Journal of the American Dietetic Association Volume 106 issue 3 2006 [doi 10.1016_j.jada.2005.12.009] Barbara L. Mark; Jo Ann S. Carson -- Vitamin D and Autoimmune Disease—Implications for Practice | Vitamin D | Vitamin

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  RESEARCH Perspectives in Practice  Vitamin D and Autoimmune Disease—Implications for Practice from the MultipleSclerosis Literature BARBARA L. MARK, PhD, RD; JO ANN S. CARSON, PhD, RD ABSTRACT Recent studies and commentaries link vitamin D withseveral autoimmune diseases, including multiple sclero-sis (MS). Adequate vitamin D intake reduces inflamma-tory cytokines through control of gene expression, thusinadequate vitamin D intake is suggested as a mecha-nism that could contribute to inflammation and, conse-quently, development of MS. Poor vitamin D status hasbeen associated with increased risk for development of MS, and patients with MS may suffer consequences of  vitamin D deficiency, such as bone loss. Animal studiesand very limited human data suggest possible benefitfrom vitamin D supplementation in patients with MS.Based on the current state of research, a key principlefor practicing dietetics professionals is to include vita-min D status in nutritional assessment. For those atrisk for poor vitamin D status, intake can be enhancedby food-based advice and, when indicated, vitamin Dsupplementation.  J Am Diet Assoc. 2006;106:418-424. A s translators of nutrition science, dietetics profes-sionals should be attuned to the latest insights intointeraction of genes and the nutritional environ-ment. Current research points to a role of vitamin D inregulation of gene expression and production of cytokinesthat could thwart autoimmune diseases. Dietetics profes-sionals should consider vitamin D carefully in nutritionalassessment and when advising the public. This articlefocuses on the link between vitamin D and multiple scle-rosis (MS) and presents implications for dietetics prac-tice. VITAMIN D METABOLISM  Vitamin D status is influenced by both exposure to sunlight and vitamin D content of the diet (Table 1) (1,2). Skin sebaceousglandsproduce7-dehydrocholesterol,whichuponultraviolet (UV) B irradiation becomes cholecalciferol or vitaminD-3andiscarriedinthebloodbyvitaminDbinding protein.DietaryvitaminDisprovidedprimarilybyvitaminD–fortified milk and fish, as shown in Table 1. As a fat- soluble vitamin, dietary vitamin D is absorbed in the smallintestineandcarriedinthebloodbychylomicrons.Whetherits srcin was diet or UV synthesis, vitamin D is first trans-portedtotheliver,whereitishydroxylated,andthentothekidney, where a second hydroxylation results in the activeform, 1,25-dihydroxyvitamin D, also known as calcitriol (3). Formation of the active molecule is inhibited by severalconditions: high plasma concentrations of calcitriol, cal-cium, and phosphorus; absence of parathyroid hormone;and kidney disease (1,4). Under normal conditions, only small amounts of the dihydroxy compound are found incirculation, thus vitamin D status is typically assessed us-ing serum 25-hydroxyvitamin D levels (5). The Dietary Ref- erence Intakes describes the normal range as 8 ng/mL (20nmol/L) to 15 ng/mL (37.5 nmol/L) (5).  At a cellular level, 1,25-dihydroxyvitamin D binds to aplasma membrane receptor, resulting in second messengersignaling within the cell. It also acts as a fat-soluble hor-mone. Its hormone action occurs when 1,25-dihydroxyvita-min D complexes in the cytoplasm with the vitamin Dreceptor and the retinoid X receptor and is transportedthrough the cytoplasm and across the nuclear membrane.The hormone-receptor complex then binds to DNA, regulat-ing gene expression for different proteins, such as osteocal-cin, which fosters bone formation, and cytokines that mod-ulate the immune system (6-10). By regulating production ofcytokines,vitaminDcanaffectinflammation,ahallmarkof active autoimmune disease. For instance, by regulating transcription of interleukin-12, 1,25-dihydroxyvitamin Dcan inhibit secretion of interferon-   , reducing an inflamma-tory response (6,11). The role of calcitriol in regulation of  gene expression also affects cellular differentiation and pro-liferation; preliminary evidence suggests a role in reducing malignancy (12). VITAMIN D SOURCES AND RECOMMENDED INTAKE  According to the current Dietary Reference Intakes, the Adequate Intake (AI) for vitamin D is between 5   g and15   g per day (depending on age, sex, pregnancy, andlactation), assuming