z-2.7;P<0.007) and HOMA 2-%B- C Peptide(Z-1.923;P<0.05) by Wilcoxon Signed Rank Test. Insulin resistance measured by HOMA is unchanged. CONCLUSIONS: Optimizing serum 25OHD concentrations and supplementationofcalciumimprovesthefastingplasmaglucoselevelsandβ cellsecretoryreserve.Largerrandomizedcontrolstudiesareneededtoseeif correction of vitamin D deficiency will improve insulin secretion and prevent abnormalitiesofglucosehomeostasis. EndocrPract.
SERUM 25-HYDROXYVITAMIN D CONCENTRATION AND ARTERIAL STIFFNESS AMONG TYPE 2 DIABETES. DiabetesResClinPract.2012Jan;95(1):42-7 AIM: To evaluate the association between serum 25-hydroxyvitamin D [25(OH)D]andarterialstiffnessinpatientswithtype2diabetes. METHODS: Serum 25(OH)D was measured in a cross-sectional sample of 131 men and 174 women aged 30 years and over in Korea. Arterial stiffness was assessed by pulse wave velocity (PWV) obtained with a VP-2000 pulse wave unit. Fasting plasma glucose, insulin, lipid profile, HbA1c, calcium, phosphorous,andHS-CRPweremeasured. RESULTS: The prevalence of vitamin D deficiency was high (85.9%). Those withlowervitaminDlevelshadincreasedPWV.Usingmultivariateregression analysis, low 25(OH)D concentrations independently predicted PWV (p<0.001) in people with type 2 diabetes after adjustment for other risk factors such as age, smoking, hypertension, HS-CRP, diabetes duration, hypertensionduration,HbA1c,andBMI. CONCLUSIONS: Vitamin D may influence the development of cardiovascular disease. Clinical intervention studies are needed to clarify whether treatment with vitamin D decreases the risk of cardiovascular disease in patientswithtype2diabetes. Vitamin D deficiency is common in type 2 diabetes, and a low 25(OH)D level is significantly associated with increased arterial stiffness in these patients.
SERUM 25-HYDROXYVITAMIN D LEVELS AND PREDIABETES AMONG SUBJECTS FREE OF DIABETES. DiabetesCare.2011May;34(5):1114-9. OBJECTIVE: Animal studies suggest that low serum 25-hydroxyvitamin D (25[OH]D) may impair insulin synthesis and secretion and be involved in the pathogenesis of diabetes. Results in studies in humans have not been consistent, however. Prediabetes is a stage earlier in the hyperglycemia/diabetes continuum where individuals are at increased risk of developing diabetes and where prevention efforts have been shown to be effective in delaying or preventing the onset of diabetes. However, previous studies have not examined the association between low serum 25(OH)D levelsandprediabetes. RESEARCH DESIGN AND METHODS: We examined the 12,719 participants (52.5% women) in the third National Health and Nutrition Examination Survey aged >20 years who were free of diabetes. Serum 25(OH)D levels were categorized into quartiles (≤ 17.7, 17.8-24.5, 24.6-32.4, >32.4 ng/mL). Prediabeteswasdefinedasa2-hglucoseconcentrationof140-199mg/dL,or a fasting glucose concentration of 110-125 mg/dL, or an A1C value of 5.7- 6.4%. RESULTS: Lower serum 25(OH)D levels were associated with prediabetes after adjusting for age, sex, race/ethnicity, season, geographic region, smoking, alcohol intake, BMI, outdoor physical activity, milk consumption, dietary vitamin D, blood pressure, serum cholesterol, C-reactive protein, and glomerular filtration rate. Compared with quartile 4 of 25(OH)D (referent), the odds ratio of prediabetes associated with quartile 1 was 1.47 (95% CI 1.16-1.85; P = 0.001 for trend). Subgroup analyses examining the relation between 25(OH)D and prediabetes by sex, BMI, and hypertension categories alsoshowedaconsistentpositiveassociation. CONCLUSIONS: Lower serum 25(OH)D levels are associated with prediabetes inarepresentativesampleofU.S.adults.
SERUM 25-HYDROXYVITAMIN D, CALCIUM INTAKE, AND RISK OF TYPE 2 DIABETES AFTER 5 YEARS: RESULTS FROM A NATIONAL, POPULATION-BASED PROSPECTIVE STUDY (THE AUSTRALIAN DIABETES, OBESITY AND LIFESTYLE STUDY). DiabetesCare.2011May;34(5):1133-8. OBJECTIVE: To examine whether serum 25-hydroxyvitamin D (25OHD) and dietarycalciumpredictincidenttype2diabetesandinsulinsensitivity. RESEARCH DESIGN AND METHODS: A total of 6,537 of the 11,247 adults evaluated in 1999-2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004- 2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted formultiplepotentialconfounders,includingfastingplasmaglucose(FPG). RESULTS: During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58vs.65nmol/L;P<0.001)andcalciumintake(mean881vs.923mg/day;P= 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63-0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-Sat5years. CONCLUSIONS: Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adultmenandwomen.
PLASMA 25-HYDROXYVITAMIN D LEVELS ARE FAVORABLY ASSOCIATED WITH B-CELL FUNCTION. Pancreas.2012Jan17. OBJECTIVE: The association of hypovitaminosis D with type 2 diabetes is well recognized.AlthoughhypovitaminosisDisassociatedwithinsulinresistance, thereismuchlessinformationaboutitsimpactonβ-cellfunctioninhumans. METHODS: We enrolled 150 healthy, glucose-tolerant subjects for the assessment of β-cell function (acute insulin response) and insulin sensitivity index (ISI) using a hyperglycemic clamp. Adjusted β-cell function (ABCF) was defined as the product of acute insulin response and ISI. The relations of plasma 25-hydroxyvitamin D [25(OH)D] level with insulin sensitivity and ABCFwereexamined. RESULTS: Plasma 25(OH)D levels were positively associated with ABCF (P = 0.00004) and ISI (P < 0.00001). The associations remained significant after adjustment for age, sex, body mass index, physical activity, ethnicity, and seasonofstudy. CONCLUSIONS:Plasma25(OH)Dlevelsarepositivelyassociationwithbothβ- cell function and insulin sensitivity. Our observations suggest the roles of vitaminDdeficiencyinthedualdefectoftype2diabetes.
VITAMIN D LEVELS AND ASYMPTOMATIC CORONARY ARTERY DISEASE IN TYPE 2 DIABETIC PATIENTS WITH ELEVATED URINARY ALBUMIN EXCRETION RATE. DiabetesCare.2012Jan;35(1):168-72.. OBJECTIVE: Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has beenshowntopredictcardiovascularmortalityintype2diabeticpatients. RESEARCH DESIGN AND METHODS: We investigated the association among severevitaminDdeficiency,coronarycalciumscore(CCS),andasymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was definedasplasma25-hydroxyvitaminD(p-25[OH]D3)<12.5nmol/L.Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients' p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandemmassspectrometry. RESULTS: The median (range) vitamin D level was 36.9 (3.8-118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiencywas associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5-12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5-13.9, P = 0.007). Furthermore,severevitaminDdeficiencywasassociatedwithasymptomatic CAD(adjustedOR2.9,1.02-7.66,P=0.047). CONCLUSIONS: In high-risk type 2 diabetic patients with elevated UAER, low levelsofvitaminDareassociatedwithasymptomaticCAD.
VITAMIN D IN AUTO-IMMUNE DISEASES AND PAINS REFERENCE:ByStewartB.Leavitt,MA,PhD;PracticalPAINMANAGEMENT,July/August2008
According to extensive clinical research examining adult patients of all ages, inadequate concentrations of vitamin D have been linked to nonspecific muscle, bone, or joint pain, muscle weakness or fatigue, fibromyalgia syndrome, rheumatic disorders, osteoarthritis, hyperesthesia, migraine headaches,andotherchronicsomaticcomplaints. Deficiency of Vitamin D leads to Hypocalcemia, which leads to a cascade of bio-chemical reactions that negatively affects bone metabolism and health. Even mild hypocalcemia results in an elevation of parathyroid hormone (PTH) that can diminish bone density (osteopenia) and/or more severely affect bone architecture (osteoporosis). The effect relating more closely to musculoskeletal aches and pains is the increased PTH levels. This also impair properbonemineralizationcausingaspongymatrixtoformunderperiosteal membranes covering the skeleton. This gelatin-like matrix can absorb fluid, expand, and cause outward pressure on periosteal tissues, which generates pain since these tissues are highly innervated with sensory pain fibers. This dysfunction of bone metabolism (osteomalacia) is proposed in the literature as an explanation of why many patients with vitamin D inadequacies may complain of dull, persistent, generalized musculoskeletal aches, pains, and weakness. Therefore, experts recommend that vitamin D deficiency and its potential for associated osteomalacia should be considered in the differential diagnosis of all patients with chronic musculoskeletal pain, muscleweaknessorfatigue,fibromyalgia,orchronicfatiguesyndrome. Clinical researchers have also found that the role of vitamin D extends beyond bone and muscle involvement in chronic pain syndromes. For example, vitamin D receptors have been identified in various brain structures, the spinal cord, and sensory ganglia. Accordingly, results of some studies suggest non-musculoskeletal benefits of vitamin D supplementation, asfollows: VITAMIN D - AUTO-IMMUNE DISEASE OR PAINS
Neuropathy - A recently reported prospective study of 51 patients with type 2 diabetes and associated with neuropathy found that conservative vitamin D supplementation (about 2000 IU/day) for 3 months resulted in nearly a 50%decreaseinpainscores Inflammation - Clinical research indicates that vitamin D supplementation modulates or decreases pro-inflammatory cytokines (eg, C-reactive protein, interleukin 6 and 12, and tumor necrosis factor-alpha) while increasing anti- inflammatory cytokines (eg, interleukin-10). Investigators have further suggestedthatvitaminDmayhelptomoderatepainfulchronicinflammatory autoimmune conditions that are influenced by excessive cytokine activity, suchasinflammatoryboweldisease. Migraine Headaches -There have been case reports of vitamin D combined with calcium supplementation to alleviate migraine headaches in postmenopausal and premenopausal women. Reductions in both frequency andintensityofmigraineswereachievedwithin2months. Affective (Mood) Disturbances - In patients with fibromyalgia syndrome, pain, depression, and anxiety were found to be strongly associated with insufficient vitamin D. Furthermore, large studies examining older persons (aged >65 years) found significant associations between 25(OH)D deficiencies and depressive disorders. In one of the studies, inadequate 25(OH)Danddepressionalsowerehighlycorrelatedwithchroniclower-back painspecificallyinfemalepatients. VITAMIN D - AUTO-IMMUNE DISEASE OR PAINS
Fibromyalgia syndrome patients are highly Vitamin D deficient, (4.76 ± 1.46 ng/mL), and lower vitamin D levels were significantly correlated withgreaterwidespreadpain. More than half of 313 patients undergoing spinal fusion surgery had inadequate levels of vitamin D; a quarter of them were severely deficient 93% of 150 patients with persistent, nonspecific musculoskeletal pain wereovertlydeficientinvitaminD. There is high prevalence of vitamin D deficiency in children with limb pain, and vitamin D supplementation ameliorated pain within three months. Vitamin D deficiency is found in 83% of 299 patients with low-back pain, and supplementation with 5,000–10,000 IU of vitamin D per day lead to painreductioninnearly100%ofpatientsafterthreemonths. Current best evidence demonstrates that supplemental vitamin D can help many patients who have been unresponsive to other therapies for pain. VITAMIN D - AUTO-IMMUNE DISEASE OR PAINS
Speaking at the 26th Annual Meeting of the North American Spine Society, orthopaedic surgeons from Washington University School of Medicine in St. Louis reported that more than half of 313 patients undergoing spinal fusion surgery had inadequate levels of vitamin D; a quarter of them were severely deficient[Stokeretal.2011]. One of the study authors, Jacob M. Buchowski, MD, said he became aware of thevitaminDproblemwhenapatientinher40sexperiencedaslowrecovery after spinal fusion surgery. While he was trying to determine why the vertebrae did not fuse properly the woman mentioned that she had recently been diagnosed with vitamin D deficiency. “It was like a 'light bulb' went off,” he stated. Consequently, Buchowski and colleagues started routinely screeningpatientspriortospinalfusionsurgeryforvitaminDdeficiency. Low vitamin D levels are known to be common in elderly patients; surprisingly, however, patients in this study most likely to have inadequate levels were younger; on average, 55 years old. One quarter of the patients, predominantly those who were older, had taken vitamin D supplements in thepast. The researchers found that the main risk factors for inadequate vitamin D were smoking, obesity, disability prior to surgery, and never having taken vitaminDormultivitaminsupplements.Althoughanearlierstudyhadshown inadequate vitamin D levels in 43% of patients undergoing orthopedic procedures,thisisthefirsttolooksolelyatpatientshavingspinesurgery. Vitamin D is important for calcium absorption and patients with a deficiency are at risk for osteomalacia that hinders new bone formation. As a follow-up to this study, Buchowski and colleagues are planning an investigation of whether there is a link between low vitamin D and poor outcomes following spinal fusion. In the meantime, he recommends that patients should be gettingsufficientvitaminDpriortoorthopedicsurgery. VITAMIN D DEFICIENCIES HAMPER RECOVERY FROM SPINE SURGERY
This one from researchers at Johns Hopkins University, Baltimore — suggests that vitamin D levels are significantly lower in patients with recurrent inflammatory spinal cord disease, including transverse myelitis and neuromyelitis optica [Mealy et al. 2011]. In transverse myelitis (TM) there is involvement of the myelin sheath that protects nerve fibers; symptoms include back pain and weakness in the legs. Neuromyelitis optica (NMO) is a disease of the central nervous system that affects the optic nerves and spinal cord. Writing in an early online edition of the Archives of Neurology, Maureen A. Mealy, RN, BSN, and colleagues report a retrospective analysis of vitamin D levels among 77 patients, comparing monophasic versus recurrent inflammatory diseases of the spinal cord (TM/NMO), and adjusting for season,age,sex,andrace.TheyfoundthatvitaminDlevelsweresignificantly deficient — 25(OH)D < 20 ng/mL — in patients who developed recurrent spinal cord disease compared with those having nonrecurring monophasic disease. This is consistent with other recurrent autoimmune conditions and points to a common link between low vitamin D levels and immunologic dysregulation,” the researchers write. They suggest that further studies are needed to assess the relationship between vitamin D and painful, recurrent spinalcorddisease. LOW VITAMIN D MAY INFLUENCE INFLAMMATORY SPINAL CORD DISEASE
Pseudoarthrosis and fracture: interaction between severe vitamin D deficiencyandprimaryhyperparathyroidism. A young woman with severe vitamin D deficiency presented with proximal muscle weakness, fragility fracture and pseudoarthrosis. On evaluation, she was found to have hypercalcaemia, a single parathyroid adenoma and an undetectable 25-hydroxyvitamin D level. She received parenteral cholecalciferol and subsequently underwent curative parathyroidectomy. Postoperatively, she had hungry bone syndrome, which she gradually recoveredfromwithcalciumandcalcitriolreplacement.Notably,hercalcium levels were in the lower limit of normal range and associated with elevated alkaline phosphatase levels at postoperative Day 14. Follow-up for the next four years showed that the patient had remarkable symptomatic and radiological improvements. In this report, we discuss the pathophysiological interactions between vitamin D deficiency and associated primary hyperparathyroidism. SingaporeMedJ.2013Nov;54(11):e224-7.
SERUM VITAMIN D LEVEL AND BONE MINERAL DENSITY IN PREMENOPAUSAL EGYPTIAN WOMEN WITH FIBROMYALGIA. RheumatolInt.2012Feb4. Patients with fibromyalgia syndrome (FMS) have impaired mobility and therefore get less sunlight exposure, we postulated that they may be at increased risk of developing osteoporosis (OP). The aim of this study was to assess and compare serum vitamin D level and bone mineral density (BMD) value in patients with primary FMS (PFMS) and healthy controls. A total of 50 patients with PFMS participated in this case-control study, and 50 healthy females who were age-matched to the patients were used as the control group. Venous blood samples collected from all subjects were used to evaluate serum 25-hydroxyvitamin D3 (25-OHD). BMD was measured at the lumbar spine (L2-L4) anteroposterior, femoral neck and forearm by dual- energy X-ray absorptiometry. Patients with PFMS had significantly lower serum 25-OHD than controls (15.1 ± 6.1 and 18.8 ± 5.4 ng/ml, respectively, p = 0.0018). Apart from the BMD in the lumbar spine, which was significantly lower in the PFMS patients compared with controls (p = 0.0012), no significant difference was found in other measures of BMD. Compared to PFMS patients who had serum level of the 25-OHD >20 ng/ml, the patients with 25-OHD ≤20 ng/ml are more likely to have impaired short memory (46.4 vs. 13.6%, respectively, p = 0.0136), confusion (50 vs. 18.2%, respectively, p = 0.0199), mood disturbance (60.7 vs. 27.3%, respectively, p = 0.0185), sleep disturbance (53.6 vs. 22.7%, respectively, p = 0.0271), restless leg syndrome (57.1 vs. 27.3%, respectively, p = 0.0346) and palpitation (67.9 vs. 36.4%, respectively, p = 0.0265). Serum level of the 25-OHD is inversely correlated withvisualanaloguescale(VAS)ofpain(p=0.016),Beckscorefordepression (p = 0.020) and BMD at lumbar spine (p = 0.012). The lumbar BMD inversely correlated with VAS of pain (p = 0.013) and Beck score for depression (p = 0.016). This study confirmed high prevalence of hypovitaminosis D among in patients with PFMS. This study confirmed the concept that FMS is a risk factor for OP. Based on this, an early nutrition program rich in calcium and vitamin D, appropriate exercise protocols, and medical treatment should be consideredinthesepatientsintermsofpreventingOPdevelopment.
THE PREVALENCE OF VITAMIN D DEFICIENCY IN CONSECUTIVE NEW PATIENTS SEEN OVER A 6-MONTH PERIOD IN GENERAL RHEUMATOLOGY CLINICS. ClinRheumatol.2011Jun;30(6):789-94. The objectives of this study are to assess: (a) the prevalence of vitamin D deficiency among new patients attending rheumatology outpatient departments, (b) the age profile of these low vitamin D patients and (c) whether any diagnostic category had a particularly high number of vitamin D-deficient patients. All new patients seen consecutively in general rheumatologyclinicsbetweenJanuarytoJune2007inclusivewereeligibleto partake in this study, and 231 out of 264 consented to do so. Parathyroid hormone, 25-hydroxyvitamin D, creatinine, calcium, phosphate, albumin and alkaline phosphatase levels were measured. We defined vitamin D deficiency as ≤53 nmol/l and severe deficiency as ≤25 nmol/l. Overall, 70% of 231 patients had vitamin D deficiency, and 26% had severe deficiency. Sixty- five percent of patients aged ≥65 and 78% of patients aged ≤30 years had low vitamin D levels. Vitamin D deficiency in each diagnostic category was as follows: (a) inflammatory joint diseases/connective tissue diseases (IJD/CTD), 69%; (b) soft tissue rheumatism, 77%; (c) osteoarthritis, 62%; (d) non-specific musculoskeletal back pain, 75% and (e) osteoporosis, 71%. SeasonalvariationofvitaminDlevelswasnotedinalldiagnosticgroupsapart fromIJD/CTDgroup,wherethedegreeofvitaminDdeficiencypersistedfrom latewintertopeaksummer.VeryhighprevalenceofvitaminDdeficiencywas noted in all diagnostic categories (p = 0.006), and it was independent of age (p = 0.297). The results suggest vitamin D deficiency as a possible modifiable risk factor in different rheumatologic conditions, and its role in IJD/CTD warrantsfurtherattention.
VITAMIN D IN CANCERS REFERENCE:VITAMIN DAND CANCER PREVENTION:STRENGTHS AND LIMITS OF THE EVIDENCE;NATIONAL CANCER INSTITUTE AT NIH
ROLE OF VITAMIN D IN REDUCING CANCERS. A large number of scientific studies have investigated the possible role for vitaminDincancerprevention. The first results came from epidemiologic studies known as geographic correlation studies. In these studies, an inverse relationship was found between sunlight exposure levels in a given geographic area and the rates of incidence and death for certain cancers in that area. Individuals living in southern latitudes were found to have lower rates of incidence and death for these cancers than those living at northern latitudes. Because sunlight/UV exposure is necessary for the production of vitamin D3, researchers hypothesized that variation in vitamin D levels accounted for the observed relationships. Evidence of a possible cancer-protective role for vitamin D has also been found in laboratory studies of the effect of vitamin D treatment on cancer cells in culture. In these studies, vitamin D promoted the differentiation and death (apoptosis) of cancer cells, and it slowed their proliferation. Randomized clinical trials designed to investigate the effects of vitamin D intake on bone health have suggested that higher vitamin D intakes may reduce the risk of cancer. One study involved nearly 1,200 healthy postmenopausal women who took daily supplements of calcium (1,400 mg or 1,500 mg) and vitamin D (25 μg vitamin D, or 1,100 IU―a relatively large dose) or a placebo for 4 years. The women who took the supplements had a 60 percent lower overall incidence of cancer; however, the study did not include a vitamin D-only group. Moreover, the primary outcome of the study was fracture incidence; it was not designed to measure cancer incidence. This limits the ability to draw conclusions about the effect of vitamin D intake oncancerrisk.
ROLE OF VITAMIN D IN REDUCING CANCERS. A number of observational studies have investigated whether people with higher vitamin D levels or intake have lower risks of specific cancers, particularly colorectal cancer and breast cancer. Associations of vitamin D with risks of prostate, pancreatic, and other, rarer cancers have also been examined. These studies have yielded inconsistent results, most likely because of the challenges of conducting observational studies of diet. Information about dietary intakes is obtained from the participants through the use of food frequency questionnaires, diet records, or interviews in which the participants are asked to recall information about their dietary intakes. Information collected in this manner can be inaccurate. In addition, only recently has a comprehensive food composition database with vitamin D values for the U.S. food supply become available. Other dietary componentsorenergybalancemayalsomodifyvitaminDmetabolism. Measuring blood levels of 25-hydroxyvitamin D to determine vitamin D status avoids some of the limitations of assessing dietary intake. However, vitamin D levels in the blood vary by race, with the season, and possibly with the activity of genes whose products are involved in vitamin D transport and metabolism. These variations complicate the interpretation of studies that measuretheconcentrationofvitaminDinserumatasinglepointintime. Finally, it is difficult to separate the effects of vitamin D and calcium because of the complicated biological interactions between these substances. To fully understand the effect of vitamin D on cancer and other health outcomes, new randomized trials will need to be carried out. However, the appropriate dose of vitamin D to use in such trials is still not clear.
VITAMIN D AND COLORECTAL CANCERS Epidemiologic studies of the association between vitamin D and the risk of colorectal cancer have provided some indications that higher levels of intakeareassociatedwithareducedrisk.However,thedataareinconsistent. In the American Cancer Society's Cancer Prevention Study (CPS) II Nutrition Cohort, the diet, medical history, and lifestyle of more than 120,000 men and women were analyzed. Men who had the highest intakes of vitamin D through both their diet and supplement use (greater than 13 μg, or 525 IU, per day) had a slightly lower risk of colorectal cancer than men who had the lowest vitamin D intakes. However, this association was not observed among women. In a pooled analysis of data from 10 cohort studies (including the CPS II cohort), individuals with the highest dietary vitamin D intakes had a slightly lower risk of colorectal cancer than those with the lowest intakes, but the reductioninriskwasnotstatisticallysignificant. In the Women's Health Initiative randomized trial, healthy postmenopausal women took daily supplements that contained both calcium (1,000 mg) and vitamin D (10 μg, or 400 IU) or a placebo for an average of 7 years. Supplementation did not reduce the incidence of colorectal cancer. However, some scientists have raised the possibility that the relatively low level of vitamin D supplementation and the short duration ofparticipantfollow-upmightaccountforthenegativeresults. At least one epidemiologic study has reported an association between vitamin D and reduced mortality from colorectal cancer. Among the 16,818 participants in the Third National Health and Nutrition Examination Survey, those with higher vitamin D blood levels (≥80 nmol/L) had a 72 percent lower risk of colorectal cancer death than those with lower vitamin D blood levels (<50nmol/L).
VITAMIN D AND COLORECTAL CANCERS Most colorectal cancers develop from pre-existing colorectal adenomas, and interventions that reduce the risk of adenoma development or recurrence are likely to reduce the risk of colorectal cancer. Several large studies have investigated the association of vitamin D intake or serum status withadenomarisk. A cohort from the National Cancer Institute (NCI)-sponsored Polyp Prevention Trial (PPT) was evaluated for the association of vitamin D intake with recurrence of colorectal adenomas in individuals who previously had one or more adenomas removed during a qualifying colonoscopy. PPT was a multicenter randomized clinical trial to determine the effects of a diet high in fiber, fruits, and vegetables and low in fat on adenoma recurrence. The detailed dietary information obtained during the trial allowed the researchers to investigate the association between additional dietary factors andadenomarecurrence.TotalvitaminDintake(thatis,fromdietarysources and supplements combined) was not associated with a reduced risk of adenoma recurrence. However, individuals who used any amount of vitamin Dsupplementshadalowerriskofadenomarecurrence. In another study, the vitamin D intakes of 3,000 people from several Veterans Affairsmedicalcenterswereexaminedto determinewhetherthere was an association between intake and advanced colorectal neoplasia (an outcome that included high-risk adenomas as well as colon cancer). Individuals with the highest vitamin D intakes (more than 16 μg, or 645 IU, per day) had a lower risk of developing advanced neoplasia than those with lowerintakes. A pooled analysis of data from these and a number of other observational studies found that higher circulating levels of vitamin D and higher vitamin D intakes were associated with lower risks of colorectal adenoma.Inverseassociationswereseenwithbothdietaryandtotalvitamin DintakebutnotwithsupplementalvitaminDintake.Howevertheassociati-
VITAMIN D AND COLORECTAL CANCERS onswithdietaryintakewerenotstatisticallysignificant. Another large, NCI-sponsored randomized, placebo-controlled trial explored the effects of calcium supplementation and blood levels of vitamin D on adenoma recurrence. Calcium supplementation reduced the risk of adenoma recurrence only in individuals with vitamin D blood levels above 73 nmol/L. Among individuals with vitamin D levels at or below this level, calciumsupplementationwasnotassociatedwithareducedrisk.
