A interrupção da ingestão de carne e a administração de B2 recupera Parkinson

A interrupção da ingestão de carne e a administração de B2 recupera Parkinson

Direito à Vida

Direito à informação científica, artigo 5o. da Constituição Federal, inciso IX

Agência de Notícias da Fundação de Amparo à Pesquisa do Estado de São Paulo ofereceu Noticia em 23/09/2003 20:01

Agência FAPESP –  Doses de 30 miligramas de riboflavina (vitamina B2) a cada oito horas. Proibição de se ingerir qualquer tipo de carne vermelha. Com essas duas atitudes, alguns portadores da doença de Parkinson conseguiram aumentar de 44% para 71% a recuperação de funções motoras.  A descoberta está saindo na edição de outubro do Brazilian Journal of Medical and Biological Research , em artigo assinado por Cícero Galli Coimbra, professor do Departamento de Neurologia e Neurocirurgia da Universidade Federal de São Paulo, e por Virgínia Junqueira, do Centro de Estudos do Envelhecimento, da mesma universidade.

Brazilian Journal of Medical and Biological Research

versão On-line ISSN 1678-4510

Braz J Med Biol Res v.36 n.10 Ribeirão Preto out. 2003

doi: 10.1590/S0100-879X2003001000019 

Braz J Med Biol Res, October 2003, Volume 36(10) 1409-1417
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2003001000019&lng=pt&nrm=iso&tlng=en
High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson’s disease patients
C.G. Coimbra1,2 and V.B.C. Junqueira3,4
1Setor de Neurologia,Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP, Brasil
2Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo, São Paulo, SP, Brasil
3Disciplina de Geriatria, Departamento de Medicina, Centro de Estudos do Envelhecimento, Universidade Federal de São Paulo, São Paulo, SP, Brasil
4VITÆ – Cromatografia Líquida em Análises Clínicas S/C Ltda., São Paulo, SP, Brasil


Abstract
Abnormal riboflavin status in the absence of a dietary deficiency was detected in 31 consecutive outpatients with Parkinson’s disease (PD), while the classical determinants of homocysteine levels (B6, folic acid, and B12) were usually within normal limits. In contrast, only 3 of 10 consecutive outpatients with dementia without previous stroke had abnormal riboflavin status. The data for 12 patients who did not complete 6 months of therapy or did not comply with the proposed treatment paradigm were excluded from analysis. Nineteen PD patients (8 males and 11 females, mean age ± SD = 66.2 ± 8.6 years; 3, 3, 2, 5, and 6 patients in Hoehn and Yahr stages I to V) received riboflavin orally (30 mg every 8 h) plus their usual symptomatic medications and all red meat was eliminated from their diet. After 1 month the riboflavin status of the patients was normalized from 106.4 ± 34.9 to 179.2 ± 23 ng/ml (N = 9). Motor capacity was measured by a modification of the scoring system of Hoehn and Yahr, which reports motor capacity as percent. All 19 patients who completed 6 months of treatment showed improved motor capacity during the first three months and most reached a plateau while 5/19 continued to improve in the 3- to 6-month interval. Their average motor capacity increased from 44 to 71% after 6 months, increasing significantly every month compared with their own pretreatment status (P < 0.001, Wilcoxon signed rank test). Discontinuation of riboflavin for several days did not impair motor capacity and yellowish urine was the only side effect observed. The data show that the proposed treatment improves the clinical condition of PD patients. Riboflavin-sensitive mechanisms involved in PD may include glutathione depletion, cumulative mitochondrial DNA mutations, disturbed mitochondrial protein complexes, and abnormal iron metabolism. More studies are required to identify the mechanisms involved.
Key words: Parkinson’s disease, Riboflavin, Flavin-adenine dinucleotide, Glutathione, Iron, Hemin


Introduction
During absorption of riboflavin, flavokinase phosphorylates the vitamin to yield flavin mononucleotide (FMN) that, according to the cellular requirements, is transformed into flavin-adenine dinucleotide (FAD) by FAD synthase (1,2). Progressive deficiency of riboflavin is associated with co-factor loss in a controlled manner, apparently ensuring that essential catalytic activity such as that related to aerobic metabolism is preserved (3,4).
Low riboflavin status may also result from defective absorption. In spite of an adequate dietary intake of riboflavin (FAD, vitamin B2), 10-15% of the inhabitants of London and of Florence present low activities of two riboflavin-dependent enzymes – erythrocyte glutathione reductase (EGR) and pyridoxin(pyridoxamine)-phosphate oxidase (5). The activity of both enzymes was corrected by adding their respective co-factors (FAD or FMN) to a test tube assay or by administering high doses of riboflavin (24-30 mg per day for 5-8 weeks) to the affected individuals (6). The dependency of both FMN and FAD levels on riboflavin absorption (i.e., on flavokinase activity), and the normalization of the activities of both FMN- and FAD-dependent enzymes only at a high riboflavin intake, taken together, are consistent with the expression of flavokinase isoforms with low affinity for the substrate – riboflavin (5). Anderson et al. (5) suggested that the relatively large percent of persons with altered riboflavin absorption (10-15%) may reflect the situation in the world population rather than being a feature of a particular ethnic group.
Low EGR activity may explain glutathione depletion with impaired antioxidant defense, the earliest neurochemical abnormality in Parkinson’s disease (PD), already observed in the substantia nigra before the disorder becomes clinically evident (7). Moreover, the reduced bioavailability of FMN and/or FAD may also explain the impaired oxidative metabolism of PD patients (8-10).
The first objective of the present study was to determine the status of riboflavin in PD patients. The second was to evaluate the specificity of the alterations of riboflavin status for PD by measuring the levels of vitamin B2 and of other determinants of homocystinemia (vitamins B6, B12, and folic acid) in PD patients and comparing them with those of individuals with dementia (11-13). Third, we also determined the effect of normalization of riboflavin status on the motor capacity of PD patients. Part of the data reported here, obtained during the first 3 months of treatment, were reported at the 6th International Conference on Parkinson’s and Alzheimer’s Diseases (14).