insufficient sun exposure (5). As 1  g equals 40 IU of vitamin D, intake goals are 5  g or 200  B. L. Mark is an instructor and J. A. S. Carson is a professor, Department of Clinical Nutrition, Universityof Texas Southwestern Medical Center at Dallas. Address correspondence to: Barbara L. Mark, PhD, RD, Department of Clinical Nutrition, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines, Dallas, TX 75390-8877. E-mail: barbara.mark@utsouthwestern.eduCopyright © 2006 by the American Dietetic Association.0002-8223/06/10603-0010$32.00/0doi: 10.1016/j.jada.2005.12.009 418  Journal of the AMERICAN DIETETIC ASSOCIATION  ©   2006 by the American Dietetic Association  IU for adults, 10   g or 400 IU for adults 51 to 70, and 15  g or 600 IU for those over 70 years of age. In contrast tothe AI, information on the nutrition label is based on therecommended daily intake of 400 IU per day. Some re-searchers suggest increasing the daily intake from 5 to 15  g per day up to 20 or 25  g per day to reach serum levelsof 25-hydroxyvitamin D of 28 ng/mL (70 nmol/L)(6,13,14). Analysis of data from the Third National Health and Nutrition Examination Survey 1988-1994and from the Continuing Survey of Food Intakes by In-dividuals (CSFII 1994-1996, 1998) reveals that mean vi-tamin D intake for US men reaches the AI of 5  g per day,but the average intake for US women reaches the AI onlywhen supplements are included (15). VITAMIN D INTAKE AND RISK OF MS MS is an autoimmune disease in which the body makesautoantibodies against the myelin sheaths surrounding neuron axons, destroying the nerve insulation and thusnerve transmission. Emerging evidence f or the role of vita-min D in MS has been reviewed recently (16,17). Interest in  vitamin D and MS srcinated from identification of a nega-tive correlation between exposure to sunlight and preva-lenceofMS.Attheequator,whereonereceivesthemostUV irradiation over time, MS occurrence is near 0%. The prev-alence significantly increases to 50 cases per million peopleat 45° north or south of the equator (halfway to the NorthPolefromtheequator).IntheUnitedStates,thisfallsinthe vicinity of Wisconsin or Michigan. The body synthesizes vitamin D from sunlight in northern latitudes at a lesserrate than it does in latitudes near the equator. Thus, theprevalence of MS parallels the reduction in sunlig ht expo-sure and potential for vitamin D production (18,19). Epidemiological data also associate poor dietary vitaminD with incidence of MS. Food frequency questionnaires(FFQs), administered every 4 years to almost 200,000women in the Nurses’ Health Study (followed for 20 years)and the Nurses’ Health Study II (followed for 10 years),were assessed for vitamin D intake from food and supple-ments. Because amounts of vitamin D in supplements werenot available, daily supplementation with 400 IU was as-sumed if supplements were reported. Plasma levels of 25-hydroxyvitamin D were also obtained. Those women in thehighestquintileofvitaminDintake(599to714IU/day)hada mean plasma 25-hydroxyvitamin D concentration of 30ng/mL (75 nmol/L), while those in the lowest quintile (87 to135 IU/day) had a mean 25-hydroxyvitamin D concentra-tionof22ng/mL(55nmol/L).Womeninthehighestquintilefor intake of vitamin D were more likely to take multivita-min-mineral supplements and less likely to smoke thanwomen in the lowest quintile, confounding results to someextent, because other nutrients may contribute to diseasestatus. MS was reported by 173 participants post baseline.Based on combined diet and supplement intake, a 40%reduced risk of MS was found among women in the highestquintile of vitamin D intake compared with those in thelowest quintile. When analyzed separately, vitamin D sup-plementation, but not vitamin D from food alone, showed aconsiderable relationship with MS incidence (20). This lack of association from diet alone may be a result of the diffi-culty in accurately capturing dietary intake of vitamin D byuseofFFQorperhapsbecauseofasmallerrangeofvitaminD intake based on diet alone. Although validity of the FFQwas supported by correlation of FFQ data with analysis of food records in a subgroup of participants, as well as lowerplasma 25-hydroxyvitamin D levels among those in thelowest quintile of vitamin D intake, others have raisedquestions regarding this study’s analyses (21).  