VITAMIN D AND BREAST CANCERS Epidemiologic studies of the association between vitamin D and breast cancer risk had conflicting results. Although several studies have suggested aninverseassociationbetweenvitaminDintakeandtheriskofbreastcancer, others have shown no association or even a positive association (that is, individuals with higher intakes had higher risks). A meta-analysis of six studies that investigated the relationship between vitamin D intake and breast cancer risk found no association. However, most women in these studies had relatively low vitamin D intakes, and, when the analysis was restrictedtowomenwiththehighestvitaminDintakes(>10μg,or400IU,per day), their breast cancer risks were lower than those of women with the lowestintakes(typically<1.25μg,or50IU,perday). IntheWomen'sHealthInitiative,calciumplusvitaminDsupplementationfor an average of 7 years did not reduce the incidence of invasive breast cancer comparedwithplacebo. . The association between blood levels of vitamin D and breast cancer risk was examined in a cohort of postmenopausal women who were enrolled in NCI's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and from whom blood was drawn at study entry. During the subsequent follow- up period, 1,005 of these women developed breast cancer. When researchers compared the blood vitamin D levels of these women with those of 1,005 similar control women who did not develop breast cancer, they foundnoassociationbetweenvitaminDstatusandriskofbreastcancer.
VITAMIN D AND PROSTATE CANCERS Somegeographiccorrelationstudieshavesuggestedthatmenexposed to higherlevelsof sunlight may havea lowerriskof prostatecancer.Although some epidemiologic studies have suggested that men with higher vitamin D levels have an increased risk of prostate cancer, most studies have not shown suchanassociation. In one relatively large study of men diagnosed 1 to 8 years after their blood was drawn, higher vitamin D blood levels were not associated with a lower risk of prostate cancer overall. Indeed, there was some evidence that men withhighervitaminDlevelshadanincreasedriskforaggressivedisease. In another study, the European Prospective Investigation into Cancer and Nutrition (EPIC), blood samples obtained at study entry were examined for 652 men who developed prostate cancer during follow-up and 752 matched control subjects. No association was observed between serum vitamin D levelsandriskofprostatecancer,eitheroverallorbycancerstage.
VITAMIN D AND PANCREATIC CANCERS There is conflicting evidence about vitamin D's relationship to risk of pancreatic cancer. A study of more than 120,000 men and women from the Health Professionals Follow-Up Study and the Nurses' Health Study showed that participants with higher dietary intake of vitamin D had progressively lower risk of pancreatic cancer, compared with those who had the lowest intake. The estimates of vitamin D intake were based on detailed dietary informationprovidedthroughquestionnaires.Participantswerefollowedfor 16 years for the incidence of pancreatic cancer, and 365 cases were identified. In a study of men and women enrolled in the PLCO Screening Trial, no association between vitamin D level and pancreatic cancer risk was observed. The PLCO study examined vitamin D levels in blood from 184 individuals who were diagnosed with pancreatic cancer during nearly 12 yearsoffollow-upand368matchedcancer-freecontrolsubjects.Incontrast, among Finnish male smokers participating in the Alpha-Tocopherol, Beta- Carotene (ATBC) Cancer Prevention Study, higher blood levels of vitamin D wereassociatedwithanincreasedriskofpancreaticcancer.Morerecently,in the NCI Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, men and women with the highest blood vitamin D levels (greater than 100 nmol/L, or 40 ng/mL) had twice the pancreatic cancer risk of men and women whose blood vitamin D levels were in the normal range of 50-75 nmol/L(20-30ng/mL).
VITAMIN D AND RARE CANCERS A recent large collaborative effort analyzed data from 10 prospective cohort studies to examine whether vitamin D levels in blood were associated with seven rare cancers. The NCI Cohort Consortium Vitamin D Pooling Project of Rarer Cancers included information on blood vitamin D levels and incidence of rare cancers in a subset of more than 12,000 men and women. The researchers matched participants on date and season of blood draw and used other statistical techniques to adjust for seasonal variation in blood vitamin D levels. When the data from the different studies were pooled, there was no overall association between vitamin D level and risk of non- Hodgkin lymphoma or cancers of the endometrium, esophagus, stomach, kidney,orovary.Anincreasedriskofpancreaticcancerwasobservedinthose with the highest blood levels of vitamin D (greater than 100 nmol/L or 40 ng/mL). VITAMIN D AND SKIN CANCER AlthoughpeopleobtainsomevitaminDfromdietarysources,mostvitaminD is made in the body after the skin is exposed to sunlight. Despite the known and potential health benefits of vitamin D, increasing sun exposure increases the risk of skin cancer. In general, most experts believe that people should continue to use sun protection when UV levels are moderate or higher. Some researchers have suggested that brief daily exposure to UV will ensure adequate vitamin D production, but many variables (such as skin color, latitude, and season) can affect the production of vitamin D, and such recommendations have proven controversial. Other experts recommend vitamin D supplementation to avoid the problem of increasing skin cancer risk.
VITAMIN D IN MODIFYING THE CANCER RISK Mechanisms by which vitamin D may modify cancer risk are not fully understood.LaboratorystudieshaveshownthatvitaminDpromotescellular differentiation,decreasescancercellgrowth,andstimulatesapoptosis. Vitamin D acts on cells by binding to the vitamin D receptor (VDR). The VDR is a regulator of gene transcription that is found in the nucleus of cells. Vitamin D-bound VDR binds to the retinoid-X receptor (RXR), and the resulting complex activates the expression of specific genes. Among the many genes regulated by vitamin D are those that produce the proteins calbindin and TPRV6, both of which are involved in the absorption of calcium by intestinal cells. Another vitamin D-regulated gene is CYP3A4, whose protein product detoxifies the bile acid lithocholic acid (LCA). LCA is believed to damage the DNA of intestinal cells and may promote colon carcinogenesis. Stimulating the production of a detoxifying enzyme by vitamin D could explain a protectiveroleforvitaminDagainstcoloncancer. Further insight into the mechanisms by which vitamin D might modify cancer risk could come from study of the vitamin D receptor itself. A large number of variant forms of the VDR gene have been identified, some of which are known to alter the structure or function of the VDR protein. Some of these variants have been linked to risk for certain cancers, including prostate, colorectal, breast, bladder, and melanoma. The association of VDR variants with cancer risk differs by cancer site and appears to be modified by environmentalexposures,suchasdietandsunexposure.
VITAMIN D IN PREGNANCY
VITAMIN D IN PREGNANCY VitaminDstatusandhypertensivedisordersduringpregnancy Maternal vitamin D deficiency in pregnancy has been associated with an increased risk of pre-eclampsia (new-onset gestational hypertension and proteinuria after 20 weeks of gestation), a condition associated with an increaseinmaternalandperinatalmorbidityandmortality. Womenwithpre-eclampsiahavelowerconcentrationsof25-hydroxyvitamin D compared with women with normal blood pressure. The low levels of urinary calcium (hypocalciuria) in women with pre-eclampsia may be due to a reduction in the intestinal absorption of calcium impaired by low levels of vitamin D. Additionally, pre-eclampsia and vitamin D deficiency are directly and indirectly associated through biologic mechanisms including immune dysfunction, placental implantation, abnormal angiogenesis, excessive inflammation,andhypertension. VitaminDstatusandothermaternalconditions Maternal vitamin D deficiency in early pregnancy has been associated with elevated risk for gestational diabetes mellitus, Poor control of maternal diabetes in early pregnancy is inversely correlated with low bone mineral contentininfants,asislowmaternalvitaminDstatus. VDD may lead to a high bone turnover, bone loss, osteomalacia (softening of the bones) and myopathy (muscle weakness) in the mother in addition to neonatal and infant VDD. An adequate vitamin D status may also protect against other ad verse pregnancy outcomes. For example, maternal vitamin D deficiency has been linked to caesarean section in a single recent study. Low prenatal and perinatal maternal vitamin D concentrations can affect the function of other tissues, leading to a greater risk of multiple sclerosis, cancer,insulin-dependentdiabetesmellitus,andschizophrenialaterinlife
VITAMIN D IN PREGNANCY VitaminDstatusandpretermbirthandlowbirth-weight A potential inverse association between maternal vitamin D status and preterm birth(lessthan37 weeks’ gestation) has been reported. Conversely, not all the studies show significant associations between maternal calcidiol levelsand any measureof the child’s sizeat birth or during the first months of life. There is not much information on maternal vitamin D status and low birth weight or preterm birth in children born from HIV-infected pregnant women. VitaminDstatusandpostnatalgrowth Some observational studies suggest that vitamin D levels during pregnancy influence fetal bone development and children’s growth. While head circumference in children nine years of age has been significantly associated withmaternalcalcidiollevels,thereisstillinconsistentinformationaboutthe association of maternal vitamin D status and infants’ bone mass. It is not clearifmaternalvitaminDdeficiencyleadstoneonatalrickets,sincericketsis usually identified later in childhood. Early studies indicate a possible risk for neonatal rickets in the offspring of women with osteomalacia, abnormal softeningofthebonebydeficiencyofphosphorus,calciumorvitaminD. More recent studies have found that vitamin D deficiency (serum levels lower than 25 nmol/L) was identified in 92% of rachitic (having rickets) Arab children and 97% of their mothers compared with 22% of nonrachitic childrenand 52%of theirmothers.Apositivecorrelationwasfound between maternalandchildvitaminDlevels.
VITAMIN D IN PREGNANCY VitaminDstatusandimmuneresponse Vitamin D has direct effects on both adaptive and innate immune systems. In children, vitamin D insufficiency is linked to autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis, allergies and atopic diseases. Various studies have also shown that vitamin D deficiency is strongly associated with tuberculosis, pneumonia, and cystic fibrosis and both prenatal and perinatal vitamin D deprivation might influence early-life respiratory morbidity as this vitamin is important for lung growth and development.VitaminDmayhavepositiveeffectsontheimmunesystemby up-regulating the production of the antimicrobial peptides by macrophages and endothelial cells which may inactivate viruses and suppress inflammation, andsubsequentlyreducetheseverityofinfections. CochraneDatabaseofSystematicReviews2012,Issue2
Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. 2013Sep;143(9):1432-8. Unfavorable metabolic profiles and oxidative stress in pregnancy are associated with several complications. This study was conducted to determine the effects of vitamin D supplementation on serum concentrations of high-sensitivity C-reactive protein (hs-CRP), metabolic profiles, and biomarkers of oxidative stress in healthy pregnant women. This randomized, double-blind, placebo-controlled clinical trial was conducted in 48pregnantwomenaged18-40yoldat25wkofgestation.Participantswere randomly assigned to receive either 400 IU/d cholecalciferol supplements (n = 24) or placebo (n = 24) for 9 wk. Fasting blood samples were taken at study baseline and after 9 wk of intervention to quantify serum concentrations of hs-CRP,lipidconcentrations,insulin,andbiomarkersofoxidativestress.After 9 wk of intervention, the increases in serum 25-hydroxyvitamin D and calcium concentrations were greater in the vitamin D group (+3.7 μg/L and +0.20 mg/dL, respectively) than in the placebo group (-1.2 μg/L and -0.12 mg/dL,respectively;P<0.001forboth).VitaminDsupplementationresulted in a significant decrease in serum hs-CRP (vitamin D vs. placebo groups: -1.41 vs. +1.50 μg/mL; P-interaction = 0.01) and insulin concentrations (vitamin D vs. placebo groups: -1.0 vs. +2.6 μIU/mL; P-interaction = 0.04) and a significant increase in the Quantitative Insulin Sensitivity Check Index score (vitamin D vs. placebo groups: +0.02 vs. -0.02; P-interaction = 0.006), plasma total antioxidant capacity (vitamin D vs. placebo groups: +152 vs. -20 mmol/L; P-interaction = 0.002), and total glutathione concentrations (vitamin D vs. placebo groups: +205 vs. -32 μmol/L; P-interaction = 0.02) compared with placebo. Intake of vitamin D supplements led to a significant decrease in fasting plasma glucose (vitamin D vs. placebo groups: -0.65 vs. - 0.12 mmol/L; P-interaction = 0.01), systolic blood pressure (vitamin D vs. placebo groups: -0.2 vs. +5.5 mm Hg; P-interaction = 0.01), and diastolic blood pressure (vitamin D vs. placebo groups: -0.4 vs. +3.1 mm Hg; P- interaction = 0.01) compared with placebo. In conclusion, vitamin D supplementation for 9 wk among pregnant women has beneficial effects on metabolicstatus JNutr.
Maternal Vitamin D Supplementation to Improve the Vitamin D Status of Breast-fedInfants:ARandomizedControlledTrial. OBJECTIVE: To determine whether a single monthly supplement is as effective as a daily maternal supplement in increasing breast milk vitamin D toachievevitaminDsufficiencyintheirinfants. PATIENTS AND METHODS: Forty mothers with exclusively breast-fed infants wererandomizedtoreceiveoralcholecalciferol(vitaminD3)5000IU/dfor28 days or 150,000 IU once. Maternal serum, breast milk, and urine were collected on days 0, 1, 3, 7, 14, and 28; infant serum was obtained on days 0 and28.EnrollmentoccurredbetweenJanuary7,2011,andJuly29,2011. RESULTS:Inmothersgivendailycholecalciferol,concentrationsofserumand breast milk cholecalciferol attained steady levels of 18 and 8 ng/mL, respectively, from day 3 through 28. In mothers given the single dose, serum and breast milk cholecalciferol peaked at 160 and 40 ng/mL, respectively, at day 1 before rapidly declining. Maternal milk and serum cholecalciferol concentrations were related (r=0.87). Infant mean serum 25-hydroxyvitamin D concentration increased from 17±13 to 39±6 ng/mL in the single-dose group and from 16±12 to 39±12 ng/mL in the daily-dose group (P=.88). All infantsachievedserum25-hydroxyvitaminDconcentrationsofmorethan20 ng/mL. CONCLUSION: Either single-dose or daily-dose cholecalciferol supplementation of mothers provided breast milk concentrations that result invitaminDsufficiencyinbreast-fedinfants. MayoClinProc.2013Dec;88(12):1378-87
Prevalence of maternal vitamin D deficiency in neonates with delayed hypocalcaemia. ActaMedIran.2012Nov;50(11):740-5. Maternal vitamin D deficiency is one of the major risk factors for neonatal vitamin D deficiency followed by neonatal hypocalcaemia. The aim of this study is to determine the relationship between delayed neonatal hypocalcaemia and maternal vitamin D deficiency. This is a descriptive cross- sectionalstudy.Targetpopulationofthisstudyincludedalltermandpreterm neonates with delayed hypocalcaemia (after the first 72 hours of birth) admitted to Ali-Asghar Hospital. The sample size was 100 neonates included in the study. Demographic, clinical and paraclinical data including Ca, P, PTH and level of maternal and neonatal vitamin D were recorded according to patients records. 67 neonates (67%) were term and 33(33%) were preterm neonates. The mean of serum calcium in neonates was 6.49± 0.68mg/dL (in the range of 4.3-7.8 mg/dL). 85% of neonates and 74% of mothers had vitamin D deficiency. 100% of neonates born to mothers with vitamin D deficiencywerehypocalcaemia.Astatisticallysignificantdifferencewasseen between the mean values of serum Ca (6.67 in term vs. 6.12 in preterm neonates) and vitamin D in term and preterm neonates was 16.34 vs. 20.18 (P= 0.0001 and P=0.01 respectively). Also, a significant correlation was seen between maternal and neonatal level of vitamin D (P=0.0001, r=0.789). With regard to the socio-cultural status in Iran besides women's clothing style and nutritional deficiencies before and during pregnancy, health authorities and policy makers are responsible to focus their serious attention on hypocalcaemiaandhypovitaminosisDinneonates. 85% of neonates and 74% of mothers had vitamin D deficiency. 100% of neonatesborntomotherswithvitaminDdeficiencywerehypocalcaemia.
Effect of calcium plus vitamin D supplementation during pregnancy in Brazilianadolescentmothers:arandomized,placebo-controlledtrial. AmJClinNutr.2013Jul;98(1):82-91. OBJECTIVE: We investigated the effect of calcium plus vitamin D supplementation during pregnancy on bone mass during lactation in Brazilianadolescentmotherswithlow-calciumdiets(∼600 mg/d). DESIGN: Pregnant adolescents (14-19 y) randomly received daily calcium (600 mg) plus vitamin D3 (200 IU) (n = 30) or a placebo (n = 26) from 26 wk of pregnancy (baseline) until parturition. The bone mineral content (BMC), bone area (BA), and bone mineral density (BMD) at the total body, lumbar spine, and hip (total and femoral neck) were evaluated by using dual-energy X-ray absorptiometry at 5 and 20 wk postpartum. Serum hormones and 25- hydroxyvitamin D [25(OH)D] were measured. Group comparisons were adjustedforsignificantcovariates. RESULTS: The mean serum 25(OH)D concentration was 59 nmol/L at baseline. In comparison with the placebo, 25(OH)D tended to be 14-15 nmol/L higher postpartum in the supplemented group (P = 0.08). Total body and hip BMC and BMD decreased over time (P ≤ 0.005) in both groups with a group × time interaction at the femoral neck (P < 0.04). Supplemented mothers had higherlumbarspineBA(6.7%;P= 0.002)and lumbarspineBMC (7.9%, P = 0.08) than did mothers who consumed the placebo at 5 wk postpartum. At 20 wk postpartum, differences between groups were more evident, with higher lumbar spine BMC (13.9%), lumbar spine BA (6.2%), and lumbarspineBMD(10.6%)inthesupplementedgroup(P≤0.008). CONCLUSIONS: Calcium plus vitamin D supplementation during pregnancy of adolescents with low calcium intake results in higher lumbar spine bone massandareducedrateoffemoralneckbonelossduringlactation.
Pharmacokinetics of high-dose weekly oral vitamin D3 supplementation duringthethirdtrimesterofpregnancyinDhaka,Bangladesh. Nutrients.2013Mar12;5(3):788-810. A pharmacokinetic study was conducted to assess the biochemical dose- response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka, Bangladesh (23°N). Pregnant women at 27-30 weeks gestation (n = 28) were randomized to 70,000 IU once + 35,000 IU/week vitamin D3 (group PH: pregnant, higher dose) or 14,000 IU/week vitamin D3 (PL: pregnant, lower dose) until delivery. A group of non-pregnant women (n = 16) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks (NH: non-pregnant, higher-dose). Rise (∆) in serum 25-hydroxyvitamin D concentration ([25(OH)D]) above baseline was the primary pharmacokinetic outcome. Baseline mean [25(OH)D] were similar in PH and PL (35 nmol/L vs. 31 nmol/L, p = 0.34). A dose-response effect was observed: ∆[25(OH)D] at modeled steady-state was 19 nmol/L (95% CI, 1 to 37) higher in PH vs. PL (p = 0.044). ∆[25(OH)D] at modeled steady-state was lower in PH versus NH but the difference was not significant (-15 nmol/L, 95% CI -34 to 5; p = 0.13). In PH, 100% attained [25(OH)D] ≥ 50 nmol/L and 90% attained [25(OH)D] ≥ 80 nmol/L; in PL, 89% attained [25(OH)D] ≥ 50 nmol/L but 56% attained [25(OH)D] ≥ 80 nmol/L. Cord [25(OH)D] (n = 23) was slightly higher in PH versusPL(117nmol/Lvs.98nmol/L;p=0.07).VitaminD3waswelltolerated; there were no supplement-related serious adverse clinical events or hypercalcemia. In summary, Further research is required to establish the safety of high- dose vitamin D3 in pregnancy and to determine if supplement-induced [25(OH)D]elevationsleadtomaternal-infanthealthbenefits. a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non- hypercalcemic and attained [25(OH)D] ≥ 80 nmol/L in virtually all mothers and newborns.
The efficacy and safety of a high dose of vitamin d in mothers with gestationaldiabetesmellitus:arandomizedcontrolledclinicaltrial. IranJMedSci.2012Sep;37(3):159-65. BACKGROUND: During pregnancy and lactation outstanding changes occur in mother's vitamin D metabolism. This study was carried out to evaluate the efficacy of 300,000 IU vitamin D given intramuscularly on body status in new casesofgestationaldiabetesmellitus(GDM). METHODS: This is a randomized clinical trial with the follow-up period of 3 months. Totally 45 participants were randomly divided into intervention group (IG) and control group (CG). The IG received an IM injection of 300,000 IU of vitamin D, whereas CG did not. The glycosylated hemoglobin A1C (HBA1C), serum 25-OH-D, parathyroid hormone (PTH), serum calcium and phosphorusweremeasured. RESULTS: Forty five patients including 24 with the mean age of 30.7±6.2 years in the IG and 21 with the mean age of 29.5±4.0 years in the CG participated in the study. The median concentration of serum 25(OH)D3 in the IG was to 62.10 nmol/l after the intervention, showing an increase of around 158%, compared to before intervention (24.25 nmol/l) whereas the CG showed a decrease of around 4.5%. Of the patients, 79.2% of IG and 81.9% of CG suffered to some degree from vitamin D deficiency. These figures were 4.2% and 71.4% for the IG and CG, respectively after the intervention.For the IG, the PTH was significantly lower and Ca was significantlyhigheraftertheintervention.TheserumPhosphorusbeforeand after the intervention in each group or between the two groups was not significant. CONCLUSIONS: The single 300,000 IM dose of vitamin D is regarded as an effectiveandsafetopromptlyimprovevitaminDstatusinGDM.
VITAMIN D IN CHILDREN
VITAMIN D IN CHILDREN VITAMIN D IS a prohormone that is essential for normal absorption of calcium from the gut, and deficiency of vitamin D is associated with rickets in growing children. Vitamin D deficiency that presents as hypocalcemic seizures or tetany is reported more frequently in infancy and adolescence thaninchildhood. VitaminDDeficiencyResultingFromPoorMaternalVitaminDStatus In 1 US study, 12% of women 20 to 29 years old (peak childbearing years) had serum 25(OH)-D levels below the accepted threshold of deficiency (37.5 nmol/L [15 ng/mL]), and in another study, vitamin D deficiency was reported to be more common in black (42%) than white (4%) women.137 High rates of vitaminDdeficiencyhavebeenreportedindarker-skinnedpregnantwomen, particularlyinthewintermonthsand athigherlatitudes,140and lowvitamin D levels during pregnancy have been associated with intrauterine growth retardation,prematurelabor,andhypertension,allofwhichincreasetherisk of low birth weight. Indeed black and Asian American mothers have higher rates of low birth weight infants in the United States than do Americans of European or Hispanic descent. Decreased vitamin D levels in the mother resultindecreasedtransplacentaltransferofvitaminDandreducedstoresat birth. Serum 25(OH)-D levels in infants correlate with maternal serum 25(OH)-D. VitaminDDeficiencyResultingFromPrematurity Prematurely born infants have a shorter duration in which to accumulate vitamin D stores from transplacental transfer from the mother and also have a higher requirement for vitamin D than term infants. Therefore, they are more likely to be vitamin D deficient. They have been reported to be more likely to have enamel defects in both primary and permanent teeth, because vitaminDsufficiencyisnecessaryfornormalfetaltoothdevelopment
VITAMIN D IN CHILDREN VitaminDDeficiencyResultingFromExclusiveBreastfeeding Exclusive breastfeeding without sun exposure would provide only 11 to 38 IU/day of vitamin D. It is important to note that the vitamin D content of breast milk varies on the basis of skin color, with lower vitamin D concentrations in breast milk of black compared with white women. Therefore, breastfed infants need to obtain additional vitamin D through eithersunexposureorsupplementation. The current recommendations of the AAP that limit sun exposure for infants 6 months old because of harmful effects on the skin by UV-B radiation make breastfed infants more vulnerable to developing vitamin D deficiency. Exclusive breastfeeding without adequate sun exposure or vitamin D supplementation is an important risk factor for vitamin D deficiency. In a reviewof65clinicalcasesofricketsinchildrenaged2to45monthspublished between 1975 and 1985 in 11 publications, Cosgrove and Dietrich noted that thechildrenwereeitherstillbreastfeedingorwereonamilk-freevegetarian diet at the time of diagnosis. Weisberg et al then reviewed 166 published cases of rickets in children aged 4 to 54 months between 1986 and 2003 in 22 publications and reported that 96% were breastfed. Of the breastfed infants, only 5% were receiving vitamin D supplements. Exclusively breastfed infants born in winter in Wisconsin had mean 25(OH)-D levels of 25 nmol/L (10 ng/mL) at 6 months of age if they were not given any supplements, and 98% of infants in Alaska noted to have 25(OH)-D levels of 62.5 nmol/L (25 ng/mL) were exclusively breastfed. Thus, breastfed infants need to obtain additional vitamin D through supplementation (infant or maternal159,160) or adequatesunexposure. Pediatrics2008;122;398
Effect of Vitamin D Supplementation on Moderate to Severe Bronchial Asthma. IndianJPediatr.2013Nov6. OBJECTIVE: To define the therapeutic role of vitamin D in children with moderatetoseverebronchialasthmaasanadjuncttostandardtreatment. METHODS: Hundred asthmatic children of either sex, attending the respiratory and asthma clinic were enroled in the study. Diagnosis was made on the basis of history and clinical examination. Randomization was done using sealed opaque envelop method. In addition to the treatment as per GINA guidelines, one group received oral vitamin D3 (Cholecalciferol) 60,000 IU per month for 6 mo and the other group received placebo powder in the form of glucose sachet with a double blinded design. Monthly follow up of every patient was done and during every visit change in severity, level of control, Peak expiratory flow rate (PEFR), steroid dosage, number of exacerbationsandnumberofemergencyvisitswereassessed. RESULTS: Monthly doses of 60,000 IU vitamin D significantly reduced the number of exacerbations as compared to placebo (p=0.011). PEFR significantly increased in the treatment group (p=0.000). Monthly doses of vitamin D significantly reduced the requirement of steroids (p=0.013) and emergency visits (p=0.015). Control of asthma was achieved earlier in patients who received monthly vitamin D. Vitamin D significantly reduced thelevelofseverityofasthmapatientsover6mooftreatment(p=0.016). CONCLUSIONS: Vitamin D has a definite role in the management of moderate to severe persistent bronchial asthma as an adjunct to standard treatment.