Patients and Methods
This study was approved by the Ethics Committee for Clinical Research of the Hospital do Servidor Público Municipal de São Paulo (HSPM) and informed consent was obtained from all participants or persons responsible for them.
The diagnosis of sporadic PD was made according to current criteria (15) with special care taken to exclude confounding disorders, particularly in the early stages of the disease.
Vitamin and homocysteine determinations were performed on 31 sporadic PD patients (67.5 ± 9.3 years old, 13 males and 18 females): 3, 3, 3, 8, and 14 patients were assigned, early in the morning, to stages I to V of Hoehn and Yahr (16), respectively.
Ten individuals (77.5 ± 8.8 years old, 5 males and 5 females) with dementia without stroke (DwoSt) and a low Mini-Mental score (13) were used as the control group for blood chemistry. They had no history of stroke or evidence for ischemic lesions of the brain by CT or NMRI and had been consecutively attended in the Neurology Clinic of HSPM.
Blood samples were obtained after a 10- to 12-h fast for serum assays of vitamin B12 by electrochemiluminescence immunoassay (11820753 Roche Diagnostics GmbH, Mannheim, Germany) and of homocysteine by HPLC (17). Heparinized plasma was assayed for FAD (18), vitamin B6 (19), and folic acid (20)by HPLC, as well as for the determination of the EGR-activation coefficient (EGR-AC) (21) in red blood cell lysates (22).
A food questionnaire covered the weekly dietary habits of all PD and DwoSt patients from 5 years prior to the onset of PD until the appearance of spontaneous changes associated with the onset of chewing and/or swallowing impairment or until the medical interview in the absence of these impairments. The questionnaire also evaluated the adequacy of daily vitamin intake.
All PD patients received 30 mg riboflavin orally at about 8-h intervals (90 mg/day) and their usual symptomatic medications. This dosage was used to avoid decreased absorption associated with higher doses or shorter intervals between administrations. Due to the renal excretion of riboflavin (3), the treatment was only initiated after confirmation of normal blood levels of creatinine (0.5-1.4 mg/dl). Because the PD patients had a higher consumption of red meat (beef and pork) than sex-matched controls (19 healthy non-consanguineous relatives or neighbors of similar age recruited for controlling the dietary habits), all PD patients were required to eliminate all red meat from their diets. The symptomatic drugs for PD in use included L-DOPA with carbidopa (200/50 mg tablets), L-DOPA with benserazide hydrochloride (200/50 mg tablets), biperiden (2 or 4 mg tablets), amantadine hydrochloride (100 mg tablets), selegiline (5 mg tablets), and pramipexole (0.25 or 1.0 mg tablets) taken alone or in diverse combinations. The treatment paradigm with symptomatic drugs for PD for each patient when the study began was maintained.
The motor capacities of the 19 PD patients who complied with the proposed treatment for 6 months by early August 2003 were rated monthly according to a motor function scale (Table 1), and compared with their own pretreatment values. The scale was based on that of Hoehn and Yahr (16) and new categories were added in order to detect subtle changes in the patients’ motor capacity. In addition, the presence or absence of responses to symptomatic drugs for PD is also used for more accurate characterization of the residual motor capacity of PD patients (for instance, compare the descriptions corresponding to 0 and 15% of motor capacity, Table 1). Although there are no direct validation studies of this rating system, the different levels of motor capacity in Table 1 represent a simple increase in the number of components within stages I to V of the widely employed Hoehn and Yahr system (16).
After the first month of treatment, compliance with the dietary directions and vitamin intake was determined in all patients, and the fasting plasma levels of FAD and EGR-AC values were re-evaluated in 9 of them approximately 9-12 h after the latest riboflavin dose.
The blood chemistry data obtained from both groups were compared statistically by the Student t-test and the motor function data were analyzed statistically by the Wilcoxon signed rank test, with the level of significance set at P < 0.05.


Results
Diversified food intake, including daily ingestion of milk, which is particularly rich in vitamin B2, was confirmed in all patients, with PD patients frequently declaring a strong preference for red meat. The content of the daily family meals was usually adapted to meet the high demand for red meat of most PD patients. In contrast, all 10 DwoSt patients passively accepted the family diet. The estimated red meat consumption prior to the onset of impaired chewing/swallowing by 19 PD patients (8 males and 11 females, mean age ± SD = 66.2 ± 8.6 years) at lunch and dinner within a 7-day period was significantly higher (mean consumption = 2,044 ± 1,439 g/week, range = 0-5,100 g/week) than that of their 19 diet controls (8 males and 11 females, all healthy individuals of similar social and cultural background, recruited among non-consanguineous relatives and neighbors of PD patients of similar age; mean age = 64.6 ± 11.3 years, mean consumption = 789 ± 509 g/week, range = 150-1800 g/week; P < 0.01, Mann-Whitney U-test). The calorie intake did not differ significantly between the two groups.
The basal plasma concentrations of FAD of the PD patients (100.9 ± 22 ng/ml) were significantly lower than those observed in the patients with DwoSt (128.8 ± 25.6 ng/ml, P < 0.01, Student t-test) while other determinants of homocysteine levels (pyridoxine, folic acid, and methylcobalamin) were usually within normal limits, and did not differ significantly between the two groups (Table 2). The PD group also had significantly higher EGR-AC levels than DwoSt patients (1.43 ± 0.26 vs 1.20 ± 0.11, respectively, P < 0.01, Student t-test).
It is important to point out that all 31 PD patients (including 3 newly diagnosed individuals not on symptomatic drugs for PD) but only 3 of 10 DwoSt patients had low plasma riboflavin levels. Normalization of the plasma concentrations of riboflavin and EGR-AC values was confirmed after 1 month of treatment (from 106.4 ± 34.9 to 179.2 ± 23.0 ng/ml, and from 1.40 ± 0.25 to 1.11 ± 0.08, N = 9, respectively).
About 10 to 15 days after the beginning of high-dose riboflavin treatment, PD patients often reported better (progressively less interrupted) sleep at night, improved reasoning, higher motivation, and reduced depression. Their family members usually started noticing motor improvements after 20 days of treatment, but in some cases of advanced disability the patient was able to change body position in bed at night as early as on the third day of treatment.
By the time of writing this report in August 2003, 19 PD patients (respectively, 3, 3, 2, 5, and 6 patients initially rated as stages I to V of Hoehn and Yahr (16)) had completed 6 months of treatment with riboflavin administration and dietary red meat elimination. The data in Figure 1A show that all of them improved their motor capacity during the first 3 months and most reached a plateau, while 5/19 continued to improve in the 3- to 6-month interval. Figure 1B shows that the average motor capacity for these 19 patients increased from 44 to 71%. Their motor capacity increased significantly during the first month and every month for the next 5 months of treatment compared with their own pretreatment status, demonstrating a progressive and marked improvement (P < 0.001, Wilcoxon signed rank test). The rate of motor recovery was higher in the first 3 months than in the last 3 months of treatment. No patient on high doses of riboflavin reported adverse effects.
Because they could stand and walk with improved (although still altered) balance by 2 months of treatment, two male patients (initially in stage V (16) with associated dementia and hallucinations) started striking imaginary persons and/or often attempted to leave home unaccompanied, reacting aggressively against the relative who tried to stop them. These episodes of agitation and aggressiveness were observed less often by the end of the third month of riboflavin treatment and disappeared thereafter, but caused transient concern and distress among their family members who initially regarded them as signs of neurological worsening.
Three patients (2 individuals initially in stage II and 1 in stage I of Hoehn and Yahr (16)) reached 100% motor capacity within the first 3 months of treatment (Figure 1A). Four patients had run out of riboflavin tablets for up to 7 days between two consecutive clinical appointments, but sustained the benefit already achieved by then.
Twelve of 31 patients initially assessed for riboflavin status who either did not complete 6 months of therapy or did not comply with the proposed treatment paradigm were excluded from statistical analysis.