Another observation of vitamin D intake and MS comesfrom a 1952 study of regions in Norway, where vitamin Dsynthesis from UV irradiation is limited. Intake wasbased on measurement of food entering homes in selectedcoastal and inland locations. Among the residents inlower economic coastal locations, where intake of foodsrich in vitamin D was high (cod liver oil and herring), fewcases of MS occurred. Incidence of MS increased inland,where farming and dairy provide good income, and thusdiets were high in dairy fats and low in good sources of  vitamin D (18,22). An MS incidence ratio of 4.1:1.2 was determined when comparing inland to coastal regions. VITAMIN D IN MS PATIENTSVitamin D Status and Bone Loss in MS  Although vitamin D has been associated with developmentofMS,onceadiagnosisofMShasbeenestablished,vitamin Table 1.  Sample of sources of vitamin D a SourcePer CommonServing SizeIU   g b Dairy foods Milk, whole, fortified, 1 cup 99 2.5Edam cheese, 1 oz 10 0.3Parmesan cheese (hard), 1 oz 8 0.2Swiss cheese, 1 oz 12 0.3 Eggs and soy Egg, whole fresh chicken, 1 large 17 0.4Soy milk, fortified, 1 cup 100 2.5 Seafood Fish oil, cod liver, 1 Tbsp 1,360 34Mackerel, Atlantic, canned in oil, 3 oz 205 5.1Herring, pickled, 3 oz 612 15.3Salmon, canned pink, 3 oz 562 14.0Sardines, canned in oil, drained solidswith bone 77 1.9Oysters, 3 oz 320 8.0Shrimp, 3 oz 137 3.4 Meat Braunschweiger, 1 oz 12 0.3Olive loaf, 1 oz 12 0.3Salami, Cotto beef, 1 oz 14 0.3 Vegetables Mushrooms, shiitake, dried, 4mushrooms 249 6.2 a Data from: US Department of Agriculture. National Nutrient Database for Standard Refer-ence, version 17. Available at: http://www.ars.usda.gov/fnic/foodcomp/search/index.html. Accessed February 28, 2005. Provisional table on the vitamin D content of foods. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/Other/vit_d99.pdf. Accessed February 28, 2005. b Micrograms, 40 IU  1   g. March 2006  ●  Journal of the AMERICAN DIETETIC ASSOCIATION  419  D status continues to be of concern. Increased prevalence of clinical vitamin D deficiency and decreased bone mineraldensity have been reported in a cross-sectional study of  vitamin D status in MS. The majority (80%) of patients in aNew York group of 80 women with MS had dietary vitaminD intake below the recommended amount, with about onefourth of the women having a serum 25-hydroxyvitamin Dlevel below 10 ng/mL (25 nmol/L) (23). Among  men with MS, 37.5% had low serum 25-hydroxyvitamin D (24). Dual x-rayabsorptiometryscansinNewYork(23,24)andTurkey (25) reported lower bone density among MS patients com- pared with control subjects. Among  the New York maleswith MS, 37.5% had osteoporosis (24). Bone health of MS patients can be especially compro-mised by glucocorticoids, frequently a part of the treatmentregimen.Onestudyof71femalepatientswithage-matchedcontrols considered glucocorticoid use, immobilization, vita-min D deficiency, and muscle atrophy in relation to bonehealth. Compared to controls, nonambulatory patients withMS had significantly decreased total bone mineral content(  0.6  0.1 [mean  standard deviation];  P  0.01) and fat-free mass (  0.6  0.1 [mean  standard deviation];  P  0.01). Ambulatory MS patients fared better, but still had re-duced bone mass because of decreased physical acti vityand loss of muscle mass from glucocorticoid use (26). In another study, approximately 50 MS patients withmatched controls were followed for 2 years for vitamin Dstatus and the occurrence of fractures and bone loss. MSpatients had significantly higher occurrence of fracturesthan controls (22% vs 2%) and greater bone loss in thefemoral head (3% to 6% per year vs 0.5% to 0.8% forwomen, 7.3% per year vs 1.6% for men). Spine bone losswas more rapid among the MS patients with lower (  20ng/mL [  50 nmol/L]) 25-hydroxyvitamin D levels. Theauthors conclude that patients might reduce the rate of bone loss and fractures with adequate vitamin D (27). Cytokine Profiles of MS Patients In addition to bone abnormalities, MS patients typicallydisplay immune parameters consistent with limited vita-min D activity available to influence gene expression of cytokines. Cytokines are proteins used as a source of communication between immune system cells and cells of other organ systems. Most importantly, cytokines canconsiderably enhance or attenuate an inflammatory re-sponse. Cytokines are typically out of balance in patientswith autoimmune disease, with proinflammatory cyto-kines high and anti-inflammatory cytokines low. Thus,compared with a healthy person, MS patients have in-creased levels of inflammatory cytokines (eg, interleu-kin-2, tumor necrosis