The relationship between vitamin D status and adrenal insufficiency in criticallyillchildren. JClinEndocrinolMetab.2013May;98(5):E877-81. OBJECTIVE: The aim of the study was to investigate potential relationships between vitamin D status, adrenal status, and cardiovascular dysfunction in criticallyillchildren. DESIGN: We conducted a secondary analysis of data from a prospective cohortstudy. SETTING AND PATIENTS: The study was conducted on 319 children admitted to6Canadiantertiary-carepediatricintensivecareunits. MAIN OUTCOME MEASURES: Vitamin D status was determined through total 25-hydroxyvitamin D (25OHD) levels. AI was defined as a cortisol increment under 9 μg/dL after low-dose cosyntropin. Clinically significant cardiovascular dysfunction was defined as catecholamine requirement duringpediatricintensivecareunitadmission. RESULTS: Using 3 different thresholds to define vitamin D deficiency, no association was found between vitamin D status and AI. Furthermore, linear regression failed to identify a relationship between 25OHD and baseline or post-cosyntropin cortisol. However, the association between AI and cardiovascular dysfunction was influenced by vitamin D status; compared to children with 25OHD above 30 nmol/L, AI in the vitamin D-deficient group was associated with significantly higher odds of catecholamine use (odds ratio,5.29vs1.63;P=.046). CONCLUSIONS: Our results do suggest that vitamin D deficiency exacerbates theeffectofAIoncardiovascularstabilityincriticallyillchildren.
Impact of anesthesia and surgery for congenital heart disease on the vitamindstatusofinfantsandchildren:aprospectivelongitudinalstudy. Anesthesiology.2013Jul;119(1):71-80. BACKGROUND: Vitamin D is recognized as a pleiotropic hormone important for the functioning of organ systems, including those central to critical illness pathophysiology. Recent studies have reported associations between vitamin D status and outcome among critically ill adults and children. Preoperative vitamin D status, impact of operative techniques, and relationship between immediate postoperative vitamin D levels and clinical course have not been described in the pediatric congenital heart disease (CHD) population. The objective of this study was to describe the impact of CHD surgery on vitamin D status and relationship between postoperative levelsandclinicalcourse. METHODS: A prospective cohort study was conducted from 2009 to 2011 at a single tertiary care pediatric hospital. A total of 58 children with CHD were enrolled and blood collected preoperatively, intraoperatively, and postoperatively. Serum 25-hydroxyvitamin D (25OHD) was measured using liquidchromatography-massspectrometry. RESULTS: The mean preoperative 25OHD was 58.0 nM (SD, 22.4), with 42% being deficient (<50 nM). Postoperatively, we identified a 40% decline in 25OHD to 34.2 nM (SD, 14.5) with 86% being deficient. Intraoperative measurements determined that initiation of cardiopulmonary bypass coincided with abrupt decline. CHD patients requiring catecholamines had lower postoperative 25OHD (38.2 vs. 26.5 nM, P=0.007), findings confirmed through multivariate logistic regression. Lower postoperative 25OHD was associatedwithincreasedfluidrequirementsandintubationduration. CONCLUSIONS: Most CHD patients are vitamin-D deficient postoperatively due to low preoperative levels and a significant intraoperative decline. Interventional studies will be required to determine whether prevention of postoperativevitaminDdeficiencyimprovesoutcome.
Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents:arandomizedcontrolledtrial. AmJClinNutr.2013Apr;97(4):774-81. OBJECTIVE:Theobjectivewastodetermineinobeseadolescentstheefficacy and safety of 4000 IU vitamin D3/d and whether subsequent increased circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with improved markers of insulin sensitivity and resistance and reduced inflammation. DESIGN: Obese adolescent patients [n = 35; mean ± SD age: 14.1 ± 2.8 y; BMI (in kg/m(2)): 39.8 ± 6.1; 25(OH)D: 19.6 ± 7.1 ng/mL] were recruited from the University of Missouri Adolescent Diabetes and Obesity Clinic and were randomly assigned to receive either vitamin D3 (4000 IU/d) or placebo as part of their standard care. Anthropometric measurements, inflammatory markers (IL-6, TNF-α, C-reactive protein), adipokines (leptin, adiponectin), fasting glucose, fasting insulin, and HOMA-IR values were measured at baselineandat2follow-upvisits(3and6mo). RESULTS: After 6 mo, there were no significant differences in BMI, serum inflammatory markers, or plasma glucose concentrations between groups. Participants supplemented with vitamin D3 had increases in serum 25(OH)D concentrations (19.5 compared with 2.8 ng/mL for placebo; P < 0.001), fasting insulin (-6.5 compared with +1.2 μU/mL for placebo; P = 0.026), HOMA-IR (-1.363compared with +0.27for placebo;P = 0.033),and leptin-to- adiponectin ratio (-1.41 compared with +0.10 for placebo; P = 0.045). Inflammatorymarkersremainedunchanged. CONCLUSION: The correction of poor vitamin D status through dietary supplementation may be an effective addition to the standard treatment of obesityanditsassociatedinsulinresistance.
VitaminDinsufficiencyandeffectofcholecalciferolinchildrenwithchronic kidneydisease. PediatrNephrol.2010Dec;25(12):2483-8. Vitamin D insufficiency is common in patients with chronic kidney disease (CKD) and may contribute to mineral bone disease. In a prospective interventional study, we estimated the prevalence of vitamin D insufficiency (serum 25-hydroxyvitamin D3 [25OHD] < 30 ng/ml), and examined the effect of high-dose (600,000 IU) cholecalciferol supplementation after 6 weeks on serum 25OHD and parathyroid hormone (PTH) levels in children with CKD stages 2-4. Forty-two children (86% boys) with a mean age of 7.7±3.8 (range 2--5) years were studied. Thirty-seven children (82.1%) had vitamin D insufficiency; 18 (42.8%) had 25OHD < 16 ng/ml. The median 25OHD increased significantly from 16.7 (95% CI 11.3, 19.8) to 46.2 (34.5, 44.6) ng/ml in patients with vitamin D insufficiency (P <0.001). The median PTH decreased significantly from 51.3 (95% CI 46.7, 71.5) to 37.1 (29.0, 54.6) pg/ml (P=0.003). Nineteen patients (47.5%) had >30% reduction in the PTH after supplementation. Serum calcium, phosphorus, and estimated GFR did not change significantly. We conclude that vitamin D insufficiency is highly prevalent in children with CKD stages 2-4. High-dose cholecalciferol is safe and effective in correcting vitamin D insufficiency and results in a significant reductioninPTHlevelsinvitaminD-insufficientchildren.
GIST OF CLINICAL STUDIES ON VITAMIN D
VITAMIN D ON ANTIBIOTIC USE BACKGROUND: Observational data suggested that supplementation with vitaminDcouldreduceriskofinfection,buttrialdataareinconsistent. OBJECTIVE: We aimed to examine the effect of oral vitamin D supplementationonantibioticuse. DESIGN:WeconductedaposthocanalysisofdatafrompilotD-Health,which is a randomized trial carried out in a general community setting between October2010andFebruary2012.Atotalof644Australianresidentsaged60- 84 y were randomly assigned to receive monthly doses of a placebo (n = 214) or 30,000 (n = 215) or 60,000 (n = 215) IU oral cholecalciferol for ≤ 12 mo. Antibiotics prescribed during the intervention period were ascertained by linkage with pharmacy records through the national health insurance scheme(MedicareAustralia). RESULTS: People who were randomly assigned 60,000 IU cholecalciferol had nonsignificant 28% lower risk of having antibiotics prescribed at least once than did people in the placebo group (RR: 0.72; 95% CI: 0.48, 1.07). In analyses stratified by age, in subjects aged ≥ 70 y, there was a significant reductioninantibioticuseinthehigh-dosevitaminDcomparedwithplacebo groups (RR: 0.53; 95% CI: 0.32, 0.90), whereas there was no effect in participants<70yold(RR:1.07;95%CI:0.58,1.97)(P-interaction=0.1). CONCLUSION: Although this study was a post hoc analysis and statistically non-significant, this trial lends some support to the hypothesis that supplementation with 60,000 IU vitamin D/mo is associated with lower risk ofinfection,particularlyinolderadults. AmJClinNutr.2013Oct9.
VITAMIN D AND PNEUMONIA BACKGROUND: Vitamin D has been suggested to have a role in infection defence and on the immune system. We therefore investigated the effect of serum 25-hydroxyvitamin D₃ (25(OH)D₃) on the risk of incident hospitalised pneumoniainanageinggeneralpopulationineasternFinland. METHODS: The study population included 723 men and 698 women aged 53-73 years from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor study who were free of pneumonia, other pulmonary diseases and cancer at baseline in 1998-2001. Incident pneumonia episodes leading to hospitalisation were collected by record linkage to the hospital discharge register. The serum vitamin D status was assayed as 25(OH)D₃ concentration. Cox proportional hazards regression models were used to analysetheeffectofserum25(OH)D₃ontheriskofincidentpneumonia. RESULTS: The mean (SD) serum 25(OH)D₃ concentration of the study population was 43.5 (17.8) nmol/l. 73 subjects had at least one hospitalisationepisodeduetopneumoniaduringanaveragefollow-upof9.8 years. After multivariable adjustments, the subjects in the lowest serum 25(OH)D₃ tertile had a 2.6-fold (95% CI 1.4 to 5.0, p trend across tertiles=0.005) higher risk of developing pneumonia compared with the subjects in the highest tertile. This significant result remained even after adjustmentforthedeterminantsofserum25-hydroxyvitaminD₃. CONCLUSIONS: These data suggest an inverse effect of serum 25(OH)D₃ concentration on the risk of incident pneumonia in the general ageing population. JEpidemiolCommunityHealth.2013Jun;67(6):533-6.
VITAMIN D AND HEART DISEASES MI risk doubles in patients with 25OHVitD levels < 34ng/ml Scragg et al. Int J Epidemiol. 1990;19(3):559. CHF patients have much lower 25OH Vitamin D levels than controls Zitterman et al. J Am Coll Cardiol. 2003;41:105. Deaths from CAD more common in winter Scragg. Int J Epidemiol. 1981;10(4):337. MI risk doubles in patients with 25OH Vitamin D levels < 34ng/ml Scragg et al. Int J Epidemiol. 1990;19(3):559. CHF patients have much lower 25OHVitD levels than controls Zitterman et al. J Am Coll Cardiol. 2003;41:105. Deaths from CAD more common in winter Scragg. Int J Epidemiol. 1981;10(4):337. 25-(OH)D < 10 ng/mL - 80% greater risk of having a cardiovascular incident 25 (OH)D of 10-15 ng/mL - 53% increased risk Circulation 2008;117:503-51
VITAMIN D AND HYPERTENSION BP higher in winter BP higher with increasing latitude BP higher with darker skin pigmentation Hypertensive patinets given UV light treatments 3 times per week for 6 weeks had Vitamin D level increases of 162% and saw mild decreases in BP Krause et al. Lancet. 1998;352(9129):709. Small doses of Vit D (800iu) for 8 weeks decreased BP and pulse rate Pfeifer et al. J Clin Endocrinol Metab. 2001;86(4):258 BP is reduced significantly by ultraviolet radiation comparable to about oral intake of 3,000 IU of vitamin D a day Krause R, Bohring M, Hopfenmhller W, Holick MF, Sharma AM: Ultraviolet B and blood pressure. Lancet. 1998;352:709-710 BP not routinely reduced by small amounts of vitamin D Scragg R, Khaw KT, Murphy S: Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults. European Journal of Clinical Nutrition. 1995;49:640-646
VITAMIN D AND DIABETES TYPE 1 DIABETES Study in > 10,000 people shows that supplementation of infants and children withVitaminD2000iu/daydecreasedincidenceofDMtype1by80% Hypponenetal.Lancet.2001;358(9292):1500. CodliverstudiesalsoshowsignificantreductionofincidenceofTypeIDM TYPE 2 DIABETES LowVitaminDlevelsassocwithinsulinresistanceandBeta-celldysfunction Postprandial glucose and insulin sensitivity is better in healthy adults with highestVitDlevels Chiu.AmJClinNutr.2004;79:820. Metformin improves insulin sensitivity by 13% and highest Vitamin D levels associatedwith60%improvementininsulinsensitivity Chiu.AmJClinNutr.2004;79:820. Small trial of 10 women with DM Type 2 with Vitamin D 1332iu per day x 30 daysshows21%increaseininsulinsensitivity Borrisovaetal.IntJClinPract.2003;57(4):258.
VITAMIN D AND PAIN Studywith150ptswithpersistent,nonspecificmusculoskeletalpainatMayo clinicshowsthat93%hadVitaminDdeficiency Plotnikoff,Quigley.MayoClinProc.2003;78(12):1463. LOW BACK PAIN 83%of299LBPptshadVitDdef 5000-10,000iu/day decreases the pain medication in nearly 100% after 3 months AlFaraj,AlMutairi.Spine2003;28(2):177.
VITAMIN D AND AUTOIMMUNE DISEASES VITAMIN DINSUFFICIENCY IS SHOWN IN: 50%ofpatientswithfibromyalgia+SLE Huismanetal.JRheumatol.2001;28(11):2535. 58%JapaneseFemaleswithGravesDisease Yamashitaetal.EndocrJ.2001;48(1):63. 73%Austrianptsw/AnkylosingSpondylitis Falkenbachetal.WienKlinWochenschr.2001;113(9):328
VITAMIN D AND CANCER Vitamin D levels inversely correlated to colon cancer mortality (but not to all cancermortality) Freedmanetal.JNatlCancerInst.2007.99(21):1563. In 47,800 men over 14 years , 10 ng/ml rise in Vitamin D level of associated with 17%reductionincancerincidence 29%reductioninallcancermortality 45%reductioninGIcancermortality Giovanucchietal.JNatlCancerInst.2006.98(7):428. Long-term study of 50,000 men at Harvard School of Public Health suggests vitaminDmayreducetheriskofallcancersbyatleast30percent. Giovannucci.JNatlCancerInst.2006Apr5:98(7):428. Decreased sunlight assoc with increased cancer mortality Breast, colon, cancer, prostate, bladder, esophagus, kidney, lung, pancreas, rectum, stomach,uterus,non-Hodgkin’sLymphoma Grant.Cancer.2002;94(6):1867.
VITAMIN D AND FALLS IN ELDERLY VitaminDreceptorsinskeletalmuscle BischoffHA,etal.HistochemJ2001;33:19. Vitamin D deficiency reported to affect predominantly the weight-bearing antigravity muscles of the lower limb, which are necessary for postural balanceandwalking GlerupHetal.CalcifTissueInt2000;66:419. Significant correlation between serum 25(OH)D3 concentration and the occurrenceoffallsinelderlyreportedinliterature. MowéMetal.JAmGeriatrSoc1999;47:220 &SteinMSetal.JAmGeriatrSoc1999;47:1195 STOP/IT(SitesTestingOsteoporosisPreventionandInterventionTreatments) trial evaluated 489 women randomly assigned to receive estrogen, Vitamin D,bothestrogenandVitaminD,oraplacebofor3years. TheincreaseinbonedensitywastwiceaslargewithestrogenaswithVitamin D. The subjects with Vitamin D had fewer fractures from falls than did the group whotookestrogen(oddsratio:0.78and0.94,respectively). ImprovementinlowerextremitymusclestrengthandbalancewithVitaminD supplementation thought to explain the reduced number of fall-related fractures. Dawson-Hughesetal. NEnglJMed1997;337:670
VITAMIN D AND LONGEVITY Meta-analysis of 18 RCTs – 57,311 patients with a daily intake of Vitamin D (300-2000iu/day) Highestintake–7%reductioninall-causemortality Based on the total body of evidence of health conditions associated with Vitamin D deficiency, abetted with the results from this meta-analysis, a more proactive attitude to identify, prevent and treat Vitamin D deficiency shouldbepartofstandardmedicalcare. Giovannuchi.ArchInternMed.2007;167:1709-1710.
DOSING
EUROPEAN JOURNAL OF ENDOCRINOLOGY
BASED ON NHS GUIDELINES
AMERICAN ACADEMY OF PEDIATRICS RECOMMENDATIONS Treating infants and children who are vitamin D insufficient or deficient with 1000IU/dayofvitaminDforinfants1monthold. 1000to5000IU/dayforchildren1to12monthsold 5000IU/dayforchildren12monthsold. Vitamin D levels should subsequently be maintained with 400 IU of vitamin D supplementationperday. For patients who demonstrate poor compliance, a high dose of vitamin D may be given as a single dose or repeated intermittently. It is important to recognizethatsimultaneouscalciumsupplementationisnecessarybecause of the risk of hypocalcemia from decreased demineralization of bone and increased remineralization as PTH levels normalize, symptomatic hypocalcemia requires parenteral calcium replacement, and calcitriol and dihydrotachysterol can help treat hypocalcemia associated with rickets but donotbuildupvitaminDstores.
KING EDWARD MEMORIAL HOSPITAL & PRINCESS MARGARET HOSPITAL PERTH, WEST AUSTRALIA, RECOMMENDATIONS All infants born < 35 weeks who are tolerating full enteral feeds, Cholecalciferol solution 400 -500 units (0.1mL) ONCE daily with milk or formulafeeduntildischarge. ForbreastfedbabiesofVitaminDdeficientmothers MildmaternalvitaminDdeficiency(25-50nmol/L) VitaminD400unitsDAILYuntil12monthsofage ModeratetoseverematernalvitaminDdeficiency(<25nmol/L) Cholecalciferol800-1000unitsDAILYfor3monthsand400unitsdailyuntil12 monthsofage American Society for Bone and Mineral Research concludes that vitamin D supplementation of 4000IU/d for pregnant women is safe and most effective inachievingsufficiencyinallwomenandtheirneonatesregardlessofrace
Large, Single-Dose, Oral Vitamin D Supplementation in Adult Populations: ASystematicReview. OBJECTIVE: Daily supplementation is often inadequate in treating vitamin D deficiency due to poor compliance. A single, large dose of vitamin D given at timedintervalsmaybeanalternativestrategy. METHODS: We identified 2243 articles in PUBMED using the terms "high dose vitamin D," "single dose vitamin D," "bolus vitamin D," or "annual dose vitamin D." Review articles, cross-sectional studies, non-human studies, responses to other articles, and non-English articles were excluded. Manuscripts were also excluded if the study: (1) did not use oral cholecalciferol or ergocalciferol, (2) used vitamin D analogs, (3) enrolled participants under age 18, (4) administered doses <100,000 IU (2.5 mg), or (5)administered>1doseperyear.Referencesofeligiblemanuscriptsandthe Cochrane databases were also searched. Two independent reviewers identified eligible manuscripts, and a third reviewer evaluated disagreements.Thirtymanuscriptswereselectedusingthesecriteria. RESULTS: Large, single doses of vitamin D consistently increased serum 25- hydroxyvitamin D (25(OH)D) concentrations in several vitamin D sufficient and deficient populations. Vitamin D3 doses of 300,000 IU or greater providedoptimalchangesinserum25(OH)Dandparathyroidhormone(PTH) concentrations. Vitamin D supplementation also impacted bone health and extra-skeletalendpoints. CONCLUSIONS: This review recommends vitamin D3 be used for supplementation over vitamin D2, and that single vitamin D3 doses of 300,000 IU and greater are most effective at improving vitamin D status and suppressing PTH concentrations for up to 3 months. Lower doses, however, may be sufficient in certain populations. Vitamin D doses >500,000 IU should beusedjudiciouslyinordertominimizeadverseevents. EndocrPract.2013Nov18:1-36.
Effect of two different doses of oral cholecalciferol supplementation on serum 25-hydroxy-vitamin D levels in healthy Indian postmenopausal women:Arandomizedcontrolledtrial. AIM: To compare the effect of two different doses (500 and 1000 IU/day) of oral vitamin D3 (cholecalciferol) on serum 25-hydroxy vitamin D [25(OH)D] levelsinapparentlyhealthypostmenopausalIndianwomen. MATERIALS AND METHODS: Serum 25(OH)D, calcium with albumin, phosphorus, and alkaline phosphatase were measured in 92 apparently healthy postmenopausal women. The subjects were randomly assigned to one of the three groups and received supplementation for 3 months each. Each group received 1000 mg calcium carbonate daily while groups B and C received 500 and 1000 IU of cholecalciferol in addition, respectively. The testswererepeatedafter3months. RESULTS: At baseline, 83.7% subjects had vitamin D deficiency (≤20 ng/mL). The difference in the percentage change in mean serum 25(OH)D levels from baseline in group A (-30.5 ± 5.3%), group B (+8.9 ± 19.7%), and in group C (+97.8 ± 53.3%) was statistically significant (P < 0.001) between the three groups. Serum 25(OH)D level >20 ng/mL was achieved in 4.7% (1/21), 16% (4/25), and 66.67% (12/18) subjects in groups A, B, and C, respectively. No significant change was found in serum calcium, phosphorus, and alkaline phosphataselevelsat3monthsineitherofthegroupsfrombaseline. CONCLUSIONS: Standard dose of cholecalciferol available in "calcium tablets" (250 IU per 500 mg calcium carbonate) is not adequate for achieving optimum serum 25(OH)D levels in Indian postmenopausal women. Higher dose of vitamin D supplementation with 1000 IU/day (500 IU per 500 mg calcium carbonate) daily is superior to the standard dose therapy. For achievement of optimum serum 25(OH)D levels (>30 ng/mL) in Indian postmenopausal women, still higher doses of vitamin D are likely to be required. IndianJEndocrinolMetab.2013Sep;17(5):883-9.
25-hydroxyvitamin D Response to Graded Vitamin D3 Supplementation AmongObeseAdults. OBJECTIVE: The purpose of this study was to characterize the pharmacokinetics of 25(OH)D response to 3 different doses of vitamin D3 (cholecalciferol) in a group of obese subjects and to quantify the 25(OH)D dose response relationship.Design, Setting, Intervention, Patients:This was a randomized, single blind study of 3 doses of oral vitamin D3 (1,000 IU, 5,000 IU, or 10,000 IU) given daily to 67 obese subjects for 21 weeks during the wintermonths. MAIN OUTCOME MEASURES: Serum 25(OH)D levels were measured at baseline and after vitamin D replacement, and 25(OH)D pharmacokinetic parameters were determined, fitting the 25(OH)D concentrations to an exponential model.Results:Mean measured increments in 25(OH)D at week 21 were: 12.4- (SD 9.7) ng/ml in the 1,000 IU/d group, 27.8 (SD10.2) ng/mL in the 5,000 IU/d group, and 48.1(SD 19.6) ng/ml in the 10,000 IU/d group. Steady state increments computed from the model were 20.6 (SD 17.1) ng/ml, 35.2 (SD 14.6) ng/ml, and 51.3 (SD 22.0) ng/ml, respectively. There were no hypercalcuriaorhypercalcemiaeventsduringthestudy. CONCLUSION: Our data show that in obese people the 25(OH)D response to vitaminD3isdirectlyrelatedtodoseandbodysizewith2.5IU/kgrequiredfor everyunitincrementin25(OH)D(ng/ml). JClinEndocrinolMetab.2013Sep13.
Effect of different dosages of oral vitamin D supplementation on vitamin D statusinhealthy,breastfedinfants:arandomizedtrial. 2013May1;309(17):1785-92. OBJECTIVE: To investigate the efficacy of different dosages of vitamin D in supporting25(OH)Dconcentrationsininfants. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial conducted among 132 one-month-old healthy, term, breastfed infants from Montréal, Québec, Canada, between March 2007 and August 2010. Infants were followed up for 11 months ending August 2011 (74% completed study). INTERVENTION: Participants were randomly assigned to receive oral cholecalciferol (vitamin D3) supplements of 400 IU/d (n=39), 800 IU/d (n=39),1200IU/d(n=38),or1600IU/d(n=16). MAIN OUTCOMES AND MEASURES: The primary outcome was a plasma 25(OH)D concentration of 75 nmol/L or greater in 97.5% of infants at 3 months. Secondary outcomes included 25(OH)D concentrations of 75 nmol/L or greater in 97.5% of infants at 6, 9, and 12 months; 25(OH)D concentrations of 50 nmol/L or greater across all times; growth; and whole body and regional bone mineral content. Data were analyzed by intention to treat using available data, logistic regression, and mixed-model analysis of variance. RESULTS: By 3 months, 55% (95% CI, 38%-72%) of infants in the 400-IU/d groupachieveda25(OH)Dconcentrationof75nmol/Lorgreatervs81%(95% CI,65%-91%)inthe800-IU/dgroup,92%(95%CI,77%-98%)inthe1200-IU/d group, and 100% in the 1600-IU/d group. This concentration was not sustained in 97.5% of infants at 12 months in any of the groups. The 1600- IU/d dosage was discontinued prematurely because of elevated plasma 25(OH)D concentrations. All dosages established 25(OH)D concentrations of 50 nmol/L or greater in 97% (95% CI, 94%-100%) of infants at 3 months and sustained this in 98% (95% CI, 94%-100%) to 12 months. Growth and bone mineralcontentdidnotdifferbydosage. JAMA.
CONCLUSIONS AND RELEVANCE: Among healthy, term, breastfed infants, only a vitamin D supplement dosage of 1600 IU/d (but not dosages of 400, 800, or 1200 IU/d) increased plasma 25(OH)D concentration to 75 nmol/L or greater in 97.5% of infants at 3 months. However, this dosage increased 25(OH)D concentrations to levels that have been associated with hypercalcemia.