  Figure 1. Motor capacity of patients with Parkinson’s disease who received 30 mg riboflavin/8 h, orally (240 mg/day) and abstained from dietary red meat for 6 months. Motor capacity was evaluated monthly for each patient by a modification of the method of Hoehn and Yahr (16) to provide a score in percent (Table 1). A, Individual data for the evolution of motor capacity of 19 patients for 0 to 3 and 3 to 6 months of treatment. *P < 0.001 for values at 3 months (month 0) compared with those before treatment; **P < 0.05 for values at 6 months compared with those obtained at 3 months (Wilcoxon signed rank test). B, The height of the columns indicates the mean motor capacity values (see Table 1) after the indicated periods of treatment. When compared with their own basal levels (month 0), highly significant and progressively higher differences were observed for each consecutive month of treatment. *P < 0.001 (Wilcoxon signed rank test).

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Discussion
This study demonstrated a progressive and marked improvement of motor capacity in consecutively evaluated patients with sporadic PD who started with below normal laboratory indexes of riboflavin and who eliminated red meat from their diets while receiving high multiple daily doses of riboflavin over a period of 6 months while taking their usual symptomatic medications. The mean motor capacity of a group of 19 PD patients showed a progressive 50% recovery over a period of only 3 months – a most surprisingly high and fast improvement, considering that about 60% of nigral neurons have already been lost at the onset of manifestations of PD (15).
The initial riboflavin status was low in all 31 consecutively evaluated PD individuals, and significantly lower in PD patients compared with those with another neurodegenerative disease also associated with hyperhomocystinemia (DwoSt), suggesting that abnormal riboflavin status may be a specific feature of PD rather than a minor metabolic contributor to the degeneration of nigral neurons. Taken together with the rapid and profound neurological improvement associated with normalization of riboflavin status, this observation suggests that altered riboflavin status may be a cause of neurodegeneration in PD.
Although urinary excretion of riboflavin peaks within 1-2 h and returns to baseline within 5-6 h after a large oral dose (3), the benefit achieved did not vanish in four PD patients over a therapeutic interval of up to 7 days. This observation suggests the occurrence of steady plastic changes rather than a pharmacological effect of high-dose riboflavin treatment to account for the improved motor capacity shown in Figure 1. The steady build-up of the motor recovery observed during the first 3 months of treatment suggests that this treatment paradigm may inactivate fundamental neurodegenerative mechanisms (e.g., glutathione depletion, considered to be an early key event in the pathogenesis of PD (23,24)), possibly allowing regenerative plastic phenomena to occur.
The importance of the elimination of dietary red meat for the results reported here is not known. The content of vitamin B2 in meat in general is considerable (about 0.2 mg/100 g), and diverse cooking procedures cause only minor (7-18%) loss of this micronutrient (25). The daily requirement for individuals above the age of 14 years is £1.3 mg/day. Therefore, if the PD patients had a normal absorptive capacity for vitamin B2, their large ingestion of red meat (up to 700 g/day), associated with milk, rice and beans, fruits and vegetables, should have provided a normal riboflavin status. In contrast, 31 consecutive PD patients had laboratory evidence for riboflavin deficiency (Table 2) suggesting that patients with sporadic PD belong to the subset of the general population (10-15%) (3) that may express a flavokinase with low affinity for vitamin B2, leading to a decreased absorption.
However, the digestion of red meat releases hemin, a highly diffusible toxin that, when not properly inactivated, increases intracellular iron concentrations and enhances hydroxyl radical production (Fenton reaction). Most of the absorbed hemin is destroyed by the enzyme heme oxygenase (HO) in the digestive tract and liver (26). Because HO is oxidized during the catabolization of hemin to biliverdin, the HO molecules must be reduced through the coordinated activity of the flavoenzyme cytochrome P450 reductase for continued hemin inactivation (Figure 2) (27). Cytochrome P450 reductase is particularly sensitive to riboflavin deficiency because it requires both FMN and FAD as prosthetic groups (28). It is possible that individuals with decreased absorption of vitamin B2 may not completely inactivate high dietary levels of hemin, allowing this neurotoxic compound to reach the brain cells. Consistently, the staining for HO-1 isozyme is increased in astrocytes and reacts with neuronal Lewy bodies in the nigra of PD patients, suggesting that its overexpression may contribute to the pathological iron deposition and mitochondrial damage in PD (29). By binding glutathione (30) hemin may further decrease glutathione levels in the brains of PD patients through a direct mechanism.
Because humans lack efficient iron excretory mechanisms, iron excess is dealt with by increasing the synthesis of the iron-storage protein ferritin (31). Disturbed systemic (32) and brain (33) iron metabolism has been reported in PD, suggesting that a selective decrease in the levels of ferritin may result in an increase in intracellular free iron, thereby enhancing free radical production (34). Indeed, vitamin B2 deficiency in rodents is associated with low circulating iron concentrations, increased iron turnover and excretion into the intestinal lumen, which may occur in response to impaired ferritin synthesis (35,36). Therefore, the consistent finding of an abnormal riboflavin status in PD, as reported here, may help to explain the disturbed iron metabolism found in PD patients, with the underlying mechanisms possibly involving impaired hemin catabolism and reduced ferritin synthesis. Interestingly, the highest world prevalence of PD is found among the inhabitants of Buenos Aires (37), where the consumption of red meat is traditionally high. Similarly, the identification of high dietary animal fat as a risk factor for PD (37) may actually reflect a role of high dietary hemin in PD pathology.
Moreover, because FAD is required in the two alternative pathways of deoxynucleotide synthesis (2), DNA repair and replication are expected to be disturbed upon decreased bioavailability of riboflavin, and abnormal riboflavin status may also explain the cumulative mitochondrial DNA mutations reported in PD (38).
The present results with 19 PD patients who showed a significant improvement in motor function after treatment with riboflavin and the elimination of red meat from the diet suggest that an abnormal riboflavin status, possibly due to flavokinase deficiency, may be an essential requirement for triggering and sustaining the degeneration of dopaminergic neurons in PD. As a result of the reduced B2 bioavailability, ATP production is selectively preserved, while the less critical FAD- or FMN-dependent metabolic pathways are impaired (4). Consequently, free iron concentrations in the cytosol increase as a result of impaired ferritin synthesis and/or reduced hemin catabolism associated with hydrogen peroxide accumulation due to glutathione depletion, thereby triggering the Fenton reaction and ultimately leading to the selective formation of the potent neurotoxin 6(OH)DA in dopaminergic neurons.
Current concepts about the cause of sporadic PD suggest an inherited predisposition to environmental or endogenous toxic agents (39), and the data presented and reviewed here suggest that flavokinase deficiency should be considered in future research as a promising candidate to account for this inherited predisposition, while dietary factors such as red meat consumption may largely account for the environmental/endogenous toxicity. The administration of high doses of riboflavin combined or not with red meat elimination may be an effective therapeutic paradigm addressing the determinants of PD, capable of providing regression to earlier clinical stages, or even to the nonsymptomatic state without symptomatic drugs for PD (at least in some cases), rather than only disease stabilization or partial symptomatic relief.
Although the relentless progression of PD clearly contrasts with the results of the treatment paradigm reported here, a larger and more prolonged study is certainly required to document the steadiness and the full extent of the ongoing recovery. A scientifically desirable blinded clinical trial with a placebo would necessarily leave known riboflavin-deficient patients untreated for a long period of time, when their neurological disability may progress as a consequence of sustained loss of nigral neurons, possibly rendering the ultimate response to delayed normalization of their riboflavin levels less complete. Therefore, the need for controlled trials should be weighed ethically considering the contrast of the natural history of PD (progress of motor disability to death despite an increase in the efficacy of symptomatic drugs for PD treatment) with the outcome of the vitamin B2 treatment observed in larger and more prolonged studies without controls.