factor-  , and interferon-   ), as wellas lower levels of some anti-inflammatory cytokines (28-31). This imbalance of cytokines in patients with autoim-mune disease manifests in disease symptoms related toinflammation. By enhancing the vitamin D status of MSpatients, it may be possible for vitamin D to affect thegene expression of these cytokines and alleviate diseasesymptoms. However, disease manifestation may not onlybe related to poor vitamin D intake and exposure tosunlight. Among genetic variation, changes in the genefor the vitamin D receptor may reduce the action of vita-min D in gene regulation. Polymorphisms in certaingenes, such as the gene for the vitamin D receptor, havebeen associated with greater likelihood of MS (32-35). For example, in Japan when 77 MS patients were comparedwith 95 controls, the MS patients had a significantly higherincidence (  P  0.007) of an  Apa I restriction fragment lengthpolymorphism in the vitamin D receptor gene, suggesting an increased susceptibility to MS (33). Currently, MS and other inflammatory conditions aretreated with corticosteroids, resulting in substantial sideeffects, such as weight gain, development of diabetes, cata-racts, and osteoporosis. The fact that vitamin D has thepotential to ease disease inflammation is noteworthy, giventhese undesirable effects. It is interesting to note that vita-min D and glucocorticoids both quiet inflammation by mod-ulating the immune system, but in quite different manners(36). Proinflammatory cytokines are major targets of glu- cocorticoids, while major histocompatibility proteins andcostimulatory ligands are minor targets, and withdrawal of glucocorticoids may cause a rebound in inflammation. Highdosesofglucocorticoidsareoftennecessary,therebycontrib-uting to undesirable side effects. On the other hand, hor-mone action of vitamin D means it is needed in very smallamounts. Production of the active form of vitamin D istightlyregulatedbythebody,givensufficientsubstrateandproper amounts of calcium. VITAMIN D SUPPLEMENTATION IN MURINE MODEL Given increased incidence of poor vitamin D statusamong MS patients, could vitamin D supplementation bebeneficial? First, two animal studies will be considered.Experimental autoimmune encephalomyelitis (EAE) hasbeen viewed as a mouse model of human MS. EAE is adisease of the central nervous system, mediated by CD4  lymphocytes, resulting in an imbalance in cytokines.Symptoms include demyelination and paralysis. TheseMS-like symptoms can be induced in mice secondary toimmunization with myelin basic protein. If vitamin D isprovided shortly before induction, disease manifestationis prevented. In addition, if vitamin D is provided postin-duction, when disease symptoms have developed, admin-istration of vitamin D reverses disease symptoms. Fi-nally, if vitamin D supplementation is discontinued,disease symptoms will reappear (37).  A second animal study suggests apoptosis of cells se-creting proinflammatory cytokines as a possible mecha-nism of MS symptom alleviation with vitamin D. Re-searchers induced EAE in mice and then hybridizedspinal cord RNA onto DNA microarrays to determinetemporal gene expression. Mice that were administered vitamin D had a significantly increased expression of proapoptotic genes such as calpain-2 (  P  0.014) andcaspase 8–associated protein (  P  0.040). In addition,fragments of the nucleus were present, contributing toevidence of apoptosis (38). One reviewer considers results from animal studies asencouraging, as vitamin D was shown to regulate severaldifferent immune system cells in rodents (16). However, another reviewer is skeptical of use of the EAE mousemodel to parallel human MS, citing a study demonstrat-ing that the diseases have differing histologies, and thefact that the EAE studies do not explain the geographicdistribution and early life migration related to diseaseoccurrence (17). 