1. Chen, S. Law, C. S. Gardner, D. G. Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity. J Steroid Biochem Mol Biol. 2010 Feb 15; 118(3):135-41. 2. Johnson, R. C. Leopold, J. A. Loscalzo, J. Vascular calcification: pathobiological mechanisms and clinical implications.CircRes.2006Nov10;99(10):1044-59. 3. Mizobuchi, M. Ogata, H. Koiwa, F. Kinugasa, E. Akizawa, T. Vitamin D and vascular calcification in chronic kidneydisease.Bone.2009Jul;45Suppl1S26-9. 4. Takasu,H.Anti-osteoclastogenicactionofactivevitaminD.NutrRev.2008Oct;66(10Suppl2):S113-5. 5. Lappe J M et al Vitamin D status in a rural postmenopausal female population. J Am Coll Nutr. 2006 Oct; 25(5):395-402. 6. OkazakiRetalVitaminDinsufficiencydefinedbyserum25-hydroxyvitaminDandparathyroidhormone beforeandafteroralvitaminD(3)loadinJapanesesubjects.JBoneMinerMetab. 7. Hypponen,E.Boucher,B.J.Berry,D.J.Power,C.25-hydroxyvitaminD,IGF-1,andmetabolicsyndromeat 45yearsofage:across-sectionalstudyinthe1958BritishBirthCohort.Diabetes.2008Feb;57(2):298-305. 8. Lowe, G. D. Danesh, J. Lewington, S. Walker, M. Lennon, L. Thomson, A. Rumley, A. Whincup, P. H. Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J. 2004Feb;25(3):252-9. 9. Diaz, L et al. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J ReprodImmunol.2009Jul;81(8):17-24. 10. Timms, P. M. Mannan, N. Hitman, G. A. Noonan, K. Mills, P. G. Syndercombe-Court, D. Aganna, E. Price, C. P. Boucher, B. J. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanismsforinflammatorydamageinchronicdisorders?.QJM.2002Dec;95(12):787-96. 11. Derosa, G. D'Angelo, A. Scalise, F. Avanzini, M. A. Tinelli, C. Peros, E. Fogari, E. Cicero, A. F. Comparison between metalloproteinases-2 and -9 in healthy subjects, diabetics, and subjects with acute coronary syndrome.HeartVessels.2007Nov;22(6):361-70. 12. Welsh, P. Whincup, P. H. Papacosta, O. Wannamethee, S. G. Lennon, L. Thomson, A. Rumley, A. Lowe, G. D. Serum matrix metalloproteinase-9 and coronary heart disease: a prospective study in middle-aged men. QJM.2008Oct;101(10):785-91. 13. Laxton, R. C. Hu, Y. Duchene, J. Zhang, F. Zhang, Z. Leung, K. Y. Xiao, Q. Scotland, R. S. Hodgkinson, C. P. Smith, K. Willeit, J. Lopez-Otin, C. Simpson, I. A. Kiechl, S. Ahluwalia, A. Xu, Q. Ye, S. A role of matrix metalloproteinase-8inatherosclerosis.CircRes.2009Oct23;105(9):921-9. 14. Mallat, Z. Matrix metalloproteinase-8 and the regulation of blood pressure, vascular inflammation, and atheroscleroticlesiongrowth.CircRes.2009Oct23;105(9):827-9. 15. Alsafwah, S. Laguardia, S. P. Arroyo, M. Dockery, B. K. Bhattacharya, S. K. Ahokas, R. A. Newman, K. P. Congestive heart failure is a systemic illness: a role for minerals and micronutrients. Clin Med Res. 2007 Dec; 5 (4):238-43. 16. Gupta, R. Sharma, U. Gupta, N. Kalaivani, M. Singh, U. Guleria, R. Jagannathan, N. R. Goswami, R. Effect of cholecalciferol and calcium supplementation on muscle strength and energy metabolism in vitamin D deficientAsianIndians:Arandomizedcontrolledtrial.ClinEndocrinol(Oxf).2010Apr23; 17. Visvanathan,R.Chapman,I.Preventingsarcopaeniainolderpeople.Maturitas.2010Aug;66(4):383-8. 18. Schubert, L. DeLuca, H. F. Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency.ArchBiochemBiophys.2010Aug15;500(2):157-61. 19. Weber, K. T. Weglicki, W. B. Simpson, R. U. Macro- and micronutrient dyshomeostasis in the adverse structuralremodellingofmyocardium.CardiovascRes.2009Feb15;81(3):500-8. REFERENCES & FURTHER READING
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Vitamin d monograph

  • 1.
  • 2.
    CONTENTS 1. Milestones inthe history of Vitamin D 2. Introduction 3. More About of Vitamin D Synthesis Metabolism & Physiological funtions Non Calcemic functions Normal Levels of Vitamin D in Blood Benefits of Optimal Levels of Vitamin D Prevalence of Vitamin D Deficiency 4. Clinical Significance of Vitamin D Cardiovascular Disease; Hypertension; Diabetes Osteoarthritis; Multiple Sclerosis; Type 1 Diabetes Depression; Epilepsy; Migraine PCOS; Musculoskeletal Pain Critical Illnesses Cancer Prevention and Treatment 5. Vitamin D in Cardiovascular Diseases (CVD) Clinical studies in CVD 6. Vitamin D in Hypertension Clinical studies in Hypertension 7. Vitamin D in Diabetes Clinical studies in Diabetes 8. Vitamin D in Auto-Immune Disease and Pains Vitamin D deficiency in Spine Surgery Vitamin D and Spinal Cord Disease Vitamin D and BMD in premenopausal Women
  • 3.
    CONTENTS Vitamin D andRheumatology 9. Vitamin D and Cancers Colorectal Cancers Breast Cancers Prostate Cancers Pancreatic Cancers Rare Cancers Skin Cancers Modifying Cancer Risk 10. Vitamin D in Pregnancy 11. Vitamin D in Children 12.Gist of Clinical Studies Cardiovascular Disease Hypertension Diabetes Pains Auto-Immune Diseases Cancer Falls in Elderly Longevity 13.Dosing 14.References
  • 4.
    MILESTONES IN THEHISTORY OF VITAMIN D 1645-Whistlerwrotethefirstscientificdescriptionofrickets. 1865 - In his textbook on clinical medicine, Trousseau recommended cod liver oil as treatment for rickets. He also recognized the importance of sunlightandidentifiedosteomalaciaastheadultformofrickets. 1919 - Mellanby proposed that rickets is due to the absence of a fat- solubledietaryfactor. 1922 - McCollum and coworkers established the distinction between vitaminAandtheantirachiticfactor. 1925 - McCollum and coworkers named the antirachitic factor vitamin D. Hess and Weinstock show that a factor with antirachitic activity is producedintheskinbyultravioletirradiation. 1936-WindausidentifiedthestructureofvitaminDincodliveroil. 1937 - Schenck obtained crystallized vitamin D3 by activation of 7- dehydro-cholesterol. 1968 - Haussler and colleagues reported the presence of an active metaboliteofvitaminDintheintestinalmucosaofchicks. 1969 - Haussler and Norman discovered calcitriol receptors in chick intestine. 1970 - Fraser and Kodicek discovered that calcitriol is produced in the kidney. 1971-Normanandcoworkersidentifiedthestructureofcalcitriol. 1973-Fraserandassociatesdiscoveredthepresenceofaninbornerrorof
  • 5.
    vitamin D metabolismthat produces rickets resistant to vitamin D therapy. 1978 - De Luca's group discovered a second form of vitamin D-resistant rickets(TypeII). 1981 - Abe and colleagues in Japan demonstrated that calcitriol is involvedinthedifferentiationofbone-marrowcells. 1983 - Provvedini and colleagues demonstrated the presence of calcitriol receptorsinhumanleukocytes. 1984 - The same group presented the evidence that calcitriol has a regulatoryroleinimmunefunction. 1986 - Morimoto and associates suggested that calcitriol may be useful in thetreatmentofpsoriasis. 1989 - Baker and associates showed that the vitamin D receptor belongs tothesteroid-receptorgenefamily. 1994 - The U.S. Food and Drug Administration approved a vitamin D- basedtopicaltreatmentforpsoriasis,calledcalcipotriol. 2003 - A prospective study from Feskanich and coworkers among 72,000 postmenopausal women in the U.S. over 18 years indicated that women consuming at least 600 IU vitamin D/day from food plus supplements had a37%lowerriskofhipfracture. 2006 - Researchers from Harvard School of Public Health examined cancer incidence and vitamin D exposure in over 47,000 men in the Health Professionals Follow-Up Study. They found that a high level of vitamin D (~1500 IU daily) was associated with a 17% reduction in all cancerincidencesanda29%reductionintotalcancermortalitywitheven strongereffectsfordigestive-systemcancers. Reference: Whistler, D. Morbo puerili Anglorum, quem patrio idiomate indigenae vocant The Rickets. Lugduni Batavorum 1-13 (1645).; Glisson, F. De Rachitide sive morbo puerili, qui vulgoThe Rickets diciteur, London 1-416 (1650).; Glisson, F. A treatise of the rickets being a disease common to children. London 1-373 (1668).; Mellanby, E. and Cantag, M.D. Experimental investigation on rickets. Lancet 196:407-412 (1919).; Mellanby, E. Experimental rickets. Medical Research (G.B.), Special Report Series SRS-61:1-78 (1921).; Hess, A. Influence of light on the prevention of rickets. Lancet 2:1222 (1922).; Steenbock, H. The induction of growth promoting and calcifying properties in a ration by exposure to light. Science 60:224-225 (1924).; Windaus, A., Linsert, O. Luttringhaus, A. and Weidlinch, G. Uber das krystallistierte Vitamin D2. Justis. Liebigs. Ann. Chem. 492:226-231 (1932).; Brockmann, H. Die Isolierung des antirachitischen Vitamins aus Thunfischleberol. H.-S.Zeit. Physiol. Chem. 241:104-115 (1936).; Crowfoot-Hodgkin, D., Webster, M.S. and Dunitz, J.D. Structure of calciferol. Chem. Industry1148-1149(1957).;Solecki,R.S.Shanidar:TheHumanityofNeanderthalMan,NewYork:Knopf.pp.1-252(1971).
  • 6.
    INTRODUCTION VitaminDbelongstothegroupoffat-solublevitamins.Thetwoimportant forms of VitaminD are vitamin D2 or ergocalciferol - the plant source of vitamin D - and vitamin D3 also referred as cholecalciferol. Vitamin D3 is produced in the skin when the skin is exposed to the sun - when the light energy is absorbed by it. If an individual is exposed adequately to sunlight thereisnofurtherneedforVitaminDintheformofsupplements.Natural food sources might not typically have the sufficient amount of Vitamin D and so a conscious consumption of Vitamin D rich foods and deliberate exposure of the skin to sunlight is required to prevent possible deficiencies. The World Health Organization has responsibility for defining the "International Unit" of vitamin D3. Their most recent definition, provided states that "the International Unit of vitamin D recommended for adoption is the vitamin D activity of 0.025 micrograms of the internationalstandardpreparationofcrystallinevitaminD3".Thus,1.0IU ofvitaminD3is0.025micrograms,whichisequivalentto65.0pmoles. In today’s world ultraviolet light from the sun may be blocked by air pollution. The tendency to wear clothes, to live in cities where tall buildings block adequate sunlight from reaching the ground, to live indoors, to use synthetic sun-screens that block ultraviolet rays, and to live in geographical regions of the world that do not receive adequate sunlight, all contribute to the inability of the skin to biosynthesize sufficient amounts of vitamin D3. Under these conditions vitamin D becomes a true vitamin in that it must be supplied in the diet on a regular basis. Animal products constitute the bulk source of vitamin D. Salt water fish such as herring, salmon, sardines, and fish liver oils are good sources of vitamin D3. Small quantities of vitamin D3 are also derived from eggs, veal, beef, butter, and vegetable oils while plants, fruits, and nuts are extremelypoorsourcesofvitaminD.
  • 7.
    The structures ofvitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are presented below. Vitamin D is a generic term and indicatesamoleculeofthegeneralstructureshownforringsA,B,C,andD with differing side chain structures. The A, B, C, and D ring structure is derived from the cyclopentanoperhydrophenanthrene ring structure for steroids. Technically vitamin D is classified as a seco-steroid. Seco- steroids are those in which one of the rings has been broken; in vitamin D, the 9,10 carbon-carbon bond of ring B is broken, and it is indicated by the inclusionof"9,10-seco"intheofficialnomenclature. Reference: Utiger, R.D. The need for more vitamin D. N. Engl. J. Med. 228:828-829 (1998).; Holick, M.F. Vitamin D and bone health. J. Nutr. 126 Suppl. 159S-1164S (1996).; Collins, E.D. and Norman, A.W. Vitamin D. In: Handbook of vitamins, edited by Machlin, L.J. New York: Marcel Dekker, pp. 59-98 (1990).; Subcommittee on the Tenth Edition of the RDAs, Food & Nutrition Board, Commission on Life Sciences and National Research Council.Recommendeddietaryallowances,Washington,D.C.:NationalAcademyPress.Ed.10thpp.1-285(1989).
  • 8.
  • 9.
    SYNTHESIS OF VITAMIND 7-Dehydrocholesterol Cholecalciferol (Vitamin D3) Dietary Intake Liver Kidney 25 Hydroxy Vitamin D3 1, 25 Dihydroxy Vitamin D3 Vitamin D3 (fish & meat) Vitamin D2 (Supplements) SKIN Reference:ClinicalLaboratoryNews,December2007:Volume33,Number12
  • 10.
    METABOLISM OF VITAMIND Intestinal absorption of calcium PTH mediated bone resorption Renal Ca++ and phosphate excretion UV Light 7-dehydrocholesterol 7-dehydrocholesterol Liver Kidney Cholecalciferol Vitamin D3 Calcitriol 1,25 dihydroxy Vitamin D 24,25 dihydroxy Vitamin D Ergocalciferol Vitamin D2 Calcidiol 25-hydroxy Vitamin D Reference:Literaturereview,ZalmanSAgus,MDEmeritusProfessorofMedicineandPhysiology;AssociateDean,CMEPerelmanSchoolofMedicineattheUniversityofPennsylvania
  • 11.
    NON CALCEMIC FUNCTIONSOF 1,25-DIHYDROXY VITAMIN D Vitamin D Decreased Renin Adaptive Immune Modulation VDR-RXR VDR-RXR Decreased 25 (OH)D 1-OHase 1-OHase Increased 1-OHase p21, p27 etc 25 (OH) D2 1,25 (OH) D2 Activated T & B Lymphocytes Pancreas Increased Insulin Secretion Increased 25 (OH) D2 Innate Immune Modulation Cytokines Macrophage Increased VDR mRNA, 1-OHase mRNA M.Tuberculosis Death LPS TLR Solar UV Radiation Dietary Sources Liver Maintenance of normal cell proliferation in prostate, colon, breast etc Increased CD Reference: Hewison M, et al. Molecular and Cellular Endocrinology 2004; 215: 31-38.; Helming L, et al. Blood 2005; 106: 4351-4358; Abu-Amer Y, Bar-Shavit Z. Cellular Immunology 1993; 151: 356-368. Cohen MS, et al. JournalofImmunology1986;136:1049-1053.;WangTT,etal.JournalofImmunology2004;173:2909-2912.;OrvHetil.2011Aug14;152(33):1312-9.;Immunology.2011Oct;134(2):123-39
  • 12.
    NORMAL LEVELS OFCIRCULATING 25 (OH)D Severely deficient Deficient Insufficient Sufficient Optimal <8ng/ml 8 - 19ng/ml 20 - 29ng/ml 30 - 49ng/ml 50 - 99ng/ml 25 Hydroxy Vitamin D (ng/ml) PTH Levels 6-10 11-15 16-20 21-25 26-30 >30 Serum 25 (OH)D (nmol/L) AbsorptionFraction Calcium Absorption 0.0 20 40 60 80 100 120 140 0.1 0.2 0.3 0.4 0.5 Reference:EndocrineSociety’s ClinicalGuideline2011 ParaThyroidHormone(pg/ml) 20 0-5 30 40 50 60 70 80 90 100
  • 13.
    BENEFITS WITH OPTIMALLEVELS OF VITAMIN D SKELETAL-MUSCULAR STRONG MUSCLES AND BONES INFECTIONS PREVENT INFLUENZA, TREAT TUBERCULOSIS CANCER PREVENT BREAST, COLON, AND PROSTATE CANCER AUTOIMMUNE DISEASES PREVENT MULTIPLE SCLEROSIS AND TYPE 1 DIABETES CARDIOVASCULAR DISEASE SLOW PROGRESSION OF ATHEROSCLEROSIS TREAT HYPERTENSION AND CONGESTIVE HEART FAILURE NEUROPSYCHIATRIC DISORDERS PREVENT SCHIZOPHRENIA AND RELIEVE DEPRESSION
  • 14.
    PREVALENCE OF VITAMIND DEFICIENCY 67% of healthy Indians from Lucknow has serum 25(OH)D levels < 15 ng/ml -Arya V, Osteoporosis Int 2004 Vitamin D deficiency (25 (OH)D<20ng/dl) reported in 83% of healthy adults in Kashmir - Zargar et al Postgraduate Medical Journal 2007 85% of healthy Indian adult men could not achieve normal serum 25(OH)D levels despite adequate outdoor activities and sun exposure - Marwaha RK & Tandon N et al Journal of Clinical Densitometry 2009 Prevalence of vitamin D deficiency in Indian lactating women and infants (<20 ng/ml) is 93.8% - Seth A and Marwaha RK et al;JPEM 2009 Studies on bone mineral health from different parts of India indicate wide prevalence of vitamin D deficiency (VDD) in all age groups including neonates, infants, school children, pregnant / lactating women and adult males and females residing in rural and urban India- Marwaha RK et al No. of Patients History of Cancer 25-hydroxyvitamin D3 Level (ng/ml) 7 (9.6 %) 1 (colon) < 8 (severely deficient) 41 (56.2%) 6 8-19.9 (deficient) 9 (12.3%) 0 20-29.9 (insufficient) 13 (17.8%) 0 30-49.9 (sufficient) 3 (4.1%) 0 50-100 (optimal) PREOP VITAMIN D3 LEVELS IN 73 VETERANS UNDERGOING HEART SURGERY AT THE SEATTLE VA HOSPITAL
  • 15.
    CLINICAL SIGNIFICANCE OF VITAMIND REFERENCE: THE CLINICAL IMPORTANCE OF VITAMIN D (CHOLECALCIFEROL): A PARADIGM SHIFT WITH IMPLICATIONS FOR ALL HEALTHCARE PROVIDERS; Alex Vasquez, DC, ND, Gilbert Manso, MD, John Cannell, MD; ALTERNATIVETHERAPIES,sept/oct2004,VOL.10,NO.5
  • 16.
    CLINICAL SIGNIFICANCE OFVITAMIN D CARDIOVASCULAR DISEASE Deaths from cardiovascular disease are more common in the winter, more common at higher latitudes and more common at lower altitudes, observations that are consistent with vitamin D insufficiency. The risk of heart attack is twice as high for those with 25(OH)D levels less than 34 ng/ml (85 nmol/L) than for those with vitamin D status above this level. Patients with congestive heart failure were recently found to have markedlylowerlevelsofvitaminDthancontrols,andvitaminDdeficiency as a cause of heart failure has been documented in numerous case reports. HYPERTENSION It has long been known that blood pressure is higher in the winter than the summer, increases at greater distances from the equator and is affected by skin pigmentation—all observations consistent with a role for vitamin D in regulating blood pressure. When patients with hypertension were treated with ultraviolet light three times a week for six weeks their vitamin D levels increased by 162%, and their blood pressure fell significantly. Even small amounts of oral cholecalciferol (800 IU) for eight weeksloweredbothbloodpressureandheartrate. Type2Diabetes Hypovitaminosis D is associated with insulin resistance and beta-cell dysfunction in diabetics and young adults who are apparently healthy. Healthy adults with higher serum 25(OH)D levels had significantly lower 60 min, 90 min and 129 min postprandial glucose levels and significantly better insulin sensitivity than those who were vitamin D deficient. The authors noted that, compared with metformin, which improves insulin sensitivity by 13%, higher vitamin D status correlated with a 60% improvement in insulin sensitivity. In a recent clinical trial using 1,332 IU/day for only 30 days in 10 women with type 2 diabetes, vitamin D supplementationwasshowntoimproveinsulinsensitivityby21%.
  • 17.
    CLINICAL SIGNIFICANCE OFVITAMIN D OSTEOARTHRITIS We know that vitamin D prevents and treat osteoporosis, but few know that the progression of osteoarthritis, the most common arthritis, is lessened by adequate blood levels of vitamin D. Framingham data showed osteoarthritis of the knee progressed more rapidly in those with 25(OH)D levels lower than 36 ng/ml (90 nmol/L). Another study found that osteoarthritis of the hip progressed more rapidly in those with 25(OH)Dlevelslowerthan30ng/ml(75nmol/L). MULTIPLE SCLEROSIS Theautoimmune/inflammatorydiseasemultiplesclerosis(MS)isnotably rare in sunny equatorial regions and becomes increasingly prevalent among people who live farther from the equator and/or who lack adequate sun exposure. In a clinical trial with 10 MS patients, Goldberg, Fleming, and Picard prescribed daily supplementation with approximately 1,000 mg calcium, 600 mg magnesium, and 5,000 IU vitamin D (from 20 g cod liver oil) for up to two years and found a reduction in the number of exacerbations and an absence of adverse effects.Thisisoneofveryfewstudiesinhumansthatemployedsufficient daily doses of vitamin D (5,000 IU) and had sufficient duration (2 years). More recently, Mahon et al gave 800 mg calcium and 1,000 IU vitamin D per day for six months to 39 patients with MS and noted a modest anti- inflammatoryeffect. PREVENTION OF TYPE 1DIABETES Type 1 diabetes is generally caused by autoimmune/inflammatory destruction of the pancreatic beta-cells. Vitamin D supplementation shows significant preventive and ameliorative benefits in type 1 diabetics. In a study with more than 10,000 participants, showed that supplementation in infants and children with 2,000 IU of vitamin D per dayreducedtheincidenceoftype1diabetesbyapproximately80%.
  • 18.
    CLINICAL SIGNIFICANCE OFVITAMIN D Depression Seasonal affective disorder (SAD) is a particular subtype of depression characterized by the onset or exacerbation of melancholia during winter months when bright light, sun exposure, and serum 25(OH)D levels are reduced. Recently, a dose of 100,000 IU of vitamin D was found superior to light therapy in the treatment of SAD after one month. Similarly, in a study involving 44 subjects, supplementation with 400 or 800 IU per day was found to significantly improve mood within five days of supplementation. EPILEPSY Seizures can be the presenting manifestation of vitamin D deficiency.39 Hypovitaminosis D decreases the threshold for and increases the incidence of seizures, and several “anticonvulsant” drugs interfere with theformationofcalcitriolinthekidneyandfurtherreducecalcitriollevels via induction of hepatic clearance. Therefore, antiepileptic drugs may lead to iatrogenic seizures by causing iatrogenic hypovitaminosis D. Conversely, supplementation with 4,000–16,000 IU per day of vitamin D2 was shown to significantly reduce seizure frequency in a placebo controlledpilotstudybyChristiansenetal. MIGRAINE HEADACHES Calcium clearly plays a role in the maintenance of vascular tone and coagulation, both of which are altered in patients with migraine. Thys- Jacobs reported two cases showing a reduction in frequency, duration, and severity of menstrual migraine attacks following daily supplementationwith1,200mgofcalciumand 1,200–1,600IUofvitamin DinwomenwithvitaminDdeficiency.
  • 19.
    CLINICAL SIGNIFICANCE OFVITAMIN D POLYCYSTIC OVARY SYNDROME Polycystic ovary syndrome (PCOS) is a disease seen only in humans and is classically characterized by polycystic ovaries, amenorrhea, hirsuitism, insulin resistance, and obesity. Animal studies have shown that calcium is essential for oocyte activation and maturation. Vitamin D deficiency was highly prevalent among 13 women with PCOS, and supplementation with 1,500 mg of calcium per day and vitamin D normalized menstruation and/or fertility in nine of nine women with PCOS-related menstrual irregularitieswithinthreemonthsoftreatment. MUSCULOSKELETAL PAIN Patients with non-traumatic, persistent musculoskeletal pain show an impressively high prevalence of overt vitamin D deficiency. Plotnikoff and Quigley recently showed that 93% of their 150 patients with persistent, nonspecific musculoskeletal pain were overtly deficient in vitamin D. Masood et al found a high prevalence of vitamin D deficiency in children with limb pain, and vitamin D supplementation ameliorated pain within threemonths. AlFaraj and AlMutairifound vitaminD deficiencyin83%of their 299 patients with low-back pain, and supplementation with 5,000–10,000 IU of vitamin D per day lead to pain reduction in nearly 100%ofpatientsafterthreemonths.
  • 20.
    CLINICAL SIGNIFICANCE OFVITAMIN D CRITICAL ILLNESS AND AUTOIMMUNE/INFLAMMATORY CONDITIONS Deficiency of vitamin D is common among patients with inflammatory and autoimmune disorders and those with prolonged critical illness. In addition to the previously mentioned epidemic of vitamin D insufficiency in patients with MS, we also see evidence of vitamin D insufficiency in a largepercentageofpatientswithGrave’sdisease,ankylosingspondylitis, systemic lupus erythematosus, and rheumatoid arthritis. Clinical trials with proper dosing and duration need to be performed in these patient groups. C-reactive protein was reduced by 23% and matrix metalloproteinase-9 was reduced by 68% in healthy adults following bolusinjectionsofvitaminDthatresultedinanaveragedoseof547IUper day for 2.5 years. A recent trial of vitamin D supplementation in patients withprolongedcriticalillnessshowedasignificantanddose-dependent “anti-inflammatory effect” evidenced by reductions in IL-6 and CRP. However, the insufficient dose of only 400 IU per day (administered intravenously) for only ten days precluded more meaningful and beneficialresults,andwepresentguidelinesforfuturestudieslaterinthis paper.
  • 21.
    CLINICAL SIGNIFICANCE OFVITAMIN D CANCER PREVENTION AND TREATMENT The inverse relationship between sunlight exposure and cancer mortality was documented by Apperly in 1941. Vitamin D has anti-cancer effects mediated by anti-proliferative and proapoptotic mechanisms which are augmented by modulation of nuclear receptor function and enzyme action, and limited research shows that synthetic vitamin D analogs may have a role in the treatment of human cancers. Grant has shown that inadequate exposure to sunlight, and hence hypovitaminosis D, is associated with an increased risk of cancer mortality for several malignancies, namely those of the breast, colon, ovary, prostate, bladder, esophagus, kidney, lung, pancreas, rectum, stomach, uterus, and non- Hodgkin lymphoma. He proposes that adequate exposure to ultraviolet light and/or supplementation with vitamin D could save more than 23,000 American lives per year from a reduction in cancer mortality alone. The aforementioned clinical trials using vitamin D in a wide range of health conditions have helped to expand our concept of vitamin D and to appreciate its manifold benefits. However, in light of new research showing that the physiologic requirement is 3,000–5,000 IU/day for adults and that serum levels plateau only after 3-4 months of daily supplementation, we must conclude that studies using lower doses and/or shorter durations have underestimated the clinical efficacy of vitaminD.
  • 22.
    VITAMIN D INCARDIO VASCULAR DISEASES
  • 23.