  Figure 2. Dependency of hemin catabolism on riboflavin bioavailability. The elimination of hemin requires cyclic reduction of heme oxygenase by flavoprotein cytochrome P450 reductase that, in turn, utilizes both flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD) as prosthetic groups. Average or increased red meat consumption may overload the capacity of this chain of reactions already compromised by impaired intestinal absorption of riboflavin (with decreased FMN and FAD synthesis), leading to increased hemin (iron) delivery to the CNS and increased utilization of riboflavin for hemin inactivation. Modified from Figure 1, box 21-1, page 783 of Ref. 2.

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Acknowledgments
The authors are grateful to Mr. Terence O’Reilly (Novartis, Basel, Switzerland) for his suggestions about statistical analysis.


Papel potencial da vitamina D na Esclerose Múltipla

Papel potencial da vitamina D na Esclerose Múltipla

Filed in A-Featured , Health , Medical Mondays , Science on June 1, 2009 | Arquivado em A-Destaque, Saúde, Medicina segundas-feiras, Ciência, 1 de junho, 2009 | // ShareThis

Susan J. Epstein, MS, MEd, is the Program Coordinator at the Jacobs Neurological Institute . Susan J. Epstein, MS, MED, é o coordenador do Programa no Instituto Neurológico Jacobs. In her new book The Life Program For MS: Lifestyle, Independence, Fitness, and Energy , she addresses the limitations imposed by Multiple Sclerosis which results in patients becoming sedentary, gaining excess weight and developing poor eating and exercise habits.  Epstein provides a user-friendly teaching tool that helps sufferers to incorporate new behaviors into their daily routines.  In the original article below Epstein looks at the role of vitamin D in MS. Em seu novo livro O Programa Life For MS: Estilo de Vida, Independência, Centro, e da Energia, ela aborda as limitações impostas pela esclerose múltipla que os resultados em pacientes tornando-se sedentário, ganhando o excesso de peso e desenvolvimento de má alimentação e hábitos de exercício. Epstein prevê um usuário ferramenta de ensino, que ajuda pessoas que sofrem de incorporar novos comportamentos em suas rotinas diárias. No artigo original abaixo Epstein analisa o papel da vitamina D em MS.

A deficiency in vitamin D is currently one of the most studied environmental risk factors for MS and is potentially the most promising in terms of new clinical implications. A deficiência de vitamina D é atualmente um dos mais estudados fatores de risco ambientais para MS e é potencialmente mais promissores em termos de novas implicações clínicas. In particular, this vitamin could alter the immune response taking a positive role in the central nervous system. Em particular, esta vitamina pode alterar a resposta imune, tendo um papel positivo no sistema nervoso central. There are two main types of risk factors for MS: genetic and environmental. Existem dois tipos principais de fatores de risco para MS: genéticos e ambientais. In today’s world many genetic predispositions for various conditions have been discovered, and the various environmental triggers identified; making this an exciting time for learning specific ways to change behavior to improve or protect health. No mundo de hoje muitas predisposições genéticas para várias condições foram descobertas, e as várias causas ambientais identificados, tornando este um momento emocionante para aprender maneiras específicas de mudança de comportamento para melhorar ou proteger a saúde.

The following environmental factors influence the risk of MS: Os seguintes fatores ambientais influenciam o risco de MS:
1. 1. latitude latitude
2. 2. past exposure to sun exposição passada ao sol
3. 3. serum level of vitamin D nível sérico de vitamina D

Worldwide, latitude has an undeniable effect on the prevalence of MS which occurs with much greater Em todo o mundo, latitude tem um efeito inegável sobre a prevalência da esclerose múltipla que ocorre com muito maior frequency in areas further away from the equator. freqüência em áreas mais distantes do equador. Lower incidence of the disease is found in tropical regions where the high degree of sunlight is recognized as the correlate. Menor incidência da doença é encontrada em regiões tropicais, onde o elevado grau de luz solar é reconhecido como o correlato. Latitude has an overall influence on the amount of sunlight in a given region making geographical location advantageous. Latitude tem uma influência global sobre a quantidade de luz solar em uma determinada região, tornando a localização geográfica vantajosa. So if we know that the level of exposure to sunlight directly affects the level of vitamin D in our bodies and this vitamin is known as the “sunshine vitamin” where does that leave those of us who live in the northern hemisphere? Então, se nós sabemos que o nível de exposição à luz solar afeta diretamente o nível de vitamina D no nosso organismo e essa vitamina é conhecida como a vitamina do sol “, onde é que isso deixe aqueles de nós que vivem no hemisfério norte? Does this suggest people even without disease are deficient in vitamin D? Isto sugere até mesmo as pessoas sem a doença são deficientes em vitamina D? Also, the western diet lacks this crucial vitamin providing less than 100 IU a day, falling far below the daily requirement of 2,000 IU/d. Além disso, a dieta ocidental falta desta vitamina fundamental fornecer menos de 100 UI por dia, caindo muito abaixo da necessidade diária de 2.000 UI / d. It is thought that vitamin D is most likely involved in a number of regulatory activities besides just bone health, and could have a dramatic effect on immune function. Pensa-se que a vitamina D é mais provável envolvido em uma série de actividades de regulamentação, além de apenas a saúde dos ossos, e poderiam ter um efeito dramático sobre a função imunológica. Such low average levels of vitamin D raise serious public health issues and there is an urgent need for national health institutes to take preventative measures. Esses baixos níveis médios de vitamina D levantam sérias questões de saúde pública e há uma necessidade urgente de institutos nacionais de saúde para tomar medidas preventivas. With this knowledge should come behavior change, not only for the MS patient but also the general population. Com este conhecimento deve vir a mudança de comportamento, não só para o paciente MS, mas também a população em geral.