420  March 2006 Volume 106 Number 3  VITAMIN D SUPPLEMENTATION IN MS PATIENTS In the area of human research, two older reports, al-though limited, do point in the direction of benefit of nutritional supplementation for MS patients (39,40). A  group of 16 MS patients served as their own control forcomparison of daily supplementation with cod liver oilthat provided 5,000 IU vitamin D and dolomite tabletsthat provided 16 mg/kg calcium and 10 mg/kg magne-sium. Throughout the study, serum 25-hydroxyvitamin Dlevels ranged from 15 to 80 ng/mL (37.5 to 200 nmol/L). After 1 year, exacerbation of symptoms was reduced by59%, compared with the previous year without supple-mentation. However, 6 of 16 subjects dropped out of thestudy, preventing any viable conclusion from the data(39). In a study aimed at increasing n-3 fatty acids, 16 MS patients received 0.9 g/day of long-chain fatty acids and vitamins, including 10   g vitamin D. In addition, dietaryadvice resulted in doubling of fish intake. Symptoms im-proved in 11 of the 16 patients during supplementation,while they worsened in only one patient. Unfortunately,biochemical parameters of vitamin D status were notassessed (40).  A recent double-blind randomized trial included MS pa-tients with serum 25-hydroxyvitamin D levels below 20ng/mL (50 nmol/L) (less than half of the optimal range of 40to100ng/mL[100to250nmol/L]).Allpatientsreceived800mg calcium daily for 6 months. Experimental patients(n  17)alsoreceived1,000IUvitaminDdaily,whilecontrolpatients (n  22) received a placebo. In the experimentalpatients,serum25-hydroxyvitaminDimproved,butdidnotreach normal levels; values did not improve in the controlsubjects. Vitamin D supplementation increased the anti-inflammatory cytokine, transforming growth factor-  1, butother cytokines (interferon-   , interleukin-2, and inter-leukin-13) were not changed considerably. Although theresults suggest some benefit from vitamin D supplemen-tation, further research with larger numbers of patientsis needed (41).  A concern of treatment with vitamin D is that toachieve the immune-modulation benefits, calcitriol mustbe given in amounts that would produce a serious condi-tion of hypercalcemia in humans. A possible remedywould be to provide less calcium in the diet, as was donein the mice studies. Alternatively, vitamin D analogscould be used to treat MS. Although analogs have beendeveloped that would not raise serum calcium levels, theyhave not yet been shown effective in humans with MS (42). The research related to vitamin D and multiple sclerosisis summarized in Figure 1. MS is just one example of auto- immunediseaserecentlylinkedtovitaminD.Theincidenceof type 1 diabetes mellitus has been also been associatedwith vitamin D (43). Type 1 diabetes occurs less frequently among adults who received vitamin D supplementationduring infancy (44) and among children born to mothers whoconsumedavitaminD–richdietduringpregnancy(45). In addition, vitamin D is being investigated for its role inrheumatoid arthritis and other autoimmune diseases(46,47) and in the development of cancer (12,48). CONSIDERATIONS FOR FURTHER RESEARCH  As the nutrition science and medical communities inves-tigate the role of vitamin D in a growing number of chronic diseases, several issues face dietetics profession-als. Dietetics researchers should include vitamin D asthey consider design and analysis of studies related tosuch autoimmune diseases as MS and type 1 diabetesmellitus. When considering dietary intake in relation tochronic disease, dietitians should not ignore vitamin Dintake from foods (primarily milk and fish), as well as Findings ●  Limited epidemiological data suggest a link between lowvitamin D status and prevalence of multiple sclerosis (MS).This includes variations in vitamin D status due to sunlightexposure, as well as use of vitamin D supplements and routineintake of vitamin D–rich fish. ●  Patients with MS have lower serum 25-hydroxyvitamin D thancontrol subjects. These lower levels are borne out in decreasedbone mineral status, as well as a cytokine milieu consistentwith less than optimum vitamin D availability. ●  Mouse models and human studies suggest that vitamin Dsupplementation may decrease MS disease symptoms. Figure 1.  Summary of research related to vitamin D and multiplesclerosis. Table 2.  Calcium and vitamin D content of selected supplements Preparation ManufacturerServingsizeCalcium(mg)VitaminD (IU) Calcium supplementsCaltrate Wyeth, Madison, NY 1 tablet 600 200Citracal Mission Pharmaceuticals, San Antonio, TX 2 caplets 630 400Oscal GlaxoSmithKline, Pittsburgh, PA 1 tablet 600 200 Viactiv Calcium McNeil Nutritionals, Ft. Washington, PA 1 chew 500 100Multivitamin/mineral supplementsOne-A-Day Essential Bayer, Morristown, NJ 1 tablet NA  a 400Centrum Wyeth, Madison, NY 1 tablet 162 400Centrum Silver Wyeth, Madison, NY 1 tablet 200 400One-A-Day 50 Plus Bayer, Morristown, NJ 1 tablet 240 400 a NA   not available. March 2006  ●  Journal of the AMERICAN DIETETIC ASSOCIATION  421
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