    VITAMIN D -BENEFITS IN CARDIOVASCULAR DISEASES Inhibitionofvascularsmoothmuscleproliferation The hormonal metabolite of vitamin D, 1,25-dihyroxyvitamin D inhibits endothelin (ET)-dependent DNA synthesis and cell proliferation by suppressing ET-induced activation of cyclin-dependent kinase 2 (Cdk2), a key 1 cellcyclekinase . Suppressionofvascularcalcification Medial calcification is associated with proliferation of vascular smooth 2 muscle cells . Vascular calcification can be affected by vitamin D receptors (VDRs), which affect gene activation. When 25(OH)D levels are low, not enough VDRs can be activated to inhibit calcification. The benefit of vitamin D is likely due to its activation of the VDR in vasculature and cardiac 3 myocytes . One of the effects of calcitriol is to act upon osteoclast precursor cells and suppresses their differentiation in addition to intestinal and renal 4 regulationofcalciumandphosphorus . Vitamin D suppresses vascular calcification primarily by regulating parathyroid hormone (PTH). High PTH causes mineral and skeletal abnormalities predisposing to ectopic calcifications and increased 4 mortality . PTH levels decline fairly rapidly with increasing serum 25(OH)D 5,6 levels to about 75 nmol/L, with little change thereafter . There are various lines of evidence that elevated PTH levels are linked to increased risk of vascularproblemsanddementia. Reductionofinflammation An observational study in England found a statistically significant inverse correlation between serum 25(OH)D and tissue plasminogen activator (tPA) 7 antigen, with tPA levels peaking in August . (tPA is a protein involved in the breakdown of blood clots. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat only embolic or thrombotic stroke.) tPA antigen was found to be 8 associatedwithincidenceofcoronaryheartdisease .
  • 24.
    In a studyof the effects of calcitriol on synthesis of mitochondrial RNAs encoding interleukin-6 (IL-6), interferon-gamma (IFN-gamma) in trophoblasts challenged with TNF-alpha found calcitriol inhibited the expression profile of inflammatory cytokine genes in a dose-response 9 manner (P<0.05) . Further findings regarding calcitriol and TNF-alpha are 6 giveninDussoetal . Another way 25(OH)D reduces risk of CVD is through reduction in matrix 10 metalloproteinases (MMPs) such as MMP9 . MMPs are a class of enzymes that can break down proteins, such as collagen and gelatin, and, thus, damagetissuesinthevascularsystem. MMP-2,MMP-9,TIMP-1,andTIMP-2 plasma levels were higher in diabetic, ACS, and DACS patients, which may reflect abnormal extracellular matrix metabolism in diabetes and in acute 11 coronary syndrome . Serum MMP-9 has a modest association with incident CHD in the general population, which is not independent of cigarette smoking exposure and circulating markers of generalized inflammation. MMP-9 is unlikely to be a clinically useful biomarker of CHD risk, but may still 12 play a role in the pathogenesis of CHD . MMP-8 also plays a role in 13,14 atherosclerosis . Reductionofbloodpressure Hypertension is a risk factor for CVD. See the document on hypertension for evidencethatvitaminDreducestheriskofhypertension. Musclefunction 15 Muscle wasting is a characteristic of congestive heart failure . There is 16 growing evidence that vitamin D helps maintain muscle mass and strength 17 and avoid sarcopenia (lack of muscle mass) . The mechanism seems to be 18 avoidanceofhypophosphatemiarelatedtovitaminDdeficiency . VitaminD also protects the myocardium, which protect against heart failure or 19 arrhythmias . VITAMIN D - BENEFITS IN CARDIOVASCULAR DISEASES
  • 25.
    CLINICAL STUDIES OFVITAMIN D IN CARDIO VASCULAR DISEASES
  • 26.
    Short-term vitamin D3supplementation lowers plasma renin activity in patientswithstablechronicheartfailure:anopen-label,blindedendpoint, randomizedprospectivetrial(VitD-CHFtrial). 2013Aug;166(2):357-364.e2. BACKGROUND:Manychronicheartfailure(CHF)patientshavelowvitaminD (VitD) and high plasma renin activity (PRA), which are both associated with poor prognosis. Vitamin D may inhibit renin transcription and lower PRA. We investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF patients. METHODS AND RESULTS: We conducted a single-center, open-label, blinded end point trial in 101 stable CHF patients with reduced left ventricular ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3 daily or control. At baseline, mean age was 64 ± 10 years, 93% male, left ventricular ejection fraction 35% ± 8%, and 56% had VitD deficiency. The geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L (43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the control group (P < .001). The primary outcome PRA decreased from 6.5 ng/mL per hour (3.8-11.2) to 5.2 ng/mL per hour (2.9-9.5) in the VitD3 treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3 ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled by a larger decrease in plasma renin concentration in the VitD3 treatment group compared to control (P = .020). No significant changes were observed in secondary outcome parameters, including N-terminal pro-B-type natriureticpeptidenatriureticpeptideandfibrosismarkers. CONCLUSIONS: Most CHF patients had VitD deficiency and high PRA levels. Six weeks of supplementation with 2,000 IU VitD3 increased 25- hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration. AmHeartJ.
  • 27.
    VITAMIN D DEFICIENCYAND SUPPLEMENTATION AND RELATION TO CARDIOVASCULAR HEALTH. AmericanJournalofCardiology2012Feb1;109(3):359-63. Recent evidence supports an association between vitamin D deficiency and hypertension, peripheral vascular disease, diabetes mellitus, metabolic syndrome, coronary artery disease, and heart failure. The effect of vitamin D supplementation, however, has not been well studied. We examined the associations between vitamin D deficiency, vitamin D supplementation, and patient outcomes in a large cohort. Serum vitamin D measurements for 5 years and 8 months from a large academic institution were matched to patientdemographic,physiologic,anddiseasevariables.ThevitaminDlevels were analyzed as a continuous variable and as normal (≥ 30 ng/ml) or deficient (<30 ng/ml). Descriptive statistics, univariate analysis, multivariate analysis, survival analysis, and Cox proportional hazard modeling were performed. Of 10,899 patients, the mean age was 58 ± 15 years, 71% were women(n=7,758),andtheaveragebodymassindexwas30±8kg/m(2).The mean serum vitamin D level was 24.1 ± 13.6 ng/ml. Of the 10,899 patients, 3,294 (29.7%) were in the normal vitamin D range and 7,665 (70.3%) were deficient. In conclusion, vitamin D deficiency was associated with a significant risk of cardiovascular disease and reduced survival. Vitamin D supplementation was significantly associated with better survival, specificallyinpatientswithdocumenteddeficiency. Vitamin D deficiency was associated with several cardiovascular- related diseases, including hypertension, coronary artery disease, cardiomyopathy, and diabetes (all p <0.05). Vitamin D deficiency was a strong independent predictor of all-cause death (odds ratios 2.64, 95% confidence interval 1.901 to 3.662, p <0.0001) after adjusting for multiple clinical variables. Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p <0.0001).
  • 28.
    PREVALENCE OF VITAMIND DEFICIENCY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION. AmericanJournalofCardiology2011Jun1;107(11):1636-8. Deficiencyin25-hydroxyvitaminD(25[OH]D)isatreatableconditionthathas been associated with coronary artery disease and many of its risk factors. A practicaltimetoassessfor25(OH)Ddeficiency,andtoinitiatetreatment,isat the time of an acute myocardial infarction. The prevalence of 25(OH)D deficiency and the characteristics associated with it in patients with acute myocardial infarction are unknown. In this study, 25(OH)D was assessed in 239 subjects enrolled in a 20-hospital prospective myocardial infarction registry. Patients enrolled from June 1 to December 31, 2008, had serum samples sent to a centralized laboratory for analysis using the DiaSorin 25(OH)D assay. Normal 25(OH)D levels are ≥ 30 ng/ml, and patients with levels <30 and >20 ng/ml were classified as insufficient and those with levels ≤ 20 ng/ml as deficient. Vitamin D levels and other baseline characteristics were analyzed with the linear or Mantel-Haenszel trend test. Of the 239 enrolled patients, 179 (75%) were 25(OH)D deficient and 50 (21%) were insufficient, for a total of 96% of patients with abnormally low 25(OH)D levels. No significant heterogeneity was observed among age or gender subgroups, but 25(OH)D deficiency was more commonly seen in non- Caucasian patients and those with lower social support, no insurance, diabetes, and lower activity levels. Higher parathyroid hormone levels (45.3 vs 32.7 pg/ml, p = 0.029) and body mass indexes (31.2 vs 29.0 kg/m(2), p = 0.025) were also observed in 25(OH)D-deficient subjects. In conclusion, vitamin D deficiency is present in almost all patients with acute myocardial infarctioninamulticenterUnitedStatescohort. VitaminDdeficiencyispresentinalmost(96%)ofpatientswithacuteMI
  • 29.
    VITAMIN D, PARATHYROIDHORMONE, AND SUDDEN CARDIAC DEATH: RESULTS FROM THE CARDIOVASCULAR HEALTH STUDY. Hypertension.2011Dec;58(6):1021-8. Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25- OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 eventsper1000forPTH<65pg/mLand4eventsper1000forPTH≥65pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25- OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovasculardisease. Lower 25-OHD and higher PTH concentrations appears to increases sudden cardiacarrestriskby>2fold.
  • 30.
    VITAMIN D STATUSIS ASSOCIATED WITH ARTERIAL STIFFNESS AND VASCULAR DYSFUNCTION IN HEALTHY HUMANS. JournaloftheAmericanCollegeofCardiology2011Jul5;58(2):186-92. OBJECTIVES: The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25- hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascularfunctioninhealthyadults. BACKGROUND: Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function inhumans,withthehypothesisthatvitaminDinsufficiencywillbeassociated withincreasedarterialstiffnessandabnormalvascularfunction. METHODS: We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assessarterialstiffness. RESULTS: Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independentlyassociatedwithflow-mediatedvasodilation(β=0.1,p=0.03), reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = -0.09, p = 0.04), augmentation index (β = -0.11, p = 0.03), and subendocardial viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactivehyperemiaindex(0.38±0.14,p=0.009)andsubendocardialviability
  • 31.
    VITAMIN D STATUSIS ASSOCIATED WITH ARTERIAL STIFFNESS AND VASCULAR DYSFUNCTION IN HEALTHY HUMANS. ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mmHg,p=0.02). CONCLUSIONS: Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovasculardisease. 25-OH D remained independently associated with flow-mediated vasodilation (p = 0.03), reactive hyperemia index (p < 0.001), pulse wave velocity (p = 0.04), augmentation index (p = 0.03), and subendocardial viabilityratio(p=0.001).
  • 32.
    VITAMIN D STATUSAND OUTCOMES IN HEART FAILURE PATIENTS. EuropeanJournalofHeartFailure2011Jun;13(6):619-25. AIMS: Vitamin D status has been implicated in the pathophysiology of heart failure (HF). The aims of this study were to determine whether a low vitamin D status is associated with prognosis in HF and whether activation of the renin-angiotensin system (RAS) and inflammatory markers could explain this potentialassociation. METHODS AND RESULTS: We measured 25-hydroxy-vitamin D (25(OH)D), plasma renin activity(PRA), interleukin-6(IL-6), C-reactive protein (CRP), and the incidence of death or HF rehospitalization in 548 patients with HF. Median age was 74 (64-80) years, left ventricular ejection fraction was 30% (23-42), and mean follow-up was 18 months. Low 25(OH)D levels were associated with female gender (P< 0.001), higher age (P= 0.002), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P< 0.001). Multivariable linear regression analysis showed that PRA (P= 0.048), and CRP levels (P= 0.006) were independent predictors of 25(OH)D levels. During follow-up, 155 patients died and 142 patients were rehospitalized. Kaplan- Meier analysis showed that After adjustment in a multivariable Cox regression analysis, low 25(OH)D concentration remained independently associated with an increased risk for the combined endpoint [hazard ratio (HR) 1.09 per 10 nmol/L decrease; 95% confidence interval (CI) 1.00-1.16; P= 0.040] and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI 1.00- 1.22;P=0.049). CONCLUSION: A low 25(OH)D concentration is associated with a poor prognosis in HF patients. Activation of the RAS and inflammation may confer theadverseeffectsoflowvitaminDlevels. lower 25(OH)D concentration was associated with an increased risk for the combined endpoint (all-cause mortality and HF rehospitalization; log rank test P= 0.045) and increased risk for all-cause mortality (log rank test P= 0.014).
  • 33.
    VITAMIN D INHYPERTENSION
  • 34.
    VITAMIN D -BENEFITS IN HYPERTENSION Vitamin D lowers blood pressure by affecting the renin angiotensin 1 2 3 aldosterone system by suppressing renin . Renin is a proteolytic enzyme secreted by the kidneys, which catalyzes the production of angiotensin, which, in turn, mediates extracellularfluid volume (blood plasma, lymph and 4 interstitialfluid)andarterialvasoconstriction . 5 Parathyroid hormone (PTH) is associated with increased blood pressure , 6 with a larger effect on diastolic pressure . PTH decreases with increasing serum 25(OH)D until about 30 ng/ml, after which there is little additional 7 change . 8 Vitamin D also increases insulin sensitivity . Insulin resistance is a risk factor 910 forhypertension . Arterial calcification increases blood pressure by stiffening the arterial 11 walls . Serum 25(OH)D levels are inversely correlated with arterial 12 calcifications for those on hemodialysis . Related to arterial stiffening is endothelial dysfunction. (The epithelium is the thin layer of cells that lines 13 the interior surface of blood vessels.) Too little 25(OH)D and much calcium in the blood leads to endothelial dysfunction, which also contributes to 14 increased blood pressure . The paper by Rostand has a figure outlining his modelforelevatedbloodpressureamongAfrican-Americans.
  • 35.
    CLINICAL STUDIES OFVITAMIN D IN HYPERTENSION
  • 36.
    BLOOD 25-HYDROXYVITAMIN DCONCENTRATION AND HYPERTENSION: A META-ANALYSIS. JournalofHypertension2011Apr;29(4):636-45. OBJECTIVES: Increasing evidence indicates that vitamin D may influence the risk of hypertension, which is a major risk factor for cardiovascular disease. We conducted a meta-analysis to quantitatively review and summarize the results on the association between blood 25-hydroxyvitamin D concentrationsandhypertension. METHODS: Relevant studies were identified by a search of PubMed and EMBASE databases until November 2010. We also reviewed the references of retrieved articles. We included prospective and cross-sectional studies with blood 25-hydroxyvitamin D concentrations as the exposure and hypertension as the outcome. Studies had to report results as a relative risk oranoddsratio.Weusedrandom-effectsmodel. RESULTS: Of the 18 studies included in the meta-analysis, 4 were prospective studies and 14 were cross-sectional studies. The pooled odds ratio of hypertension was 0.73 [95% confidence interval (CI) 0.63-0.84] for the highest versus the lowest category of blood 25-hydroxyvitamin D concentration. In a dose-response meta-analysis, the odds ratio for a 40 nmol/l (16 ng/ml) (approximately 2 SDs) increment in blood 25- hydroxyvitaminDconcentrationwas0.84(95%CI0.78-0.90). CONCLUSION: Findings from this meta-analysis indicate that blood 25- hydroxyvitaminDconcentrationisinverselyassociatedwithhypertension.
  • 37.
    RENIN-ANGIOTENSIN SYSTEM ACTIVITYIN VITAMIN D DEFICIENT, OBESE INDIVIDUALS WITH HYPERTENSION: AN URBAN INDIAN STUDY. Indian Journal of Endocrinology and Metabolism 2011 Oct;15 Suppl 4:S395- 401. BACKGROUND: Elevated renin-angiotensin-aldosterone system (RAAS) activity is an important mechanism in the development of hypertension. Both obesity and 25-hydroxy vitamin D [25(OH)D] deficiency have been associated with hypertension and augmented renin-angiotensin system (RAS) activity. We tried to test the hypothesis that vitamin D deficiency and obesity are associated with increased RAS activity in Indian patients with hypertension. MATERIALSANDMETHODS:Fiftynewlydetectedhypertensivepatientswere screened. Patients with secondary hypertension, chronic kidney disease, or coronaryarterydiseasewereexcluded.Patientsunderwentmeasurementof vitamin D and plasma renin and plasma aldosterone concentrations. They were divided into three groups according to their baseline body mass index (BMI; normal <25 kg/m(2), overweight 25-29.9 kg/m(2) and obese ≥ 30 kg/m(2)) and 25(OH)D levels (deficient <20 ng/ml, insufficient 20-29 ng/ml andoptimal≥30ng/ml). RESULTS: A total of 50 (male:female - 32:18) patients were included, with a mean age of 49.5 ± 7.8 years, mean BMI of 28.3 ± 3.4 kg/m(2) and a mean 25(OH)D concentration of 18.5 ± 6.4 ng/ml. Mean systolic blood pressure (SBP) was 162.4 ± 20.2 mm Hg and mean diastolic blood pressure (DBP) was 100.2 ± 11.2 mm Hg. Though all the three blood pressure parameters (SBP, DBP and MAP) were higher among individuals with higher BMIs, they were not achieving statistical significance. Increasing trends in PRAandPACwerenoticedwithlower25(OH)DandhigherBMIlevels. All the three blood pressure parameters [SBP, DBP and mean arterial pressure (MAP)] were significantly higher among individuals with lower 25(OH)D levels. The P values for trends in SBP, DBP and MAP were 0.009, 0.01 and 0.007, respectively.
  • 38.
    RENIN-ANGIOTENSIN SYSTEM ACTIVITYIN VITAMIN D DEFICIENT, OBESE INDIVIDUALS WITH HYPERTENSION: AN URBAN INDIAN STUDY. Indian Journal of Endocrinology and Metabolism 2011 Oct;15 Suppl 4:S395- 401. CONCLUSION: Vitamin D deficiency and obesity are associated with stimulation of RAAS activity. Vitamin D supplementation along with weight loss may be studied as a therapeutic strategy to reduce tissue RAS activity in individualswithVitaminDdeficiencyandobesity.
  • 39.
    SERUM 25-HYDROXYVITAMIN DLEVELS AND ALL-CAUSE AND CARDIOVASCULAR DISEASE MORTALITY AMONG US ADULTS WITH HYPERTENSION: THE NHANES LINKED MORTALITY STUDY. JournalofHypertension2012Feb;30(2):284-9. OBJECTIVES: Research suggests that serum concentrations of 25- hydroxyvitamin D [25(OH)D] are inversely associated with hypertension incidence. This study examined whether concentrations of 25(OH)D are inverselyassociatedwithmortalityriskamongUSadultswithhypertension. METHODS: We analyzed data from the 2001-2004 National Health and Nutrition Examination Survey with mortality data obtained through 2006. Hazard ratios with 95% confidence intervals (CIs) for all-cause and cardiovascular disease (CVD) mortality were estimated using Cox proportionalhazardmodels. RESULTS:Of2609participantswithhypertension,191died(including68CVD deaths) during an average of 3.7-year follow-up. Compared with participants with 25(OH)D concentrations in the highest quartile (≥29ng/ml), the hazard ratios for all-cause mortality were 1.93 (95% CI 1.06-3.49), 1.32 (95% CI 0.85- 2.04), and 1.36 (95% CI 0.84-2.22), respectively (P for trend <0.05), and the hazard ratios for CVD mortality were 3.21 (95% CI 1.14-8.99), 2.42 (95% CI 0.85-6.90), and 2.33 (95% CI 0.88-6.12), respectively (P for trend <0.05), in the first (<17ng/ml), second (17-<23ng/ml) and third (23-<29ng/ml) quartiles of 25(OH)D after adjustment for potential confounding variables. Additionally, concentrations of 25(OH)D as a continuous variable were linearly and inversely associated with the risk of mortality from all causes (P=0.012) and from CVD (P=0.010). These relationships were not affected muchbyadjustmentforbaselinebloodpressureanduseofantihypertension medications. CONCLUSION: Concentrations of 25(OH)D were inversely associated with all- cause and CVD mortality among adults with hypertension in the US. Enhancing vitamin D intake may contribute to a lower risk for premature death.
  • 40.
    PREDIABETES AND PREHYPERTENSIONIN HEALTHY ADULTS ARE ASSOCIATED WITH LOW VITAMIN D LEVELS. DiabetesCare.2011Mar;34(3):658-60. OBJECTIVE: To determine whether modest elevations of fasting serum glucose(FSG)andrestingbloodpressure(BP)inhealthyadultsareassociated withdifferentialserumvitaminDconcentrations. RESEARCH DESIGN AND METHODS: Disease-free adults in the National Health and Nutrition Examination Survey 2001-2006 were assessed. Prediabetes (PreDM) and prehypertension (PreHTN) were diagnosed using American Diabetes Association and Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure criteria: FSG 100-125 mg/dL and systolic BP 120-139 mmHg and/or diastolic BP 80-89 mmHg. Logistic regression was used to assess the effects of low vitamin D levels on the odds for PreDM and PreHTN in asymptomatic adults (n=1,711). RESULTS: The odds ratio for comorbid PreDM and PreHTN in Caucasian men (n = 898) and women (n = 813) was 2.41 (P < 0.0001) with vitamin D levels ≤ 76.3versus>76.3nmol/Lafteradjustingforage,sex,andBMI. CONCLUSIONS: This study strengthens the plausibility that low serum vitamin D levels elevate the risk for early-stage diabetes (PreDM) and hypertension(PreHTN).
  • 41.
    LOW 25(OH)D3 LEVELSARE ASSOCIATED WITH TOTAL ADIPOSITY, METABOLIC SYNDROME, AND HYPERTENSION IN CAUCASIAN CHILDREN AND ADOLESCENTS. EuropeanJournalofEndocrinology2011Oct;165(4):603-11. OBJECTIVES: Evidence of the association between vitamin D and cardiovascular risk factors in the young is limited. We therefore assessed the relationships between circulating 25-hydroxyvitamin D(3) (25(OH)D(3)) and metabolic syndrome (MetS), its components, and early atherosclerotic changes in 452 (304 overweight/obese and 148 healthy, normal weight) Caucasianchildren. METHODS: We determined serum 25(OH)D(3) concentrations in relation to MetS, its components (central obesity, hypertension, low high-density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, glucose impairment, and/or insulin resistance (IR)), and impairment of flow-mediated vasodilatation (FMD) and increased carotid intima-media thickness (cIMT) - twomarkersofsubclinicalatherosclerosis. RESULTS: Higher 25(OH)D(3) was significantly associated with a reduced presence of MetS. Obesity, central obesity, hypertension, hypertriglyceridemia, low HDL-cholesterol, IR, and MetS were all associated with increased odds of having low 25(OH)D(3) levels, after adjustment for age, sex, and Tanner stage. After additional adjustment for SDS-body mass index, elevated blood pressure (BP) and MetS remained significantly associated with low vitamin D status. The adjusted odds ratio (95% confidence interval) for those in the lowest (<17 ng/ml) compared with the highest tertile (>27 ng/ml) of 25(OH)D(3) for hypertension was 1.72 (1.02- 2.92), and for MetS, it was 2.30 (1.20-4.40). A similar pattern of association between 25(OH)D(3), high BP, and MetS was observed when models were adjusted for waist circumference. No correlation was found between 25(OH)D(3)concentrationsandeitherFMDorcIMT. CONCLUSIONS: Low 25(OH)D(3) levels in Caucasian children are inversely relatedtototaladiposity,MetS,andhypertension.
  • 42.
    VITAMIN D INDIABETES
  • 43.
  • 44.
    CLINICAL STUDIES OFVITAMIN D IN DIABETES
  • 45.
    Effects of vitaminD supplementation on glucose metabolism, lipid concentrations, inflammation, and oxidative stress in gestational diabetes: adouble-blindrandomizedcontrolledclinicaltrial. OBJECTIVE: This study was designed to assess the effects of vitamin D supplementation on metabolic profiles, high-sensitivity C-reactive protein, andbiomarkersofoxidativestressinpregnantwomenwithGDM. DESIGN: This randomized, double-blind, placebo-controlled clinical trial was conducted in 54 women with GDM. Subjects were randomly assigned to receiveeithervitamin D supplements or placebo.Individuals in the vitamin D group (n = 27) received capsules containing 50,000 IU vitamin D3 2 times during the study (at baseline and at day 21 of the intervention) and those in the placebo group (n = 27) received 2 placebos at the same times. Fasting blood samples were collected at baseline and after 6 wk of the intervention toquantifyrelevantvariables. RESULTS: Cholecalciferol supplementation resulted in increased serum 25- hydroxyvitamin D concentrations compared with placebo (+18.5 ± 20.4 comparedwith+0.5±6.1ng/mL;P<0.001).Furthermore,intakeofvitaminD supplements led to a significant decrease in concentrations of fasting plasma glucose (-17.1 ± 14.8 compared with -0.9 ± 16.6 mg/dL; P < 0.001) and serum insulin (-3.08 ± 6.62 compared with +1.34 ± 6.51 μIU/mL; P = 0.01) and homeostasis model of assessment-insulin resistance (-1.28 ± 1.41 compared with +0.34 ± 1.79; P < 0.001) and a significant increase in the Quantitative Insulin Sensitivity Check Index (+0.03 ± 0.03 compared with -0.001 ± 0.02; P = 0.003) compared with placebo. A significant reduction in concentrations of total (-11.0 ± 23.5 compared with +9.5 ± 36.5 mg/dL; P = 0.01) and low- densitylipoprotein(LDL)(-10.8±22.4comparedwith+10.4±28.0mg/dL;P= 0.003)cholesterolwasalsoseenaftervitaminDsupplementation. CONCLUSIONS: Vitamin D supplementation in pregnant women with GDM had beneficial effects on glycemia and total and LDL-cholesterol concentrationsbutdidnotaffectinflammationandoxidativestress. AmJClinNutr.2013Dec;98(6):1425-32.
  • 46.
    Improvement in Pancreaticβ Cell Function with Vitamin D and Calcium SupplementationinVitaminDDeficientNon-DiabeticSubjects. 2013Sep6:1-33. OBJECTIVE: There are varied reports on the effect of vitamin D supplementation on beta cell function and plasma glucose levels. To study the effect of vitamin D and calcium supplementation on β cell function and plasmaglucoselevelsinsubjectswithvitaminDdeficiency. METHODS: Non-diabetic subjects(n=48) were screened for their serum vitamin D(25 OHD) status along with serum albumin, creatinine, calcium, phosphorus, alkaline phosphatase, and intact parathyroid hormone status(PTH). Subjects with vitamin D deficiency underwent two hour oral glucose tolerance test. Cholecalciferol (9570 IU/day)(upper tolerable level intake 10,000 IU/day-Endocrine Society guidelines for vitamin D supplementation)andcalciumof1gram/daywassupplemented. RESULTS: Thirty seven patients with vitamin D deficiency participated in the study. The baseline, post vitamin D and calcium supplementation, and(the difference) in serum calcium(corrected)(mg/dl) was 9±0.33and 8.33±1.09(- 0.66±1.11); 25 OHD(ng/ml) 8.75 ±4.75 and 36.83±18.68(28.00±18.33); PTH(pg/ml) 57.90±29.30 and 36.33±22.48(-20.25±22.45); Fasting plasma glucose(mg/dl) 78.23±7.60 and 73.47± 9.82(-4.88±10.65) and; HOMA 2-%B- C Peptide 183.17±88.74 and 194.67±54.71(11.38±94.27). There was significant difference in baseline and post vitamin D and calcium supplementation serum levels of corrected calcium(Z - 3.751;P<0.0001); 25 OHD levels(Z -4.9;P<0.0001);intact PTH(Z-4.04;P<0.0001);fasting plasma glucose(Z-2.7;P<0.007) and HOMA 2-%B- C Peptide(Z-1.923;P<0.05) by Wilcoxon Signed Rank Test. Insulin resistance measured by HOMA is unchanged. CONCLUSIONS: Optimizing serum 25OHD concentrations and supplementationofcalciumimprovesthefastingplasmaglucoselevelsandβ cellsecretoryreserve.Largerrandomizedcontrolstudiesareneededtoseeif correction of vitamin D deficiency will improve insulin secretion and prevent abnormalitiesofglucosehomeostasis. EndocrPract.