Clinically most MS patients have low levels of vitamin D in their blood and are in a state of deficiency compared to the international norm. Clinicamente, a maioria dos pacientes de MS têm baixos níveis de vitamina D no sangue e estão em um estado de deficiência em relação à norma internacional. A recent study found a direct link between the level of vitamin D circulating in the blood and the disease, without factoring in the effect of latitude or sun exposure. Um estudo recente descobriu uma ligação directa entre o nível de vitamina D circula no sangue ea doença, sem ter em conta o efeito da latitude ou exposição ao sol. Further research trials are necessary before any firm recommendations can be made but in the meantime, physicians can no longer ignore that many MS patients have a lack of vitamin D, which could be detected through systematic blood tests. Ensaios mais pesquisas são necessárias antes que qualquer empresa de recomendações podem ser feitas mas, entretanto, os médicos não podem mais ignorar que muitos pacientes de MS têm uma falta de vitamina D, que poderia ser detectado através de exames de sangue sistemáticos. Vitamin D supplements are appropriate to restore their levels to within normal range. Os suplementos de vitamina D são adequadas para restabelecer os seus níveis, para dentro da escala normal. This should be considered a general medical recommendation simply to increase levels in the blood to the current recommended amount of at least 2,000 IU /d. Isto deve ser considerado uma recomendação médica geral, simplesmente para aumentar os níveis no sangue para a quantidade atual recomendada de pelo menos 2.000 UI / d. This would mean taking between 1,000 and 3,000 IU of vitamin D3 (cholecalciferol) on average per day. Isso significaria, tendo entre 1.000 e 3.000 UI de vitamina D3 (colecalciferol), em média, por dia. There are two types of vitamin D: D2 and D3. Existem dois tipos de vitamina D: D2 e D3. Vitamin D3 is the healthy kind your body makes when exposed to sunshine. A vitamina D3 é o tipo saudável seu corpo faz quando exposta ao sol. D2 is the synthetic form used in prescriptions and is considered inferior to D3. D2 é a forma sintética usada na prescrição e é considerado inferior ao D3.

Having this knowledge regarding the benefits of vitamin D as well as the current published research indicating the prevalence of vitamin D deficiency; behavioral strategies seem appropriate and can be very safe when discussed with your physician. Tendo este conhecimento a respeito dos benefícios da vitamina D, bem como a atual pesquisa publicada indicando a prevalência de deficiência de vitamina D; estratégias comportamentais parecem ser adequadas e podem ser muito seguro quando discutiu com o seu médico. Since moving to a tropical region is unlikely, the options available are: Desde que se mudou para uma região tropical é improvável, as opções disponíveis são:

safe sun exposure, vitamin supplementation, and a diet with foods rich in vitamin D. exposição ao sol segura, a suplementação de vitamina A, e uma dieta com alimentos ricos em vitamina D.

Optimizing sun exposure is a topic in itself and comes with some risk along with conflicting opinions and recommendations from experts in the field though it seems reasonable to get a dose of fresh air and sunshine on days when the weather is in your favor. Otimizando a exposição ao sol é um tema em si, e vem com algum risco, juntamente com opiniões conflitantes e recomendações de especialistas na área, embora pareça razoável para obter uma dose de ar fresco e luz do sol nos dias em que o tempo está a seu favor. Some experts recommend exposing your body to sunlight for 15-minutes before applying sunscreen in order to get the benefits from the UV rays which naturally provide the vitamin D needed for good health. Alguns especialistas recomendam expondo seu corpo à luz solar durante 15-minutos antes de aplicar o protetor solar, a fim de obter os benefícios dos raios UV que, naturalmente, fornecer a vitamina D, necessária para uma boa saúde. Luckily a vitamin D3 supplement can provide the same benefits when given in the appropriate dose to bring blood levels to within normal range. Felizmente, um suplemento de vitamina D3 pode fornecer os mesmos benefícios quando utilizado na dose adequada para reduzir os níveis de sangue para dentro da escala normal.

Before purchasing a supplement you should have a blood test to determine your baseline levels of vitamin D. Your neurologist can then take the results and prescribe the amount of vitamin D3 to bring your levels up to within normal range. Antes de comprar um suplemento que você deve ter um exame de sangue para determinar os níveis de sua base de vitamina D. O neurologista pode, então, tomar os resultados e determinar a quantidade de vitamina D3 para trazer os seus níveis de até dentro da normalidade. MS patients are seen regularly to monitor their disease status and can systematically have blood levels measured. Pacientes com EM são vistos regularmente para acompanhar o seu estado de doença e pode ter sistematicamente os níveis sanguíneos de medida. You also may want to search for MS Centers that are running clinical trials to study the effects of Vitamin D on MS and inquire about being a subject. Você também pode querer procurar MS Centros que estão executando os ensaios clínicos para estudar os efeitos da vitamina D em MS e inquirir sobre a ser um assunto.

Vitamin D3 supplements are available in both liquid and capsule form. Os suplementos de vitamina D3 estão disponíveis em ambos os líquidos e cápsula formulário. They can be purchased at any pharmacy for as little as $4.49 for 100 capsules containing 1000.0 IU. Eles podem ser comprados em qualquer farmácia por tão pouco quanto $ 4,49 por 100 cápsulas contendo 1000,0 UI. Check the label to make sure the primary ingredient is Vitamin D (as cholecalciferol ). Verifique o rótulo para certificar-se o principal ingrediente é a vitamina D (como colecalciferol). As mentioned earlier the Western diet is commonly very low in vitamin D but there are good food choices to increase the amount in your diet. Como mencionado anteriormente a dieta ocidental é geralmente muito baixa em vitamina D, mas existem boas escolhas alimentares para aumentar a quantidade em sua dieta. Excellent food sources include: oily fish like salmon, mackerel, and sardines; vitamin D-fortified milk and cereals; whole eggs, liver, and beef. Excelentes fontes alimentares são: peixes oleosos como salmão, cavala e sardinha, enriquecidos com vitamina D do leite e os cereais, ovos inteiros, fígado e carne bovina. A combination of the three available sources of vitamin D is optimal, and purely from a medical point of view, supplementation is unavoidable in order to improve the general health of the MS patient. A combinação das três fontes disponíveis de vitamina D é ótima, e exclusivamente a partir de um ponto de vista médico, a suplementação é inevitável, a fim de melhorar a saúde geral do paciente MS. And with clinical research trials underway all over the globe, supplementation may soon be proven to be neurologically beneficial. E, com ensaios de investigação clínica em curso em todo o globo, a suplementação poderá em breve ser provado ser neurologicamente benéfico.