  • 47.
    SERUM 25-HYDROXYVITAMIN DCONCENTRATION AND ARTERIAL STIFFNESS AMONG TYPE 2 DIABETES. DiabetesResClinPract.2012Jan;95(1):42-7 AIM: To evaluate the association between serum 25-hydroxyvitamin D [25(OH)D]andarterialstiffnessinpatientswithtype2diabetes. METHODS: Serum 25(OH)D was measured in a cross-sectional sample of 131 men and 174 women aged 30 years and over in Korea. Arterial stiffness was assessed by pulse wave velocity (PWV) obtained with a VP-2000 pulse wave unit. Fasting plasma glucose, insulin, lipid profile, HbA1c, calcium, phosphorous,andHS-CRPweremeasured. RESULTS: The prevalence of vitamin D deficiency was high (85.9%). Those withlowervitaminDlevelshadincreasedPWV.Usingmultivariateregression analysis, low 25(OH)D concentrations independently predicted PWV (p<0.001) in people with type 2 diabetes after adjustment for other risk factors such as age, smoking, hypertension, HS-CRP, diabetes duration, hypertensionduration,HbA1c,andBMI. CONCLUSIONS: Vitamin D may influence the development of cardiovascular disease. Clinical intervention studies are needed to clarify whether treatment with vitamin D decreases the risk of cardiovascular disease in patientswithtype2diabetes. Vitamin D deficiency is common in type 2 diabetes, and a low 25(OH)D level is significantly associated with increased arterial stiffness in these patients.
  • 48.
    SERUM 25-HYDROXYVITAMIN DLEVELS AND PREDIABETES AMONG SUBJECTS FREE OF DIABETES. DiabetesCare.2011May;34(5):1114-9. OBJECTIVE: Animal studies suggest that low serum 25-hydroxyvitamin D (25[OH]D) may impair insulin synthesis and secretion and be involved in the pathogenesis of diabetes. Results in studies in humans have not been consistent, however. Prediabetes is a stage earlier in the hyperglycemia/diabetes continuum where individuals are at increased risk of developing diabetes and where prevention efforts have been shown to be effective in delaying or preventing the onset of diabetes. However, previous studies have not examined the association between low serum 25(OH)D levelsandprediabetes. RESEARCH DESIGN AND METHODS: We examined the 12,719 participants (52.5% women) in the third National Health and Nutrition Examination Survey aged >20 years who were free of diabetes. Serum 25(OH)D levels were categorized into quartiles (≤ 17.7, 17.8-24.5, 24.6-32.4, >32.4 ng/mL). Prediabeteswasdefinedasa2-hglucoseconcentrationof140-199mg/dL,or a fasting glucose concentration of 110-125 mg/dL, or an A1C value of 5.7- 6.4%. RESULTS: Lower serum 25(OH)D levels were associated with prediabetes after adjusting for age, sex, race/ethnicity, season, geographic region, smoking, alcohol intake, BMI, outdoor physical activity, milk consumption, dietary vitamin D, blood pressure, serum cholesterol, C-reactive protein, and glomerular filtration rate. Compared with quartile 4 of 25(OH)D (referent), the odds ratio of prediabetes associated with quartile 1 was 1.47 (95% CI 1.16-1.85; P = 0.001 for trend). Subgroup analyses examining the relation between 25(OH)D and prediabetes by sex, BMI, and hypertension categories alsoshowedaconsistentpositiveassociation. CONCLUSIONS: Lower serum 25(OH)D levels are associated with prediabetes inarepresentativesampleofU.S.adults.
  • 49.
    SERUM 25-HYDROXYVITAMIN D,CALCIUM INTAKE, AND RISK OF TYPE 2 DIABETES AFTER 5 YEARS: RESULTS FROM A NATIONAL, POPULATION-BASED PROSPECTIVE STUDY (THE AUSTRALIAN DIABETES, OBESITY AND LIFESTYLE STUDY). DiabetesCare.2011May;34(5):1133-8. OBJECTIVE: To examine whether serum 25-hydroxyvitamin D (25OHD) and dietarycalciumpredictincidenttype2diabetesandinsulinsensitivity. RESEARCH DESIGN AND METHODS: A total of 6,537 of the 11,247 adults evaluated in 1999-2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004- 2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted formultiplepotentialconfounders,includingfastingplasmaglucose(FPG). RESULTS: During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58vs.65nmol/L;P<0.001)andcalciumintake(mean881vs.923mg/day;P= 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63-0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-Sat5years. CONCLUSIONS: Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adultmenandwomen.
  • 50.
    PLASMA 25-HYDROXYVITAMIN DLEVELS ARE FAVORABLY ASSOCIATED WITH B-CELL FUNCTION. Pancreas.2012Jan17. OBJECTIVE: The association of hypovitaminosis D with type 2 diabetes is well recognized.AlthoughhypovitaminosisDisassociatedwithinsulinresistance, thereismuchlessinformationaboutitsimpactonβ-cellfunctioninhumans. METHODS: We enrolled 150 healthy, glucose-tolerant subjects for the assessment of β-cell function (acute insulin response) and insulin sensitivity index (ISI) using a hyperglycemic clamp. Adjusted β-cell function (ABCF) was defined as the product of acute insulin response and ISI. The relations of plasma 25-hydroxyvitamin D [25(OH)D] level with insulin sensitivity and ABCFwereexamined. RESULTS: Plasma 25(OH)D levels were positively associated with ABCF (P = 0.00004) and ISI (P < 0.00001). The associations remained significant after adjustment for age, sex, body mass index, physical activity, ethnicity, and seasonofstudy. CONCLUSIONS:Plasma25(OH)Dlevelsarepositivelyassociationwithbothβ- cell function and insulin sensitivity. Our observations suggest the roles of vitaminDdeficiencyinthedualdefectoftype2diabetes.
  • 51.
    VITAMIN D LEVELSAND ASYMPTOMATIC CORONARY ARTERY DISEASE IN TYPE 2 DIABETIC PATIENTS WITH ELEVATED URINARY ALBUMIN EXCRETION RATE. DiabetesCare.2012Jan;35(1):168-72.. OBJECTIVE: Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has beenshowntopredictcardiovascularmortalityintype2diabeticpatients. RESEARCH DESIGN AND METHODS: We investigated the association among severevitaminDdeficiency,coronarycalciumscore(CCS),andasymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was definedasplasma25-hydroxyvitaminD(p-25[OH]D3)<12.5nmol/L.Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients' p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandemmassspectrometry. RESULTS: The median (range) vitamin D level was 36.9 (3.8-118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiencywas associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5-12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5-13.9, P = 0.007). Furthermore,severevitaminDdeficiencywasassociatedwithasymptomatic CAD(adjustedOR2.9,1.02-7.66,P=0.047). CONCLUSIONS: In high-risk type 2 diabetic patients with elevated UAER, low levelsofvitaminDareassociatedwithasymptomaticCAD.
  • 52.
    VITAMIN D INAUTO-IMMUNE DISEASES AND PAINS REFERENCE:ByStewartB.Leavitt,MA,PhD;PracticalPAINMANAGEMENT,July/August2008
  • 53.
    According to extensiveclinical research examining adult patients of all ages, inadequate concentrations of vitamin D have been linked to nonspecific muscle, bone, or joint pain, muscle weakness or fatigue, fibromyalgia syndrome, rheumatic disorders, osteoarthritis, hyperesthesia, migraine headaches,andotherchronicsomaticcomplaints. Deficiency of Vitamin D leads to Hypocalcemia, which leads to a cascade of bio-chemical reactions that negatively affects bone metabolism and health. Even mild hypocalcemia results in an elevation of parathyroid hormone (PTH) that can diminish bone density (osteopenia) and/or more severely affect bone architecture (osteoporosis). The effect relating more closely to musculoskeletal aches and pains is the increased PTH levels. This also impair properbonemineralizationcausingaspongymatrixtoformunderperiosteal membranes covering the skeleton. This gelatin-like matrix can absorb fluid, expand, and cause outward pressure on periosteal tissues, which generates pain since these tissues are highly innervated with sensory pain fibers. This dysfunction of bone metabolism (osteomalacia) is proposed in the literature as an explanation of why many patients with vitamin D inadequacies may complain of dull, persistent, generalized musculoskeletal aches, pains, and weakness. Therefore, experts recommend that vitamin D deficiency and its potential for associated osteomalacia should be considered in the differential diagnosis of all patients with chronic musculoskeletal pain, muscleweaknessorfatigue,fibromyalgia,orchronicfatiguesyndrome. Clinical researchers have also found that the role of vitamin D extends beyond bone and muscle involvement in chronic pain syndromes. For example, vitamin D receptors have been identified in various brain structures, the spinal cord, and sensory ganglia. Accordingly, results of some studies suggest non-musculoskeletal benefits of vitamin D supplementation, asfollows: VITAMIN D - AUTO-IMMUNE DISEASE OR PAINS
  • 54.
    Neuropathy - Arecently reported prospective study of 51 patients with type 2 diabetes and associated with neuropathy found that conservative vitamin D supplementation (about 2000 IU/day) for 3 months resulted in nearly a 50%decreaseinpainscores Inflammation - Clinical research indicates that vitamin D supplementation modulates or decreases pro-inflammatory cytokines (eg, C-reactive protein, interleukin 6 and 12, and tumor necrosis factor-alpha) while increasing anti- inflammatory cytokines (eg, interleukin-10). Investigators have further suggestedthatvitaminDmayhelptomoderatepainfulchronicinflammatory autoimmune conditions that are influenced by excessive cytokine activity, suchasinflammatoryboweldisease. Migraine Headaches -There have been case reports of vitamin D combined with calcium supplementation to alleviate migraine headaches in postmenopausal and premenopausal women. Reductions in both frequency andintensityofmigraineswereachievedwithin2months. Affective (Mood) Disturbances - In patients with fibromyalgia syndrome, pain, depression, and anxiety were found to be strongly associated with insufficient vitamin D. Furthermore, large studies examining older persons (aged >65 years) found significant associations between 25(OH)D deficiencies and depressive disorders. In one of the studies, inadequate 25(OH)Danddepressionalsowerehighlycorrelatedwithchroniclower-back painspecificallyinfemalepatients. VITAMIN D - AUTO-IMMUNE DISEASE OR PAINS
  • 55.
    Fibromyalgia syndrome patientsare highly Vitamin D deficient, (4.76 ± 1.46 ng/mL), and lower vitamin D levels were significantly correlated withgreaterwidespreadpain. More than half of 313 patients undergoing spinal fusion surgery had inadequate levels of vitamin D; a quarter of them were severely deficient 93% of 150 patients with persistent, nonspecific musculoskeletal pain wereovertlydeficientinvitaminD. There is high prevalence of vitamin D deficiency in children with limb pain, and vitamin D supplementation ameliorated pain within three months. Vitamin D deficiency is found in 83% of 299 patients with low-back pain, and supplementation with 5,000–10,000 IU of vitamin D per day lead to painreductioninnearly100%ofpatientsafterthreemonths. Current best evidence demonstrates that supplemental vitamin D can help many patients who have been unresponsive to other therapies for pain. VITAMIN D - AUTO-IMMUNE DISEASE OR PAINS
  • 56.
    Speaking at the26th Annual Meeting of the North American Spine Society, orthopaedic surgeons from Washington University School of Medicine in St. Louis reported that more than half of 313 patients undergoing spinal fusion surgery had inadequate levels of vitamin D; a quarter of them were severely deficient[Stokeretal.2011]. One of the study authors, Jacob M. Buchowski, MD, said he became aware of thevitaminDproblemwhenapatientinher40sexperiencedaslowrecovery after spinal fusion surgery. While he was trying to determine why the vertebrae did not fuse properly the woman mentioned that she had recently been diagnosed with vitamin D deficiency. “It was like a 'light bulb' went off,” he stated. Consequently, Buchowski and colleagues started routinely screeningpatientspriortospinalfusionsurgeryforvitaminDdeficiency. Low vitamin D levels are known to be common in elderly patients; surprisingly, however, patients in this study most likely to have inadequate levels were younger; on average, 55 years old. One quarter of the patients, predominantly those who were older, had taken vitamin D supplements in thepast. The researchers found that the main risk factors for inadequate vitamin D were smoking, obesity, disability prior to surgery, and never having taken vitaminDormultivitaminsupplements.Althoughanearlierstudyhadshown inadequate vitamin D levels in 43% of patients undergoing orthopedic procedures,thisisthefirsttolooksolelyatpatientshavingspinesurgery. Vitamin D is important for calcium absorption and patients with a deficiency are at risk for osteomalacia that hinders new bone formation. As a follow-up to this study, Buchowski and colleagues are planning an investigation of whether there is a link between low vitamin D and poor outcomes following spinal fusion. In the meantime, he recommends that patients should be gettingsufficientvitaminDpriortoorthopedicsurgery. VITAMIN D DEFICIENCIES HAMPER RECOVERY FROM SPINE SURGERY
  • 57.
    This one fromresearchers at Johns Hopkins University, Baltimore — suggests that vitamin D levels are significantly lower in patients with recurrent inflammatory spinal cord disease, including transverse myelitis and neuromyelitis optica [Mealy et al. 2011]. In transverse myelitis (TM) there is involvement of the myelin sheath that protects nerve fibers; symptoms include back pain and weakness in the legs. Neuromyelitis optica (NMO) is a disease of the central nervous system that affects the optic nerves and spinal cord. Writing in an early online edition of the Archives of Neurology, Maureen A. Mealy, RN, BSN, and colleagues report a retrospective analysis of vitamin D levels among 77 patients, comparing monophasic versus recurrent inflammatory diseases of the spinal cord (TM/NMO), and adjusting for season,age,sex,andrace.TheyfoundthatvitaminDlevelsweresignificantly deficient — 25(OH)D < 20 ng/mL — in patients who developed recurrent spinal cord disease compared with those having nonrecurring monophasic disease. This is consistent with other recurrent autoimmune conditions and points to a common link between low vitamin D levels and immunologic dysregulation,” the researchers write. They suggest that further studies are needed to assess the relationship between vitamin D and painful, recurrent spinalcorddisease. LOW VITAMIN D MAY INFLUENCE INFLAMMATORY SPINAL CORD DISEASE
  • 58.
    Pseudoarthrosis and fracture:interaction between severe vitamin D deficiencyandprimaryhyperparathyroidism. A young woman with severe vitamin D deficiency presented with proximal muscle weakness, fragility fracture and pseudoarthrosis. On evaluation, she was found to have hypercalcaemia, a single parathyroid adenoma and an undetectable 25-hydroxyvitamin D level. She received parenteral cholecalciferol and subsequently underwent curative parathyroidectomy. Postoperatively, she had hungry bone syndrome, which she gradually recoveredfromwithcalciumandcalcitriolreplacement.Notably,hercalcium levels were in the lower limit of normal range and associated with elevated alkaline phosphatase levels at postoperative Day 14. Follow-up for the next four years showed that the patient had remarkable symptomatic and radiological improvements. In this report, we discuss the pathophysiological interactions between vitamin D deficiency and associated primary hyperparathyroidism. SingaporeMedJ.2013Nov;54(11):e224-7.
  • 59.
    SERUM VITAMIN DLEVEL AND BONE MINERAL DENSITY IN PREMENOPAUSAL EGYPTIAN WOMEN WITH FIBROMYALGIA. RheumatolInt.2012Feb4. Patients with fibromyalgia syndrome (FMS) have impaired mobility and therefore get less sunlight exposure, we postulated that they may be at increased risk of developing osteoporosis (OP). The aim of this study was to assess and compare serum vitamin D level and bone mineral density (BMD) value in patients with primary FMS (PFMS) and healthy controls. A total of 50 patients with PFMS participated in this case-control study, and 50 healthy females who were age-matched to the patients were used as the control group. Venous blood samples collected from all subjects were used to evaluate serum 25-hydroxyvitamin D3 (25-OHD). BMD was measured at the lumbar spine (L2-L4) anteroposterior, femoral neck and forearm by dual- energy X-ray absorptiometry. Patients with PFMS had significantly lower serum 25-OHD than controls (15.1 ± 6.1 and 18.8 ± 5.4 ng/ml, respectively, p = 0.0018). Apart from the BMD in the lumbar spine, which was significantly lower in the PFMS patients compared with controls (p = 0.0012), no significant difference was found in other measures of BMD. Compared to PFMS patients who had serum level of the 25-OHD >20 ng/ml, the patients with 25-OHD ≤20 ng/ml are more likely to have impaired short memory (46.4 vs. 13.6%, respectively, p = 0.0136), confusion (50 vs. 18.2%, respectively, p = 0.0199), mood disturbance (60.7 vs. 27.3%, respectively, p = 0.0185), sleep disturbance (53.6 vs. 22.7%, respectively, p = 0.0271), restless leg syndrome (57.1 vs. 27.3%, respectively, p = 0.0346) and palpitation (67.9 vs. 36.4%, respectively, p = 0.0265). Serum level of the 25-OHD is inversely correlated withvisualanaloguescale(VAS)ofpain(p=0.016),Beckscorefordepression (p = 0.020) and BMD at lumbar spine (p = 0.012). The lumbar BMD inversely correlated with VAS of pain (p = 0.013) and Beck score for depression (p = 0.016). This study confirmed high prevalence of hypovitaminosis D among in patients with PFMS. This study confirmed the concept that FMS is a risk factor for OP. Based on this, an early nutrition program rich in calcium and vitamin D, appropriate exercise protocols, and medical treatment should be consideredinthesepatientsintermsofpreventingOPdevelopment.
  • 60.
    THE PREVALENCE OFVITAMIN D DEFICIENCY IN CONSECUTIVE NEW PATIENTS SEEN OVER A 6-MONTH PERIOD IN GENERAL RHEUMATOLOGY CLINICS. ClinRheumatol.2011Jun;30(6):789-94. The objectives of this study are to assess: (a) the prevalence of vitamin D deficiency among new patients attending rheumatology outpatient departments, (b) the age profile of these low vitamin D patients and (c) whether any diagnostic category had a particularly high number of vitamin D-deficient patients. All new patients seen consecutively in general rheumatologyclinicsbetweenJanuarytoJune2007inclusivewereeligibleto partake in this study, and 231 out of 264 consented to do so. Parathyroid hormone, 25-hydroxyvitamin D, creatinine, calcium, phosphate, albumin and alkaline phosphatase levels were measured. We defined vitamin D deficiency as ≤53 nmol/l and severe deficiency as ≤25 nmol/l. Overall, 70% of 231 patients had vitamin D deficiency, and 26% had severe deficiency. Sixty- five percent of patients aged ≥65 and 78% of patients aged ≤30 years had low vitamin D levels. Vitamin D deficiency in each diagnostic category was as follows: (a) inflammatory joint diseases/connective tissue diseases (IJD/CTD), 69%; (b) soft tissue rheumatism, 77%; (c) osteoarthritis, 62%; (d) non-specific musculoskeletal back pain, 75% and (e) osteoporosis, 71%. SeasonalvariationofvitaminDlevelswasnotedinalldiagnosticgroupsapart fromIJD/CTDgroup,wherethedegreeofvitaminDdeficiencypersistedfrom latewintertopeaksummer.VeryhighprevalenceofvitaminDdeficiencywas noted in all diagnostic categories (p = 0.006), and it was independent of age (p = 0.297). The results suggest vitamin D deficiency as a possible modifiable risk factor in different rheumatologic conditions, and its role in IJD/CTD warrantsfurtherattention.
  • 61.
    VITAMIN D INCANCERS REFERENCE:VITAMIN DAND CANCER PREVENTION:STRENGTHS AND LIMITS OF THE EVIDENCE;NATIONAL CANCER INSTITUTE AT NIH
  • 62.
    ROLE OF VITAMIND IN REDUCING CANCERS. A large number of scientific studies have investigated the possible role for vitaminDincancerprevention. The first results came from epidemiologic studies known as geographic correlation studies. In these studies, an inverse relationship was found between sunlight exposure levels in a given geographic area and the rates of incidence and death for certain cancers in that area. Individuals living in southern latitudes were found to have lower rates of incidence and death for these cancers than those living at northern latitudes. Because sunlight/UV exposure is necessary for the production of vitamin D3, researchers hypothesized that variation in vitamin D levels accounted for the observed relationships. Evidence of a possible cancer-protective role for vitamin D has also been found in laboratory studies of the effect of vitamin D treatment on cancer cells in culture. In these studies, vitamin D promoted the differentiation and death (apoptosis) of cancer cells, and it slowed their proliferation. Randomized clinical trials designed to investigate the effects of vitamin D intake on bone health have suggested that higher vitamin D intakes may reduce the risk of cancer. One study involved nearly 1,200 healthy postmenopausal women who took daily supplements of calcium (1,400 mg or 1,500 mg) and vitamin D (25 μg vitamin D, or 1,100 IU―a relatively large dose) or a placebo for 4 years. The women who took the supplements had a 60 percent lower overall incidence of cancer; however, the study did not include a vitamin D-only group. Moreover, the primary outcome of the study was fracture incidence; it was not designed to measure cancer incidence. This limits the ability to draw conclusions about the effect of vitamin D intake oncancerrisk.
  • 63.
    ROLE OF VITAMIND IN REDUCING CANCERS. A number of observational studies have investigated whether people with higher vitamin D levels or intake have lower risks of specific cancers, particularly colorectal cancer and breast cancer. Associations of vitamin D with risks of prostate, pancreatic, and other, rarer cancers have also been examined. These studies have yielded inconsistent results, most likely because of the challenges of conducting observational studies of diet. Information about dietary intakes is obtained from the participants through the use of food frequency questionnaires, diet records, or interviews in which the participants are asked to recall information about their dietary intakes. Information collected in this manner can be inaccurate. In addition, only recently has a comprehensive food composition database with vitamin D values for the U.S. food supply become available. Other dietary componentsorenergybalancemayalsomodifyvitaminDmetabolism. Measuring blood levels of 25-hydroxyvitamin D to determine vitamin D status avoids some of the limitations of assessing dietary intake. However, vitamin D levels in the blood vary by race, with the season, and possibly with the activity of genes whose products are involved in vitamin D transport and metabolism. These variations complicate the interpretation of studies that measuretheconcentrationofvitaminDinserumatasinglepointintime. Finally, it is difficult to separate the effects of vitamin D and calcium because of the complicated biological interactions between these substances. To fully understand the effect of vitamin D on cancer and other health outcomes, new randomized trials will need to be carried out. However, the appropriate dose of vitamin D to use in such trials is still not clear.
  • 64.
    VITAMIN D ANDCOLORECTAL CANCERS Epidemiologic studies of the association between vitamin D and the risk of colorectal cancer have provided some indications that higher levels of intakeareassociatedwithareducedrisk.However,thedataareinconsistent. In the American Cancer Society's Cancer Prevention Study (CPS) II Nutrition Cohort, the diet, medical history, and lifestyle of more than 120,000 men and women were analyzed. Men who had the highest intakes of vitamin D through both their diet and supplement use (greater than 13 μg, or 525 IU, per day) had a slightly lower risk of colorectal cancer than men who had the lowest vitamin D intakes. However, this association was not observed among women. In a pooled analysis of data from 10 cohort studies (including the CPS II cohort), individuals with the highest dietary vitamin D intakes had a slightly lower risk of colorectal cancer than those with the lowest intakes, but the reductioninriskwasnotstatisticallysignificant. In the Women's Health Initiative randomized trial, healthy postmenopausal women took daily supplements that contained both calcium (1,000 mg) and vitamin D (10 μg, or 400 IU) or a placebo for an average of 7 years. Supplementation did not reduce the incidence of colorectal cancer. However, some scientists have raised the possibility that the relatively low level of vitamin D supplementation and the short duration ofparticipantfollow-upmightaccountforthenegativeresults. At least one epidemiologic study has reported an association between vitamin D and reduced mortality from colorectal cancer. Among the 16,818 participants in the Third National Health and Nutrition Examination Survey, those with higher vitamin D blood levels (≥80 nmol/L) had a 72 percent lower risk of colorectal cancer death than those with lower vitamin D blood levels (<50nmol/L).
  • 65.
    VITAMIN D ANDCOLORECTAL CANCERS Most colorectal cancers develop from pre-existing colorectal adenomas, and interventions that reduce the risk of adenoma development or recurrence are likely to reduce the risk of colorectal cancer. Several large studies have investigated the association of vitamin D intake or serum status withadenomarisk. A cohort from the National Cancer Institute (NCI)-sponsored Polyp Prevention Trial (PPT) was evaluated for the association of vitamin D intake with recurrence of colorectal adenomas in individuals who previously had one or more adenomas removed during a qualifying colonoscopy. PPT was a multicenter randomized clinical trial to determine the effects of a diet high in fiber, fruits, and vegetables and low in fat on adenoma recurrence. The detailed dietary information obtained during the trial allowed the researchers to investigate the association between additional dietary factors andadenomarecurrence.TotalvitaminDintake(thatis,fromdietarysources and supplements combined) was not associated with a reduced risk of adenoma recurrence. However, individuals who used any amount of vitamin Dsupplementshadalowerriskofadenomarecurrence. In another study, the vitamin D intakes of 3,000 people from several Veterans Affairsmedicalcenterswereexaminedto determinewhetherthere was an association between intake and advanced colorectal neoplasia (an outcome that included high-risk adenomas as well as colon cancer). Individuals with the highest vitamin D intakes (more than 16 μg, or 645 IU, per day) had a lower risk of developing advanced neoplasia than those with lowerintakes. A pooled analysis of data from these and a number of other observational studies found that higher circulating levels of vitamin D and higher vitamin D intakes were associated with lower risks of colorectal adenoma.Inverseassociationswereseenwithbothdietaryandtotalvitamin DintakebutnotwithsupplementalvitaminDintake.Howevertheassociati-
  • 66.