Papel potencial da vitamina D na Esclerose Múltipla

Imunoregulador natural, a vitamina D tem papel fundamental na recuperação da Esclerose Múltipla

A vitamina D influencia o metabolismo de enzimas importantes da imunidade e da função neural protegendo o sistema nervoso.

Imunoregulador natural e com acção anti-inflamatória, a suplementação em solução de vitamina D tem papel fundamental na regulação da Esclerose Múltipla – EM ou MS.

A esclerose múltipla é uma doença crônica, doença auto-imune e degenerativa do sistema nervoso central (SNC), que ainda não está totalmente compreendida. Mas as pesquisas médidas demonstram o efeito terapeutico da solução de Vitamina D, que não só impediu, mas também reduziu a atividade da doença.

Cristiane Rozicki


Multiple sclerosis and vitamin D: an update Esclerose múltipla e vitamina D: uma atualização

European Journal of Clinical Nutrition (2004) 58, 1095–1109. European Journal of Clinical Nutrition (2004) 58, 1095-1109. doi:10.1038/sj.ejcn.1601952 Published online 31 March 2004 doi: 10.1038/sj.ejcn.1601952 Publicado em 31 de março de 2004

B M VanAmerongen 1 , 4 , C D Dijkstra 1 , P Lips 2 and C H Polman 3 BM VanAmerongen 1, 4, Dijkstra CD 1, Lips P 2 e CH Polman 3

  1. 1 Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands 1 Departamento de Biologia Celular e Molecular e Imunologia, VU Medical Center, Amsterdam, The Netherlands
  2. 2 Department of Endocrinology, VU Medical Center, Amsterdam, The Netherlands 2 Departamento de Endocrinologia, VU Medical Center, Amsterdam, The Netherlands
  3. 3 Department of Neurology, VU Medical Center, Amsterdam, The Netherlands 3 Departamento de Neurologia, VU Medical Center, Amsterdam, The Netherlands
  4. 4 Department of Dental Basic Sciences (ACTA), VU Medical Center, Amsterdam, The Netherlands 4 Departamento de Odontologia Ciências Básicas (ACTA), VU Medical Center, Amsterdam, The Netherlands

Correspondence: BM VanAmerongen, Department of Molecular Cell Biology and Immunology, VU Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Correspondência: BM VanAmerongen, Departamento de Biologia Celular e Molecular e Imunologia, VU Medical Center, PO Box 7057, 1007 MB de Amesterdão, na Holanda. E-mail: bmvan.amerongen@inter.nl.net E-mail: bmvan.amerongen @ inter.nl.net

Guarantor : CD Dijkstra. Fiador: CD Dijkstra.

Contributors : BV initiated this study together with CD. Colaboradores: BV deu início a este estudo juntamente com o CD. The paper was written by BV and CD with contribution from PL. O documento foi escrito por BV e CD com participação do PL. CD contributed her expertise on MS, EAE, the immune system and gene polymorphism. CD contribuiu com sua experiência em MS, EAE, o sistema imunológico e polimorfismo genético. PL contributed his expertise on vitamin D deficiency and consequences for bone loss, fractures and therapeutic implications. PL contribuiu com seus conhecimentos sobre a deficiência de vitamina D e as consequências para a perda óssea, fraturas e implicações terapêuticas. CP contributed his clinical expertise on patients with MS. CP contribuiu com sua experiência clínica em pacientes com EM. All authors read and contributed to the manuscript. Todos os autores leram e contribuíram para o manuscrito.

Received 9 June 2003; Revised 23 December 2003; Accepted 10 January 2004; Published online 31 March 2004. Recebido 9 de junho de 2003, revisado 23 de dezembro de 2003, aceito 10 de janeiro de 2004; Publicado em 31 de março de 2004.

Abstract Abstract

MS is a chronic, immune-mediated inflammatory and neurodegenerative disease of the central nervous system (CNS), with an etiology that is not yet fully understood. A esclerose múltipla é uma doença crônica, doença imune-mediada inflamatórias e degenerativas do sistema nervoso central (SNC), com uma etiologia que ainda não está totalmente compreendida. The prevalence of MS is highest where environmental supplies of vitamin D are lowest. A prevalência de MS é a mais elevada do ambiente onde o abastecimento de vitamina D são menores. It is well recognized that the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH) 2 D), is a natural immunoregulator with anti-inflammatory action. É reconhecido que o ativo forma hormonal da vitamina D, 1,25-dihidroxivitamina D (1,25 – (OH) 2 D), é um imunorreguladoras natural com ação anti-inflamatória. The mechanism by which vitamin D nutrition is thought to influence MS involves paracrine or autocrine metabolism of 25OHD by cells expressing the enzyme 1 O mecanismo pelo qual a nutrição vitamina D é pensado para influenciar MS envolve o metabolismo parácrina ou autócrina de 25OHD por células que expressam a enzima 1 alfa -OHase in peripheral tissues involved in immune and neural function. -OHase nos tecidos periféricos envolvidos na função imune e neural. Administration of the active metabolite 1,25-(OH) 2 D in mice and rats with experimental allergic encephalomyelitis (EAE, an animal model of MS) not only prevented, but also reduced disease activity. Administração do metabólito ativo 1,25 – (OH) 2 D em camundongos e ratos com encefalomielite alérgica experimental (EAE, um modelo animal de MS), não só impediu, mas também reduziu a atividade da doença. 1,25-(OH) 2 D alters dendritic cell and T-cell function and regulates macrophages in EAE. 1,25 – (OH) 2 D altera células dendríticas e T-função das células e regula macrófagos na EAE. Interestingly, 1,25-(OH) 2 D is thought to be operating on CNS constituent cells as well. Curiosamente, 1,25 – (OH) 2 D é pensado para ser operacional em células constituintes CNS também.

Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary vitamin D 3 intake. A deficiência de vitamina D é causada pela exposição à luz solar ou baixa dieta insuficiente em vitamina D 3 de admissão. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly be involved as well. Sutil defeitos no metabolismo da vitamina D, incluindo polimorfismos genéticos relacionados com a vitamina D, poderá, eventualmente, estar envolvida também. Optimal 25OHD serum concentrations, throughout the year, may be beneficial for patients with MS, both to obtain immune-mediated suppression of disease activity, and also to decrease disease-related complications, including increased bone resorption, fractures, and muscle weakness. Optimal concentrações séricas de 25OHD, durante todo o ano, pode ser benéfico para pacientes com EM, tanto para a obtenção de supressão imunológica mediada da actividade da doença, e também para diminuir as complicações relacionadas à doença, incluindo o aumento da reabsorção óssea, fraturas, e fraqueza muscular.

Keywords: Palavras-chave:

multiple sclerosis, vitamin D metabolism, sunlight, vitamin D nutrition, vitamin D status, immunomodulation, bone loss and fractures, muscle weakness esclerose múltipla, o metabolismo da vitamina D, a luz solar, nutrição vitamina D, o status da vitamina D, imunomodulação, a perda óssea e fraturas, fraqueza muscular

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Introduction Introdução

Multiple sclerosis (MS) is a slowly progressive, often disabling disease of the central nervous system (CNS), characterized by disseminated patches of demyelination in the brain and spinal cord. A esclerose múltipla (EM) é lentamente progressiva, muitas vezes incapacitantes doenças do sistema nervoso central (SNC), caracterizada por manchas disseminadas de desmielinização no cérebro e medula espinhal. This disease results in multiple and varied neurologic symptoms and signs, usually with exacerbations and remissions at the onset: relapsing-remitting (RR) MS, followed in later years by a more chronic progressive course: secondary progressive (SP) MS. Esta doença resulta em múltiplos e variados sintomas e sinais neurológicos, geralmente com exacerbações e remissões no início: remitente-recorrente (RR), MS, seguido nos últimos anos por um curso mais crônico e progressivo: secundária progressiva (SP) MS. A primary progressive form (PP) of MS is also recognized. A forma primária progressiva (PP) de MS é reconhecido também. Women are affected more often than men. As mulheres são mais afetadas que os homens. Age at onset of the clinical symptoms is typically between 20 and 40 y. A idade de início dos sintomas clínicos é tipicamente entre 20 e 40 y. It is uncertain whether MS is a single disease or whether the varying clinical patterns, for example, the relapsing and progressive forms, represent distinct entities ( Noseworthy, 1999 ). É incerto se o MS é uma única doença ou se os padrões variáveis clínicas, por exemplo, os surtos e formas progressivas, representam entidades distintas (Dixon, 1999). In some MS patients (10–20%), the course of the disease can be classified as benign as they do not develop the characteristic disabilities ( McAlpine, 1961 ; Ramsaransing et al , 2001 ). Em alguns pacientes com esclerose múltipla (10-20%), o curso da doença pode ser classificada como benigna, pois não desenvolver a deficiência característica (McAlpine, 1961; Ramsaransing et al, 2001). Plaques of demyelination, with perivascular inflammation and destruction of oligodendroglia, preceded by violation of the blood–brain barrier (BBB), are scattered throughout the white matter of the CNS. Placas de desmielinização, com inflamação perivascular e destruição de oligodendroglia, precedido por violação da barreira hemato-encefálica (BBB), estão espalhadas por toda a substância branca do SNC. Apart from demyelination, axonal damage occurs in early stages of MS ( Trapp et al , 1999 ; Bjartmar et al , 2003 ). Além de desmielinização, lesão axonal ocorre nas fases iniciais de MS (Trapp et al, 1999; Bjartmar et al, 2003). Within one person, recent inflamed and more chronic lesions may coexist. Dentro de uma pessoa, os recentes lesões inflamadas e mais crônicas podem coexistir. Between MS patients, four basic patterns of neuropathological lesion characteristics suggest distinct, divergent disease mechanisms ( Lucchinetti et al , 1996 ). Entre pacientes com esclerose múltipla, quatro padrões básicos de características da lesão neuropatológicas sugerem distintas, divergentes mecanismos da doença (Lucchinetti et al, 1996).

A role for vitamin D in MS has been suggested ( Goldberg, 1974a , 1974b ; Hayes et al , 1997 ; Hayes, 2000 ). Um papel para a vitamina D em MS tem sido sugerido (Goldberg, 1974a, 1974b; Hayes et al, 1997; Hayes, 2000). The key questions concerning vitamin D are, one: is MS prevented by an adequate supply of vitamin D 3 , two: is MS aggravated by vitamin D deficiency, three: is MS aggravated by a vitamin D metabolic disorder, including four: a genetic vitamin D-related disorder? As questões-chave sobre a vitamina D, uma: MS é impedido por um fornecimento adequado de vitamina D 3, dois: MS é agravada pela deficiência de vitamina D, três: MS é agravada por um distúrbio metabólico da vitamina D, incluindo quatro: a vitamina genética D-transtorno relacionado?

Etiological factors of MS Os fatores etiológicos da MS

The etiology of MS is unknown. A etiologia da EM é desconhecida. It is regarded as a complex multicausal disease. É considerada uma doença complexa multicausal. The etiological factors comprise (a) genetic factors, (b) dysfunction of the immune system (autoimmunity), and (c) environmental factors. Os fatores etiológicos incluem: (a) fatores genéticos, (b) disfunção do sistema imune (auto), e (c) fatores ambientais.

An increased family incidence and association with certain HLA allotypes suggests genetic susceptibility ( Ebers & Sadovnick, 1994 ). Uma incidência familiar aumentada e associação com HLA alotipos certos sugere susceptibilidade genética (Sadovnick & Ebers, 1994). The genetic epidemiology indicates that MS is not a single-gene disorder ( Ebers, 1994 ; Compston, 1997 ; Noseworthy, 1999 ). A epidemiologia genética indica que o MS não é um distúrbio único gene-(Ebers, 1994; Compston, 1997; Noseworthy, 1999).

Autoimmune responses to myelin components may play an important role in the initiation of MS. Respostas auto-imunes a mielina componentes podem desempenhar um papel importante na iniciação do MS. The autoimmune character of MS is supported by the presence of numerous T lymphocytes in MS lesions and various deviating immune parameters for MS patients ( Lucchinetti et al , 1996 ). O caráter auto-imune de MS é suportado pela presença de numerosos linfócitos T em lesões de MS e de vários parâmetros imunológicos desviando para pacientes com esclerose múltipla (Lucchinetti et al, 1996). Furthermore, the autoimmune animal model for MS, experimental allergic encephalomyelitis (EAE), has supported the role of autoimmunity in the pathogenesis of MS. Além disso, o modelo animal para o auto-MS, encefalomielite alérgica experimental (EAE), tem apoiado o papel da autoimunidade na patogênese da esclerose múltipla.