    VITAMIN D ANDCOLORECTAL CANCERS onswithdietaryintakewerenotstatisticallysignificant. Another large, NCI-sponsored randomized, placebo-controlled trial explored the effects of calcium supplementation and blood levels of vitamin D on adenoma recurrence. Calcium supplementation reduced the risk of adenoma recurrence only in individuals with vitamin D blood levels above 73 nmol/L. Among individuals with vitamin D levels at or below this level, calciumsupplementationwasnotassociatedwithareducedrisk.
  • 67.
    VITAMIN D ANDBREAST CANCERS Epidemiologic studies of the association between vitamin D and breast cancer risk had conflicting results. Although several studies have suggested aninverseassociationbetweenvitaminDintakeandtheriskofbreastcancer, others have shown no association or even a positive association (that is, individuals with higher intakes had higher risks). A meta-analysis of six studies that investigated the relationship between vitamin D intake and breast cancer risk found no association. However, most women in these studies had relatively low vitamin D intakes, and, when the analysis was restrictedtowomenwiththehighestvitaminDintakes(>10μg,or400IU,per day), their breast cancer risks were lower than those of women with the lowestintakes(typically<1.25μg,or50IU,perday). IntheWomen'sHealthInitiative,calciumplusvitaminDsupplementationfor an average of 7 years did not reduce the incidence of invasive breast cancer comparedwithplacebo. . The association between blood levels of vitamin D and breast cancer risk was examined in a cohort of postmenopausal women who were enrolled in NCI's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and from whom blood was drawn at study entry. During the subsequent follow- up period, 1,005 of these women developed breast cancer. When researchers compared the blood vitamin D levels of these women with those of 1,005 similar control women who did not develop breast cancer, they foundnoassociationbetweenvitaminDstatusandriskofbreastcancer.
  • 68.
    VITAMIN D ANDPROSTATE CANCERS Somegeographiccorrelationstudieshavesuggestedthatmenexposed to higherlevelsof sunlight may havea lowerriskof prostatecancer.Although some epidemiologic studies have suggested that men with higher vitamin D levels have an increased risk of prostate cancer, most studies have not shown suchanassociation. In one relatively large study of men diagnosed 1 to 8 years after their blood was drawn, higher vitamin D blood levels were not associated with a lower risk of prostate cancer overall. Indeed, there was some evidence that men withhighervitaminDlevelshadanincreasedriskforaggressivedisease. In another study, the European Prospective Investigation into Cancer and Nutrition (EPIC), blood samples obtained at study entry were examined for 652 men who developed prostate cancer during follow-up and 752 matched control subjects. No association was observed between serum vitamin D levelsandriskofprostatecancer,eitheroverallorbycancerstage.
  • 69.
    VITAMIN D ANDPANCREATIC CANCERS There is conflicting evidence about vitamin D's relationship to risk of pancreatic cancer. A study of more than 120,000 men and women from the Health Professionals Follow-Up Study and the Nurses' Health Study showed that participants with higher dietary intake of vitamin D had progressively lower risk of pancreatic cancer, compared with those who had the lowest intake. The estimates of vitamin D intake were based on detailed dietary informationprovidedthroughquestionnaires.Participantswerefollowedfor 16 years for the incidence of pancreatic cancer, and 365 cases were identified. In a study of men and women enrolled in the PLCO Screening Trial, no association between vitamin D level and pancreatic cancer risk was observed. The PLCO study examined vitamin D levels in blood from 184 individuals who were diagnosed with pancreatic cancer during nearly 12 yearsoffollow-upand368matchedcancer-freecontrolsubjects.Incontrast, among Finnish male smokers participating in the Alpha-Tocopherol, Beta- Carotene (ATBC) Cancer Prevention Study, higher blood levels of vitamin D wereassociatedwithanincreasedriskofpancreaticcancer.Morerecently,in the NCI Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, men and women with the highest blood vitamin D levels (greater than 100 nmol/L, or 40 ng/mL) had twice the pancreatic cancer risk of men and women whose blood vitamin D levels were in the normal range of 50-75 nmol/L(20-30ng/mL).
  • 70.
    VITAMIN D ANDRARE CANCERS A recent large collaborative effort analyzed data from 10 prospective cohort studies to examine whether vitamin D levels in blood were associated with seven rare cancers. The NCI Cohort Consortium Vitamin D Pooling Project of Rarer Cancers included information on blood vitamin D levels and incidence of rare cancers in a subset of more than 12,000 men and women. The researchers matched participants on date and season of blood draw and used other statistical techniques to adjust for seasonal variation in blood vitamin D levels. When the data from the different studies were pooled, there was no overall association between vitamin D level and risk of non- Hodgkin lymphoma or cancers of the endometrium, esophagus, stomach, kidney,orovary.Anincreasedriskofpancreaticcancerwasobservedinthose with the highest blood levels of vitamin D (greater than 100 nmol/L or 40 ng/mL). VITAMIN D AND SKIN CANCER AlthoughpeopleobtainsomevitaminDfromdietarysources,mostvitaminD is made in the body after the skin is exposed to sunlight. Despite the known and potential health benefits of vitamin D, increasing sun exposure increases the risk of skin cancer. In general, most experts believe that people should continue to use sun protection when UV levels are moderate or higher. Some researchers have suggested that brief daily exposure to UV will ensure adequate vitamin D production, but many variables (such as skin color, latitude, and season) can affect the production of vitamin D, and such recommendations have proven controversial. Other experts recommend vitamin D supplementation to avoid the problem of increasing skin cancer risk.
  • 71.
    VITAMIN D INMODIFYING THE CANCER RISK Mechanisms by which vitamin D may modify cancer risk are not fully understood.LaboratorystudieshaveshownthatvitaminDpromotescellular differentiation,decreasescancercellgrowth,andstimulatesapoptosis. Vitamin D acts on cells by binding to the vitamin D receptor (VDR). The VDR is a regulator of gene transcription that is found in the nucleus of cells. Vitamin D-bound VDR binds to the retinoid-X receptor (RXR), and the resulting complex activates the expression of specific genes. Among the many genes regulated by vitamin D are those that produce the proteins calbindin and TPRV6, both of which are involved in the absorption of calcium by intestinal cells. Another vitamin D-regulated gene is CYP3A4, whose protein product detoxifies the bile acid lithocholic acid (LCA). LCA is believed to damage the DNA of intestinal cells and may promote colon carcinogenesis. Stimulating the production of a detoxifying enzyme by vitamin D could explain a protectiveroleforvitaminDagainstcoloncancer. Further insight into the mechanisms by which vitamin D might modify cancer risk could come from study of the vitamin D receptor itself. A large number of variant forms of the VDR gene have been identified, some of which are known to alter the structure or function of the VDR protein. Some of these variants have been linked to risk for certain cancers, including prostate, colorectal, breast, bladder, and melanoma. The association of VDR variants with cancer risk differs by cancer site and appears to be modified by environmentalexposures,suchasdietandsunexposure.
  • 72.
    VITAMIN D INPREGNANCY
  • 73.
    VITAMIN D INPREGNANCY VitaminDstatusandhypertensivedisordersduringpregnancy Maternal vitamin D deficiency in pregnancy has been associated with an increased risk of pre-eclampsia (new-onset gestational hypertension and proteinuria after 20 weeks of gestation), a condition associated with an increaseinmaternalandperinatalmorbidityandmortality. Womenwithpre-eclampsiahavelowerconcentrationsof25-hydroxyvitamin D compared with women with normal blood pressure. The low levels of urinary calcium (hypocalciuria) in women with pre-eclampsia may be due to a reduction in the intestinal absorption of calcium impaired by low levels of vitamin D. Additionally, pre-eclampsia and vitamin D deficiency are directly and indirectly associated through biologic mechanisms including immune dysfunction, placental implantation, abnormal angiogenesis, excessive inflammation,andhypertension. VitaminDstatusandothermaternalconditions Maternal vitamin D deficiency in early pregnancy has been associated with elevated risk for gestational diabetes mellitus, Poor control of maternal diabetes in early pregnancy is inversely correlated with low bone mineral contentininfants,asislowmaternalvitaminDstatus. VDD may lead to a high bone turnover, bone loss, osteomalacia (softening of the bones) and myopathy (muscle weakness) in the mother in addition to neonatal and infant VDD. An adequate vitamin D status may also protect against other ad verse pregnancy outcomes. For example, maternal vitamin D deficiency has been linked to caesarean section in a single recent study. Low prenatal and perinatal maternal vitamin D concentrations can affect the function of other tissues, leading to a greater risk of multiple sclerosis, cancer,insulin-dependentdiabetesmellitus,andschizophrenialaterinlife
  • 74.
    VITAMIN D INPREGNANCY VitaminDstatusandpretermbirthandlowbirth-weight A potential inverse association between maternal vitamin D status and preterm birth(lessthan37 weeks’ gestation) has been reported. Conversely, not all the studies show significant associations between maternal calcidiol levelsand any measureof the child’s sizeat birth or during the first months of life. There is not much information on maternal vitamin D status and low birth weight or preterm birth in children born from HIV-infected pregnant women. VitaminDstatusandpostnatalgrowth Some observational studies suggest that vitamin D levels during pregnancy influence fetal bone development and children’s growth. While head circumference in children nine years of age has been significantly associated withmaternalcalcidiollevels,thereisstillinconsistentinformationaboutthe association of maternal vitamin D status and infants’ bone mass. It is not clearifmaternalvitaminDdeficiencyleadstoneonatalrickets,sincericketsis usually identified later in childhood. Early studies indicate a possible risk for neonatal rickets in the offspring of women with osteomalacia, abnormal softeningofthebonebydeficiencyofphosphorus,calciumorvitaminD. More recent studies have found that vitamin D deficiency (serum levels lower than 25 nmol/L) was identified in 92% of rachitic (having rickets) Arab children and 97% of their mothers compared with 22% of nonrachitic childrenand 52%of theirmothers.Apositivecorrelationwasfound between maternalandchildvitaminDlevels.
  • 75.
    VITAMIN D INPREGNANCY VitaminDstatusandimmuneresponse Vitamin D has direct effects on both adaptive and innate immune systems. In children, vitamin D insufficiency is linked to autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis, allergies and atopic diseases. Various studies have also shown that vitamin D deficiency is strongly associated with tuberculosis, pneumonia, and cystic fibrosis and both prenatal and perinatal vitamin D deprivation might influence early-life respiratory morbidity as this vitamin is important for lung growth and development.VitaminDmayhavepositiveeffectsontheimmunesystemby up-regulating the production of the antimicrobial peptides by macrophages and endothelial cells which may inactivate viruses and suppress inflammation, andsubsequentlyreducetheseverityofinfections. CochraneDatabaseofSystematicReviews2012,Issue2
  • 76.
    Vitamin D supplementationaffects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. 2013Sep;143(9):1432-8. Unfavorable metabolic profiles and oxidative stress in pregnancy are associated with several complications. This study was conducted to determine the effects of vitamin D supplementation on serum concentrations of high-sensitivity C-reactive protein (hs-CRP), metabolic profiles, and biomarkers of oxidative stress in healthy pregnant women. This randomized, double-blind, placebo-controlled clinical trial was conducted in 48pregnantwomenaged18-40yoldat25wkofgestation.Participantswere randomly assigned to receive either 400 IU/d cholecalciferol supplements (n = 24) or placebo (n = 24) for 9 wk. Fasting blood samples were taken at study baseline and after 9 wk of intervention to quantify serum concentrations of hs-CRP,lipidconcentrations,insulin,andbiomarkersofoxidativestress.After 9 wk of intervention, the increases in serum 25-hydroxyvitamin D and calcium concentrations were greater in the vitamin D group (+3.7 μg/L and +0.20 mg/dL, respectively) than in the placebo group (-1.2 μg/L and -0.12 mg/dL,respectively;P<0.001forboth).VitaminDsupplementationresulted in a significant decrease in serum hs-CRP (vitamin D vs. placebo groups: -1.41 vs. +1.50 μg/mL; P-interaction = 0.01) and insulin concentrations (vitamin D vs. placebo groups: -1.0 vs. +2.6 μIU/mL; P-interaction = 0.04) and a significant increase in the Quantitative Insulin Sensitivity Check Index score (vitamin D vs. placebo groups: +0.02 vs. -0.02; P-interaction = 0.006), plasma total antioxidant capacity (vitamin D vs. placebo groups: +152 vs. -20 mmol/L; P-interaction = 0.002), and total glutathione concentrations (vitamin D vs. placebo groups: +205 vs. -32 μmol/L; P-interaction = 0.02) compared with placebo. Intake of vitamin D supplements led to a significant decrease in fasting plasma glucose (vitamin D vs. placebo groups: -0.65 vs. - 0.12 mmol/L; P-interaction = 0.01), systolic blood pressure (vitamin D vs. placebo groups: -0.2 vs. +5.5 mm Hg; P-interaction = 0.01), and diastolic blood pressure (vitamin D vs. placebo groups: -0.4 vs. +3.1 mm Hg; P- interaction = 0.01) compared with placebo. In conclusion, vitamin D supplementation for 9 wk among pregnant women has beneficial effects on metabolicstatus JNutr.
  • 77.
    Maternal Vitamin DSupplementation to Improve the Vitamin D Status of Breast-fedInfants:ARandomizedControlledTrial. OBJECTIVE: To determine whether a single monthly supplement is as effective as a daily maternal supplement in increasing breast milk vitamin D toachievevitaminDsufficiencyintheirinfants. PATIENTS AND METHODS: Forty mothers with exclusively breast-fed infants wererandomizedtoreceiveoralcholecalciferol(vitaminD3)5000IU/dfor28 days or 150,000 IU once. Maternal serum, breast milk, and urine were collected on days 0, 1, 3, 7, 14, and 28; infant serum was obtained on days 0 and28.EnrollmentoccurredbetweenJanuary7,2011,andJuly29,2011. RESULTS:Inmothersgivendailycholecalciferol,concentrationsofserumand breast milk cholecalciferol attained steady levels of 18 and 8 ng/mL, respectively, from day 3 through 28. In mothers given the single dose, serum and breast milk cholecalciferol peaked at 160 and 40 ng/mL, respectively, at day 1 before rapidly declining. Maternal milk and serum cholecalciferol concentrations were related (r=0.87). Infant mean serum 25-hydroxyvitamin D concentration increased from 17±13 to 39±6 ng/mL in the single-dose group and from 16±12 to 39±12 ng/mL in the daily-dose group (P=.88). All infantsachievedserum25-hydroxyvitaminDconcentrationsofmorethan20 ng/mL. CONCLUSION: Either single-dose or daily-dose cholecalciferol supplementation of mothers provided breast milk concentrations that result invitaminDsufficiencyinbreast-fedinfants. MayoClinProc.2013Dec;88(12):1378-87
  • 78.
    Prevalence of maternalvitamin D deficiency in neonates with delayed hypocalcaemia. ActaMedIran.2012Nov;50(11):740-5. Maternal vitamin D deficiency is one of the major risk factors for neonatal vitamin D deficiency followed by neonatal hypocalcaemia. The aim of this study is to determine the relationship between delayed neonatal hypocalcaemia and maternal vitamin D deficiency. This is a descriptive cross- sectionalstudy.Targetpopulationofthisstudyincludedalltermandpreterm neonates with delayed hypocalcaemia (after the first 72 hours of birth) admitted to Ali-Asghar Hospital. The sample size was 100 neonates included in the study. Demographic, clinical and paraclinical data including Ca, P, PTH and level of maternal and neonatal vitamin D were recorded according to patients records. 67 neonates (67%) were term and 33(33%) were preterm neonates. The mean of serum calcium in neonates was 6.49± 0.68mg/dL (in the range of 4.3-7.8 mg/dL). 85% of neonates and 74% of mothers had vitamin D deficiency. 100% of neonates born to mothers with vitamin D deficiencywerehypocalcaemia.Astatisticallysignificantdifferencewasseen between the mean values of serum Ca (6.67 in term vs. 6.12 in preterm neonates) and vitamin D in term and preterm neonates was 16.34 vs. 20.18 (P= 0.0001 and P=0.01 respectively). Also, a significant correlation was seen between maternal and neonatal level of vitamin D (P=0.0001, r=0.789). With regard to the socio-cultural status in Iran besides women's clothing style and nutritional deficiencies before and during pregnancy, health authorities and policy makers are responsible to focus their serious attention on hypocalcaemiaandhypovitaminosisDinneonates. 85% of neonates and 74% of mothers had vitamin D deficiency. 100% of neonatesborntomotherswithvitaminDdeficiencywerehypocalcaemia.
  • 79.
    Effect of calciumplus vitamin D supplementation during pregnancy in Brazilianadolescentmothers:arandomized,placebo-controlledtrial. AmJClinNutr.2013Jul;98(1):82-91. OBJECTIVE: We investigated the effect of calcium plus vitamin D supplementation during pregnancy on bone mass during lactation in Brazilianadolescentmotherswithlow-calciumdiets(∼600 mg/d). DESIGN: Pregnant adolescents (14-19 y) randomly received daily calcium (600 mg) plus vitamin D3 (200 IU) (n = 30) or a placebo (n = 26) from 26 wk of pregnancy (baseline) until parturition. The bone mineral content (BMC), bone area (BA), and bone mineral density (BMD) at the total body, lumbar spine, and hip (total and femoral neck) were evaluated by using dual-energy X-ray absorptiometry at 5 and 20 wk postpartum. Serum hormones and 25- hydroxyvitamin D [25(OH)D] were measured. Group comparisons were adjustedforsignificantcovariates. RESULTS: The mean serum 25(OH)D concentration was 59 nmol/L at baseline. In comparison with the placebo, 25(OH)D tended to be 14-15 nmol/L higher postpartum in the supplemented group (P = 0.08). Total body and hip BMC and BMD decreased over time (P ≤ 0.005) in both groups with a group × time interaction at the femoral neck (P < 0.04). Supplemented mothers had higherlumbarspineBA(6.7%;P= 0.002)and lumbarspineBMC (7.9%, P = 0.08) than did mothers who consumed the placebo at 5 wk postpartum. At 20 wk postpartum, differences between groups were more evident, with higher lumbar spine BMC (13.9%), lumbar spine BA (6.2%), and lumbarspineBMD(10.6%)inthesupplementedgroup(P≤0.008). CONCLUSIONS: Calcium plus vitamin D supplementation during pregnancy of adolescents with low calcium intake results in higher lumbar spine bone massandareducedrateoffemoralneckbonelossduringlactation.
  • 80.
    Pharmacokinetics of high-doseweekly oral vitamin D3 supplementation duringthethirdtrimesterofpregnancyinDhaka,Bangladesh. Nutrients.2013Mar12;5(3):788-810. A pharmacokinetic study was conducted to assess the biochemical dose- response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka, Bangladesh (23°N). Pregnant women at 27-30 weeks gestation (n = 28) were randomized to 70,000 IU once + 35,000 IU/week vitamin D3 (group PH: pregnant, higher dose) or 14,000 IU/week vitamin D3 (PL: pregnant, lower dose) until delivery. A group of non-pregnant women (n = 16) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks (NH: non-pregnant, higher-dose). Rise (∆) in serum 25-hydroxyvitamin D concentration ([25(OH)D]) above baseline was the primary pharmacokinetic outcome. Baseline mean [25(OH)D] were similar in PH and PL (35 nmol/L vs. 31 nmol/L, p = 0.34). A dose-response effect was observed: ∆[25(OH)D] at modeled steady-state was 19 nmol/L (95% CI, 1 to 37) higher in PH vs. PL (p = 0.044). ∆[25(OH)D] at modeled steady-state was lower in PH versus NH but the difference was not significant (-15 nmol/L, 95% CI -34 to 5; p = 0.13). In PH, 100% attained [25(OH)D] ≥ 50 nmol/L and 90% attained [25(OH)D] ≥ 80 nmol/L; in PL, 89% attained [25(OH)D] ≥ 50 nmol/L but 56% attained [25(OH)D] ≥ 80 nmol/L. Cord [25(OH)D] (n = 23) was slightly higher in PH versusPL(117nmol/Lvs.98nmol/L;p=0.07).VitaminD3waswelltolerated; there were no supplement-related serious adverse clinical events or hypercalcemia. In summary, Further research is required to establish the safety of high- dose vitamin D3 in pregnancy and to determine if supplement-induced [25(OH)D]elevationsleadtomaternal-infanthealthbenefits. a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non- hypercalcemic and attained [25(OH)D] ≥ 80 nmol/L in virtually all mothers and newborns.
  • 81.
    The efficacy andsafety of a high dose of vitamin d in mothers with gestationaldiabetesmellitus:arandomizedcontrolledclinicaltrial. IranJMedSci.2012Sep;37(3):159-65. BACKGROUND: During pregnancy and lactation outstanding changes occur in mother's vitamin D metabolism. This study was carried out to evaluate the efficacy of 300,000 IU vitamin D given intramuscularly on body status in new casesofgestationaldiabetesmellitus(GDM). METHODS: This is a randomized clinical trial with the follow-up period of 3 months. Totally 45 participants were randomly divided into intervention group (IG) and control group (CG). The IG received an IM injection of 300,000 IU of vitamin D, whereas CG did not. The glycosylated hemoglobin A1C (HBA1C), serum 25-OH-D, parathyroid hormone (PTH), serum calcium and phosphorusweremeasured. RESULTS: Forty five patients including 24 with the mean age of 30.7±6.2 years in the IG and 21 with the mean age of 29.5±4.0 years in the CG participated in the study. The median concentration of serum 25(OH)D3 in the IG was to 62.10 nmol/l after the intervention, showing an increase of around 158%, compared to before intervention (24.25 nmol/l) whereas the CG showed a decrease of around 4.5%. Of the patients, 79.2% of IG and 81.9% of CG suffered to some degree from vitamin D deficiency. These figures were 4.2% and 71.4% for the IG and CG, respectively after the intervention.For the IG, the PTH was significantly lower and Ca was significantlyhigheraftertheintervention.TheserumPhosphorusbeforeand after the intervention in each group or between the two groups was not significant. CONCLUSIONS: The single 300,000 IM dose of vitamin D is regarded as an effectiveandsafetopromptlyimprovevitaminDstatusinGDM.
  • 82.
    VITAMIN D INCHILDREN
  • 83.
    VITAMIN D INCHILDREN VITAMIN D IS a prohormone that is essential for normal absorption of calcium from the gut, and deficiency of vitamin D is associated with rickets in growing children. Vitamin D deficiency that presents as hypocalcemic seizures or tetany is reported more frequently in infancy and adolescence thaninchildhood. VitaminDDeficiencyResultingFromPoorMaternalVitaminDStatus In 1 US study, 12% of women 20 to 29 years old (peak childbearing years) had serum 25(OH)-D levels below the accepted threshold of deficiency (37.5 nmol/L [15 ng/mL]), and in another study, vitamin D deficiency was reported to be more common in black (42%) than white (4%) women.137 High rates of vitaminDdeficiencyhavebeenreportedindarker-skinnedpregnantwomen, particularlyinthewintermonthsand athigherlatitudes,140and lowvitamin D levels during pregnancy have been associated with intrauterine growth retardation,prematurelabor,andhypertension,allofwhichincreasetherisk of low birth weight. Indeed black and Asian American mothers have higher rates of low birth weight infants in the United States than do Americans of European or Hispanic descent. Decreased vitamin D levels in the mother resultindecreasedtransplacentaltransferofvitaminDandreducedstoresat birth. Serum 25(OH)-D levels in infants correlate with maternal serum 25(OH)-D. VitaminDDeficiencyResultingFromPrematurity Prematurely born infants have a shorter duration in which to accumulate vitamin D stores from transplacental transfer from the mother and also have a higher requirement for vitamin D than term infants. Therefore, they are more likely to be vitamin D deficient. They have been reported to be more likely to have enamel defects in both primary and permanent teeth, because vitaminDsufficiencyisnecessaryfornormalfetaltoothdevelopment
  • 84.
    VITAMIN D INCHILDREN VitaminDDeficiencyResultingFromExclusiveBreastfeeding Exclusive breastfeeding without sun exposure would provide only 11 to 38 IU/day of vitamin D. It is important to note that the vitamin D content of breast milk varies on the basis of skin color, with lower vitamin D concentrations in breast milk of black compared with white women. Therefore, breastfed infants need to obtain additional vitamin D through eithersunexposureorsupplementation. The current recommendations of the AAP that limit sun exposure for infants 6 months old because of harmful effects on the skin by UV-B radiation make breastfed infants more vulnerable to developing vitamin D deficiency. Exclusive breastfeeding without adequate sun exposure or vitamin D supplementation is an important risk factor for vitamin D deficiency. In a reviewof65clinicalcasesofricketsinchildrenaged2to45monthspublished between 1975 and 1985 in 11 publications, Cosgrove and Dietrich noted that thechildrenwereeitherstillbreastfeedingorwereonamilk-freevegetarian diet at the time of diagnosis. Weisberg et al then reviewed 166 published cases of rickets in children aged 4 to 54 months between 1986 and 2003 in 22 publications and reported that 96% were breastfed. Of the breastfed infants, only 5% were receiving vitamin D supplements. Exclusively breastfed infants born in winter in Wisconsin had mean 25(OH)-D levels of 25 nmol/L (10 ng/mL) at 6 months of age if they were not given any supplements, and 98% of infants in Alaska noted to have 25(OH)-D levels of 62.5 nmol/L (25 ng/mL) were exclusively breastfed. Thus, breastfed infants need to obtain additional vitamin D through supplementation (infant or maternal159,160) or adequatesunexposure. Pediatrics2008;122;398
  • 85.
    Effect of VitaminD Supplementation on Moderate to Severe Bronchial Asthma. IndianJPediatr.2013Nov6. OBJECTIVE: To define the therapeutic role of vitamin D in children with moderatetoseverebronchialasthmaasanadjuncttostandardtreatment. METHODS: Hundred asthmatic children of either sex, attending the respiratory and asthma clinic were enroled in the study. Diagnosis was made on the basis of history and clinical examination. Randomization was done using sealed opaque envelop method. In addition to the treatment as per GINA guidelines, one group received oral vitamin D3 (Cholecalciferol) 60,000 IU per month for 6 mo and the other group received placebo powder in the form of glucose sachet with a double blinded design. Monthly follow up of every patient was done and during every visit change in severity, level of control, Peak expiratory flow rate (PEFR), steroid dosage, number of exacerbationsandnumberofemergencyvisitswereassessed. RESULTS: Monthly doses of 60,000 IU vitamin D significantly reduced the number of exacerbations as compared to placebo (p=0.011). PEFR significantly increased in the treatment group (p=0.000). Monthly doses of vitamin D significantly reduced the requirement of steroids (p=0.013) and emergency visits (p=0.015). Control of asthma was achieved earlier in patients who received monthly vitamin D. Vitamin D significantly reduced thelevelofseverityofasthmapatientsover6mooftreatment(p=0.016). CONCLUSIONS: Vitamin D has a definite role in the management of moderate to severe persistent bronchial asthma as an adjunct to standard treatment.
  • 86.
    The relationship betweenvitamin D status and adrenal insufficiency in criticallyillchildren. JClinEndocrinolMetab.2013May;98(5):E877-81. OBJECTIVE: The aim of the study was to investigate potential relationships between vitamin D status, adrenal status, and cardiovascular dysfunction in criticallyillchildren. DESIGN: We conducted a secondary analysis of data from a prospective cohortstudy. SETTING AND PATIENTS: The study was conducted on 319 children admitted to6Canadiantertiary-carepediatricintensivecareunits. MAIN OUTCOME MEASURES: Vitamin D status was determined through total 25-hydroxyvitamin D (25OHD) levels. AI was defined as a cortisol increment under 9 μg/dL after low-dose cosyntropin. Clinically significant cardiovascular dysfunction was defined as catecholamine requirement duringpediatricintensivecareunitadmission. RESULTS: Using 3 different thresholds to define vitamin D deficiency, no association was found between vitamin D status and AI. Furthermore, linear regression failed to identify a relationship between 25OHD and baseline or post-cosyntropin cortisol. However, the association between AI and cardiovascular dysfunction was influenced by vitamin D status; compared to children with 25OHD above 30 nmol/L, AI in the vitamin D-deficient group was associated with significantly higher odds of catecholamine use (odds ratio,5.29vs1.63;P=.046). CONCLUSIONS: Our results do suggest that vitamin D deficiency exacerbates theeffectofAIoncardiovascularstabilityincriticallyillchildren.
  • 87.
    Impact of anesthesiaand surgery for congenital heart disease on the vitamindstatusofinfantsandchildren:aprospectivelongitudinalstudy. Anesthesiology.2013Jul;119(1):71-80. BACKGROUND: Vitamin D is recognized as a pleiotropic hormone important for the functioning of organ systems, including those central to critical illness pathophysiology. Recent studies have reported associations between vitamin D status and outcome among critically ill adults and children. Preoperative vitamin D status, impact of operative techniques, and relationship between immediate postoperative vitamin D levels and clinical course have not been described in the pediatric congenital heart disease (CHD) population. The objective of this study was to describe the impact of CHD surgery on vitamin D status and relationship between postoperative levelsandclinicalcourse. METHODS: A prospective cohort study was conducted from 2009 to 2011 at a single tertiary care pediatric hospital. A total of 58 children with CHD were enrolled and blood collected preoperatively, intraoperatively, and postoperatively. Serum 25-hydroxyvitamin D (25OHD) was measured using liquidchromatography-massspectrometry. RESULTS: The mean preoperative 25OHD was 58.0 nM (SD, 22.4), with 42% being deficient (<50 nM). Postoperatively, we identified a 40% decline in 25OHD to 34.2 nM (SD, 14.5) with 86% being deficient. Intraoperative measurements determined that initiation of cardiopulmonary bypass coincided with abrupt decline. CHD patients requiring catecholamines had lower postoperative 25OHD (38.2 vs. 26.5 nM, P=0.007), findings confirmed through multivariate logistic regression. Lower postoperative 25OHD was associatedwithincreasedfluidrequirementsandintubationduration. CONCLUSIONS: Most CHD patients are vitamin-D deficient postoperatively due to low preoperative levels and a significant intraoperative decline. Interventional studies will be required to determine whether prevention of postoperativevitaminDdeficiencyimprovesoutcome.
  • 88.
    Correcting vitamin Dinsufficiency improves insulin sensitivity in obese adolescents:arandomizedcontrolledtrial. AmJClinNutr.2013Apr;97(4):774-81. OBJECTIVE:Theobjectivewastodetermineinobeseadolescentstheefficacy and safety of 4000 IU vitamin D3/d and whether subsequent increased circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with improved markers of insulin sensitivity and resistance and reduced inflammation. DESIGN: Obese adolescent patients [n = 35; mean ± SD age: 14.1 ± 2.8 y; BMI (in kg/m(2)): 39.8 ± 6.1; 25(OH)D: 19.6 ± 7.1 ng/mL] were recruited from the University of Missouri Adolescent Diabetes and Obesity Clinic and were randomly assigned to receive either vitamin D3 (4000 IU/d) or placebo as part of their standard care. Anthropometric measurements, inflammatory markers (IL-6, TNF-α, C-reactive protein), adipokines (leptin, adiponectin), fasting glucose, fasting insulin, and HOMA-IR values were measured at baselineandat2follow-upvisits(3and6mo). RESULTS: After 6 mo, there were no significant differences in BMI, serum inflammatory markers, or plasma glucose concentrations between groups. Participants supplemented with vitamin D3 had increases in serum 25(OH)D concentrations (19.5 compared with 2.8 ng/mL for placebo; P < 0.001), fasting insulin (-6.5 compared with +1.2 μU/mL for placebo; P = 0.026), HOMA-IR (-1.363compared with +0.27for placebo;P = 0.033),and leptin-to- adiponectin ratio (-1.41 compared with +0.10 for placebo; P = 0.045). Inflammatorymarkersremainedunchanged. CONCLUSION: The correction of poor vitamin D status through dietary supplementation may be an effective addition to the standard treatment of obesityanditsassociatedinsulinresistance.
  • 89.
    VitaminDinsufficiencyandeffectofcholecalciferolinchildrenwithchronic kidneydisease. PediatrNephrol.2010Dec;25(12):2483-8. Vitamin D insufficiencyis common in patients with chronic kidney disease (CKD) and may contribute to mineral bone disease. In a prospective interventional study, we estimated the prevalence of vitamin D insufficiency (serum 25-hydroxyvitamin D3 [25OHD] < 30 ng/ml), and examined the effect of high-dose (600,000 IU) cholecalciferol supplementation after 6 weeks on serum 25OHD and parathyroid hormone (PTH) levels in children with CKD stages 2-4. Forty-two children (86% boys) with a mean age of 7.7±3.8 (range 2--5) years were studied. Thirty-seven children (82.1%) had vitamin D insufficiency; 18 (42.8%) had 25OHD < 16 ng/ml. The median 25OHD increased significantly from 16.7 (95% CI 11.3, 19.8) to 46.2 (34.5, 44.6) ng/ml in patients with vitamin D insufficiency (P <0.001). The median PTH decreased significantly from 51.3 (95% CI 46.7, 71.5) to 37.1 (29.0, 54.6) pg/ml (P=0.003). Nineteen patients (47.5%) had >30% reduction in the PTH after supplementation. Serum calcium, phosphorus, and estimated GFR did not change significantly. We conclude that vitamin D insufficiency is highly prevalent in children with CKD stages 2-4. High-dose cholecalciferol is safe and effective in correcting vitamin D insufficiency and results in a significant reductioninPTHlevelsinvitaminD-insufficientchildren.
  • 90.
    GIST OF CLINICALSTUDIES ON VITAMIN D
  • 91.
    VITAMIN D ONANTIBIOTIC USE BACKGROUND: Observational data suggested that supplementation with vitaminDcouldreduceriskofinfection,buttrialdataareinconsistent. OBJECTIVE: We aimed to examine the effect of oral vitamin D supplementationonantibioticuse. DESIGN:WeconductedaposthocanalysisofdatafrompilotD-Health,which is a randomized trial carried out in a general community setting between October2010andFebruary2012.Atotalof644Australianresidentsaged60- 84 y were randomly assigned to receive monthly doses of a placebo (n = 214) or 30,000 (n = 215) or 60,000 (n = 215) IU oral cholecalciferol for ≤ 12 mo. Antibiotics prescribed during the intervention period were ascertained by linkage with pharmacy records through the national health insurance scheme(MedicareAustralia). RESULTS: People who were randomly assigned 60,000 IU cholecalciferol had nonsignificant 28% lower risk of having antibiotics prescribed at least once than did people in the placebo group (RR: 0.72; 95% CI: 0.48, 1.07). In analyses stratified by age, in subjects aged ≥ 70 y, there was a significant reductioninantibioticuseinthehigh-dosevitaminDcomparedwithplacebo groups (RR: 0.53; 95% CI: 0.32, 0.90), whereas there was no effect in participants<70yold(RR:1.07;95%CI:0.58,1.97)(P-interaction=0.1). CONCLUSION: Although this study was a post hoc analysis and statistically non-significant, this trial lends some support to the hypothesis that supplementation with 60,000 IU vitamin D/mo is associated with lower risk ofinfection,particularlyinolderadults. AmJClinNutr.2013Oct9.
  • 92.
    VITAMIN D ANDPNEUMONIA BACKGROUND: Vitamin D has been suggested to have a role in infection defence and on the immune system. We therefore investigated the effect of serum 25-hydroxyvitamin D₃ (25(OH)D₃) on the risk of incident hospitalised pneumoniainanageinggeneralpopulationineasternFinland. METHODS: The study population included 723 men and 698 women aged 53-73 years from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor study who were free of pneumonia, other pulmonary diseases and cancer at baseline in 1998-2001. Incident pneumonia episodes leading to hospitalisation were collected by record linkage to the hospital discharge register. The serum vitamin D status was assayed as 25(OH)D₃ concentration. Cox proportional hazards regression models were used to analysetheeffectofserum25(OH)D₃ontheriskofincidentpneumonia. RESULTS: The mean (SD) serum 25(OH)D₃ concentration of the study population was 43.5 (17.8) nmol/l. 73 subjects had at least one hospitalisationepisodeduetopneumoniaduringanaveragefollow-upof9.8 years. After multivariable adjustments, the subjects in the lowest serum 25(OH)D₃ tertile had a 2.6-fold (95% CI 1.4 to 5.0, p trend across tertiles=0.005) higher risk of developing pneumonia compared with the subjects in the highest tertile. This significant result remained even after adjustmentforthedeterminantsofserum25-hydroxyvitaminD₃. CONCLUSIONS: These data suggest an inverse effect of serum 25(OH)D₃ concentration on the risk of incident pneumonia in the general ageing population. JEpidemiolCommunityHealth.2013Jun;67(6):533-6.
  • 93.
    VITAMIN D ANDHEART DISEASES MI risk doubles in patients with 25OHVitD levels < 34ng/ml Scragg et al. Int J Epidemiol. 1990;19(3):559. CHF patients have much lower 25OH Vitamin D levels than controls Zitterman et al. J Am Coll Cardiol. 2003;41:105. Deaths from CAD more common in winter Scragg. Int J Epidemiol. 1981;10(4):337. MI risk doubles in patients with 25OH Vitamin D levels < 34ng/ml Scragg et al. Int J Epidemiol. 1990;19(3):559. CHF patients have much lower 25OHVitD levels than controls Zitterman et al. J Am Coll Cardiol. 2003;41:105. Deaths from CAD more common in winter Scragg. Int J Epidemiol. 1981;10(4):337. 25-(OH)D < 10 ng/mL - 80% greater risk of having a cardiovascular incident 25 (OH)D of 10-15 ng/mL - 53% increased risk Circulation 2008;117:503-51
  • 94.
    VITAMIN D ANDHYPERTENSION BP higher in winter BP higher with increasing latitude BP higher with darker skin pigmentation Hypertensive patinets given UV light treatments 3 times per week for 6 weeks had Vitamin D level increases of 162% and saw mild decreases in BP Krause et al. Lancet. 1998;352(9129):709. Small doses of Vit D (800iu) for 8 weeks decreased BP and pulse rate Pfeifer et al. J Clin Endocrinol Metab. 2001;86(4):258 BP is reduced significantly by ultraviolet radiation comparable to about oral intake of 3,000 IU of vitamin D a day Krause R, Bohring M, Hopfenmhller W, Holick MF, Sharma AM: Ultraviolet B and blood pressure. Lancet. 1998;352:709-710 BP not routinely reduced by small amounts of vitamin D Scragg R, Khaw KT, Murphy S: Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults. European Journal of Clinical Nutrition. 1995;49:640-646
  • 95.
    VITAMIN D ANDDIABETES TYPE 1 DIABETES Study in > 10,000 people shows that supplementation of infants and children withVitaminD2000iu/daydecreasedincidenceofDMtype1by80% Hypponenetal.Lancet.2001;358(9292):1500. CodliverstudiesalsoshowsignificantreductionofincidenceofTypeIDM TYPE 2 DIABETES LowVitaminDlevelsassocwithinsulinresistanceandBeta-celldysfunction Postprandial glucose and insulin sensitivity is better in healthy adults with highestVitDlevels Chiu.AmJClinNutr.2004;79:820. Metformin improves insulin sensitivity by 13% and highest Vitamin D levels associatedwith60%improvementininsulinsensitivity Chiu.AmJClinNutr.2004;79:820. Small trial of 10 women with DM Type 2 with Vitamin D 1332iu per day x 30 daysshows21%increaseininsulinsensitivity Borrisovaetal.IntJClinPract.2003;57(4):258.
  • 96.
    VITAMIN D ANDPAIN Studywith150ptswithpersistent,nonspecificmusculoskeletalpainatMayo clinicshowsthat93%hadVitaminDdeficiency Plotnikoff,Quigley.MayoClinProc.2003;78(12):1463. LOW BACK PAIN 83%of299LBPptshadVitDdef 5000-10,000iu/day decreases the pain medication in nearly 100% after 3 months AlFaraj,AlMutairi.Spine2003;28(2):177.
  • 97.
    VITAMIN D ANDAUTOIMMUNE DISEASES VITAMIN DINSUFFICIENCY IS SHOWN IN: 50%ofpatientswithfibromyalgia+SLE Huismanetal.JRheumatol.2001;28(11):2535. 58%JapaneseFemaleswithGravesDisease Yamashitaetal.EndocrJ.2001;48(1):63. 73%Austrianptsw/AnkylosingSpondylitis Falkenbachetal.WienKlinWochenschr.2001;113(9):328
  • 98.
    VITAMIN D ANDCANCER Vitamin D levels inversely correlated to colon cancer mortality (but not to all cancermortality) Freedmanetal.JNatlCancerInst.2007.99(21):1563. In 47,800 men over 14 years , 10 ng/ml rise in Vitamin D level of associated with 17%reductionincancerincidence 29%reductioninallcancermortality 45%reductioninGIcancermortality Giovanucchietal.JNatlCancerInst.2006.98(7):428. Long-term study of 50,000 men at Harvard School of Public Health suggests vitaminDmayreducetheriskofallcancersbyatleast30percent. Giovannucci.JNatlCancerInst.2006Apr5:98(7):428. Decreased sunlight assoc with increased cancer mortality Breast, colon, cancer, prostate, bladder, esophagus, kidney, lung, pancreas, rectum, stomach,uterus,non-Hodgkin’sLymphoma Grant.Cancer.2002;94(6):1867.
  • 99.
    VITAMIN D ANDFALLS IN ELDERLY VitaminDreceptorsinskeletalmuscle BischoffHA,etal.HistochemJ2001;33:19. Vitamin D deficiency reported to affect predominantly the weight-bearing antigravity muscles of the lower limb, which are necessary for postural balanceandwalking GlerupHetal.CalcifTissueInt2000;66:419. Significant correlation between serum 25(OH)D3 concentration and the occurrenceoffallsinelderlyreportedinliterature. MowéMetal.JAmGeriatrSoc1999;47:220 &SteinMSetal.JAmGeriatrSoc1999;47:1195 STOP/IT(SitesTestingOsteoporosisPreventionandInterventionTreatments) trial evaluated 489 women randomly assigned to receive estrogen, Vitamin D,bothestrogenandVitaminD,oraplacebofor3years. TheincreaseinbonedensitywastwiceaslargewithestrogenaswithVitamin D. The subjects with Vitamin D had fewer fractures from falls than did the group whotookestrogen(oddsratio:0.78and0.94,respectively). ImprovementinlowerextremitymusclestrengthandbalancewithVitaminD supplementation thought to explain the reduced number of fall-related fractures. Dawson-Hughesetal. NEnglJMed1997;337:670
  • 100.
    VITAMIN D ANDLONGEVITY Meta-analysis of 18 RCTs – 57,311 patients with a daily intake of Vitamin D (300-2000iu/day) Highestintake–7%reductioninall-causemortality Based on the total body of evidence of health conditions associated with Vitamin D deficiency, abetted with the results from this meta-analysis, a more proactive attitude to identify, prevent and treat Vitamin D deficiency shouldbepartofstandardmedicalcare. Giovannuchi.ArchInternMed.2007;167:1709-1710.
  • 101.
  • 102.
    EUROPEAN JOURNAL OFENDOCRINOLOGY
  • 103.
    BASED ON NHSGUIDELINES
  • 104.
    AMERICAN ACADEMY OFPEDIATRICS RECOMMENDATIONS Treating infants and children who are vitamin D insufficient or deficient with 1000IU/dayofvitaminDforinfants1monthold. 1000to5000IU/dayforchildren1to12monthsold 5000IU/dayforchildren12monthsold. Vitamin D levels should subsequently be maintained with 400 IU of vitamin D supplementationperday. For patients who demonstrate poor compliance, a high dose of vitamin D may be given as a single dose or repeated intermittently. It is important to recognizethatsimultaneouscalciumsupplementationisnecessarybecause of the risk of hypocalcemia from decreased demineralization of bone and increased remineralization as PTH levels normalize, symptomatic hypocalcemia requires parenteral calcium replacement, and calcitriol and dihydrotachysterol can help treat hypocalcemia associated with rickets but donotbuildupvitaminDstores.
  • 105.
    KING EDWARD MEMORIALHOSPITAL & PRINCESS MARGARET HOSPITAL PERTH, WEST AUSTRALIA, RECOMMENDATIONS All infants born < 35 weeks who are tolerating full enteral feeds, Cholecalciferol solution 400 -500 units (0.1mL) ONCE daily with milk or formulafeeduntildischarge. ForbreastfedbabiesofVitaminDdeficientmothers MildmaternalvitaminDdeficiency(25-50nmol/L) VitaminD400unitsDAILYuntil12monthsofage ModeratetoseverematernalvitaminDdeficiency(<25nmol/L) Cholecalciferol800-1000unitsDAILYfor3monthsand400unitsdailyuntil12 monthsofage American Society for Bone and Mineral Research concludes that vitamin D supplementation of 4000IU/d for pregnant women is safe and most effective inachievingsufficiencyinallwomenandtheirneonatesregardlessofrace
  • 106.
    Large, Single-Dose, OralVitamin D Supplementation in Adult Populations: ASystematicReview. OBJECTIVE: Daily supplementation is often inadequate in treating vitamin D deficiency due to poor compliance. A single, large dose of vitamin D given at timedintervalsmaybeanalternativestrategy. METHODS: We identified 2243 articles in PUBMED using the terms "high dose vitamin D," "single dose vitamin D," "bolus vitamin D," or "annual dose vitamin D." Review articles, cross-sectional studies, non-human studies, responses to other articles, and non-English articles were excluded. Manuscripts were also excluded if the study: (1) did not use oral cholecalciferol or ergocalciferol, (2) used vitamin D analogs, (3) enrolled participants under age 18, (4) administered doses <100,000 IU (2.5 mg), or (5)administered>1doseperyear.Referencesofeligiblemanuscriptsandthe Cochrane databases were also searched. Two independent reviewers identified eligible manuscripts, and a third reviewer evaluated disagreements.Thirtymanuscriptswereselectedusingthesecriteria. RESULTS: Large, single doses of vitamin D consistently increased serum 25- hydroxyvitamin D (25(OH)D) concentrations in several vitamin D sufficient and deficient populations. Vitamin D3 doses of 300,000 IU or greater providedoptimalchangesinserum25(OH)Dandparathyroidhormone(PTH) concentrations. Vitamin D supplementation also impacted bone health and extra-skeletalendpoints. CONCLUSIONS: This review recommends vitamin D3 be used for supplementation over vitamin D2, and that single vitamin D3 doses of 300,000 IU and greater are most effective at improving vitamin D status and suppressing PTH concentrations for up to 3 months. Lower doses, however, may be sufficient in certain populations. Vitamin D doses >500,000 IU should beusedjudiciouslyinordertominimizeadverseevents. EndocrPract.2013Nov18:1-36.
  • 107.
    Effect of twodifferent doses of oral cholecalciferol supplementation on serum 25-hydroxy-vitamin D levels in healthy Indian postmenopausal women:Arandomizedcontrolledtrial. AIM: To compare the effect of two different doses (500 and 1000 IU/day) of oral vitamin D3 (cholecalciferol) on serum 25-hydroxy vitamin D [25(OH)D] levelsinapparentlyhealthypostmenopausalIndianwomen. MATERIALS AND METHODS: Serum 25(OH)D, calcium with albumin, phosphorus, and alkaline phosphatase were measured in 92 apparently healthy postmenopausal women. The subjects were randomly assigned to one of the three groups and received supplementation for 3 months each. Each group received 1000 mg calcium carbonate daily while groups B and C received 500 and 1000 IU of cholecalciferol in addition, respectively. The testswererepeatedafter3months. RESULTS: At baseline, 83.7% subjects had vitamin D deficiency (≤20 ng/mL). The difference in the percentage change in mean serum 25(OH)D levels from baseline in group A (-30.5 ± 5.3%), group B (+8.9 ± 19.7%), and in group C (+97.8 ± 53.3%) was statistically significant (P < 0.001) between the three groups. Serum 25(OH)D level >20 ng/mL was achieved in 4.7% (1/21), 16% (4/25), and 66.67% (12/18) subjects in groups A, B, and C, respectively. No significant change was found in serum calcium, phosphorus, and alkaline phosphataselevelsat3monthsineitherofthegroupsfrombaseline. CONCLUSIONS: Standard dose of cholecalciferol available in "calcium tablets" (250 IU per 500 mg calcium carbonate) is not adequate for achieving optimum serum 25(OH)D levels in Indian postmenopausal women. Higher dose of vitamin D supplementation with 1000 IU/day (500 IU per 500 mg calcium carbonate) daily is superior to the standard dose therapy. For achievement of optimum serum 25(OH)D levels (>30 ng/mL) in Indian postmenopausal women, still higher doses of vitamin D are likely to be required. IndianJEndocrinolMetab.2013Sep;17(5):883-9.
  • 108.
    25-hydroxyvitamin D Responseto Graded Vitamin D3 Supplementation AmongObeseAdults. OBJECTIVE: The purpose of this study was to characterize the pharmacokinetics of 25(OH)D response to 3 different doses of vitamin D3 (cholecalciferol) in a group of obese subjects and to quantify the 25(OH)D dose response relationship.Design, Setting, Intervention, Patients:This was a randomized, single blind study of 3 doses of oral vitamin D3 (1,000 IU, 5,000 IU, or 10,000 IU) given daily to 67 obese subjects for 21 weeks during the wintermonths. MAIN OUTCOME MEASURES: Serum 25(OH)D levels were measured at baseline and after vitamin D replacement, and 25(OH)D pharmacokinetic parameters were determined, fitting the 25(OH)D concentrations to an exponential model.Results:Mean measured increments in 25(OH)D at week 21 were: 12.4- (SD 9.7) ng/ml in the 1,000 IU/d group, 27.8 (SD10.2) ng/mL in the 5,000 IU/d group, and 48.1(SD 19.6) ng/ml in the 10,000 IU/d group. Steady state increments computed from the model were 20.6 (SD 17.1) ng/ml, 35.2 (SD 14.6) ng/ml, and 51.3 (SD 22.0) ng/ml, respectively. There were no hypercalcuriaorhypercalcemiaeventsduringthestudy. CONCLUSION: Our data show that in obese people the 25(OH)D response to vitaminD3isdirectlyrelatedtodoseandbodysizewith2.5IU/kgrequiredfor everyunitincrementin25(OH)D(ng/ml). JClinEndocrinolMetab.2013Sep13.
  • 109.
    Effect of differentdosages of oral vitamin D supplementation on vitamin D statusinhealthy,breastfedinfants:arandomizedtrial. 2013May1;309(17):1785-92. OBJECTIVE: To investigate the efficacy of different dosages of vitamin D in supporting25(OH)Dconcentrationsininfants. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial conducted among 132 one-month-old healthy, term, breastfed infants from Montréal, Québec, Canada, between March 2007 and August 2010. Infants were followed up for 11 months ending August 2011 (74% completed study). INTERVENTION: Participants were randomly assigned to receive oral cholecalciferol (vitamin D3) supplements of 400 IU/d (n=39), 800 IU/d (n=39),1200IU/d(n=38),or1600IU/d(n=16). MAIN OUTCOMES AND MEASURES: The primary outcome was a plasma 25(OH)D concentration of 75 nmol/L or greater in 97.5% of infants at 3 months. Secondary outcomes included 25(OH)D concentrations of 75 nmol/L or greater in 97.5% of infants at 6, 9, and 12 months; 25(OH)D concentrations of 50 nmol/L or greater across all times; growth; and whole body and regional bone mineral content. Data were analyzed by intention to treat using available data, logistic regression, and mixed-model analysis of variance. RESULTS: By 3 months, 55% (95% CI, 38%-72%) of infants in the 400-IU/d groupachieveda25(OH)Dconcentrationof75nmol/Lorgreatervs81%(95% CI,65%-91%)inthe800-IU/dgroup,92%(95%CI,77%-98%)inthe1200-IU/d group, and 100% in the 1600-IU/d group. This concentration was not sustained in 97.5% of infants at 12 months in any of the groups. The 1600- IU/d dosage was discontinued prematurely because of elevated plasma 25(OH)D concentrations. All dosages established 25(OH)D concentrations of 50 nmol/L or greater in 97% (95% CI, 94%-100%) of infants at 3 months and sustained this in 98% (95% CI, 94%-100%) to 12 months. Growth and bone mineralcontentdidnotdifferbydosage. JAMA.
  • 110.
    CONCLUSIONS AND RELEVANCE:Among healthy, term, breastfed infants, only a vitamin D supplement dosage of 1600 IU/d (but not dosages of 400, 800, or 1200 IU/d) increased plasma 25(OH)D concentration to 75 nmol/L or greater in 97.5% of infants at 3 months. However, this dosage increased 25(OH)D concentrations to levels that have been associated with hypercalcemia.
  • 111.
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