Among the postulated environmental etiological factors for MS is infection by a latent virus, possibly by a human herpes virus or retrovirus, in which viral activation and expression trigger a secondary response. Entre os postulados ambientais fatores etiológicos para o MS é a infecção por um vírus latente, possivelmente por um vírus herpes humano ou retrovírus, em que a ativação viral e de expressão desencadear uma resposta secundária. However, no virus has yet been identified that causes MS ( Genain & Hauser, 1997 ; Monteyne et al , 1998 ). No entanto, nenhum vírus ainda não foi identificado que as causas da EM (Genain & Hauser, 1997; Monteyne et al, 1998). Other environmental factors, possibly contributing to susceptibility for MS, are sunlight and nutrition ( Agranoff & Goldberg, 1974 ; Alter et al , 1974 ; Goldberg, 1974a , 1974b ; Murrell et al , 1991 ; Esparza et al , 1995 ; Hutter & Laing, 1996 ; Hayes et al , 1997 ; Lauer, 1997 ; Van Noort & Amor, 1998 ). Outros fatores ambientais, podendo contribuir para a susceptibilidade para o MS, são a luz solar e nutrição (Agranoff & Goldberg, 1974; Alter et al, 1974; Goldberg, 1974a, 1974b; Murrell et al, 1991; Esparza et al, 1995; Hutter & Laing, 1996, Hayes et al, 1997; Lauer, 1997; Van Noort & Amor, 1998). The vast amount of literature on nutrition and MS indicates that food intake may be an influencing factor determining the disease susceptibility. A grande quantidade de literatura sobre a nutrição e MS indica que a ingestão de alimentos pode ser um fator que influencia a determinação da susceptibilidade à doença. For example, the intake of grain (high in phytic acid) or meat, fat, and milk from animals correlated positively with the prevalence of MS ( Swank et al , 1952 ; Goldberg, 1974a ; Murrell et al , 1991 ; Esparza et al , 1995 ). Por exemplo, a ingestão de cereais (ricos em ácido fítico) ou a carne, gordura e leite de animais foi positivamente correlacionada com a prevalência de MS (Swank et al, 1952; Goldberg, 1974a; Murrell et al, 1991; Esparza et al, 1995). Conversely, the intake of rice (low in phytic acid), fish, oil, skim milk, vegetables, and fruit correlated negatively with the prevalence of MS ( Swank, 1953 ; Goldberg, 1974a ; Lauer, 1997 ). Em contrapartida, o consumo de arroz (pobre em ácido fítico), peixes, azeite, leite desnatado, verduras e frutas correlacionada negativamente com a prevalência de MS (Swank, 1953; Goldberg, 1974a; Lauer, 1997). Both phytic acid and fat may influence the bioavailability of vitamin D metabolites. O ácido fítico e gordura podem influenciar a biodisponibilidade dos metabólitos da vitamina D. Phytic acid may reduce the absorption of calcium in the gut ( Mellanby, 1950 ). O ácido fítico podem reduzir a absorção do cálcio no intestino (Mellanby, 1950). Obesity has been associated with vitamin D deficiency ( Wortsman et al , 2000 ). A obesidade tem sido associada com a deficiência de vitamina D (Wortsman et al, 2000). Unfortunately, conclusive studies on the bioavailability of vitamin D 3 are rare as no validated methods for assessing the bioavailability are available ( Van den Berg, 1997 ). Infelizmente, os estudos conclusivos sobre a biodisponibilidade da vitamina D 3 não são raras como os métodos validados para avaliar a biodisponibilidade estão disponíveis (Van den Berg, 1997). An association has been reported in Norway between the relatively low risk of MS along its Atlantic coast and the relatively high dietary intake of fish oil, a rich source of vitamin D 3 ( Swank et al , 1952 ; Goldberg, 1974a ; Hayes et al , 1997 ). Uma associação tem sido relatada na Noruega entre o risco relativamente baixo de MS ao longo da sua costa atlântica e da ingestão dietética relativamente elevada de óleo de peixe, uma rica fonte de vitamina D 3 (Swank et al, 1952; Goldberg, 1974a; Hayes et al, 1997).

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Vitamin D metabolism Metabolismo da vitamina D

Vitamin D Vitamina D

Vitamin D 3 , a lipid-soluble vitamin, is produced by sunlight in the skin, and can also be provided by the diet. A vitamina D 3, uma vitamina solúvel em lipídios, é produzida pelo sol na pele, e também pode ser fornecido pela dieta. It is a precursor of the metabolic active hormone 1,25-(OH) 2 D. É um precursor do hormônio metabólico ativo 1,25 – (OH) 2 D. Sunlight has long been recognized as a major provider of vitamin D 3 for humans. Luz do Sol tem sido reconhecida como um importante fornecedor de vitamina D 3 para os humanos. Radiation in the UV-B (290–315 nm) portion of the solar spectrum photolyzes 7-dehydrocholesterol (provitamin D 3 ) in the skin to previtamin D 3 , which, in turn, is converted by a thermal process to vitamin D 3 ( Holick, 1987 ; Webb & Holick, 1988 ). Radiação no UV-B (290-315 nm) a porção do espectro solar photolyzes 7-dehidrocolesterol (pró-vitamina D 3) na pele a pré-vitamina D 3, que, por sua vez, é convertido por um processo térmico a vitamina D 3 ( Holick, 1987; Webb & Holick, 1988). The synthesis of vitamin D 3 in the skin is self-regulating ( Webb et al , 1989 ). A síntese da vitamina D 3 na pele é de auto-regulação (Webb et al, 1989). Excessive exposure to sunlight causes a photodegradation of previtamin D 3 and vitamin D 3 to prevent vitamin D 3 intoxication ( Clemens et al , 1982 ; Matsuoka et al , 1987 ). A exposição excessiva ao sol provoca uma fotodegradação de pré-vitamina D 3 e vitamina D 3 para evitar intoxicação por vitamina D 3 (Clemens et al, 1982; Matsuoka et al, 1987).

In addition to the production in the skin, vitamin D is supplied by food in two forms; vitamin D 2 (ergocalciferol, activated ergosterol), found in irradiated yeast, and vitamin D 3 (cholecalciferol), found in fish liver oils and fatty fish, including herring, mackerel, and sardines. Além da produção na pele, a vitamina D é fornecida pelos alimentos em duas formas, a vitamina D 2 (ergocalciferol, ativado ergosterol), encontrado no fermento irradiados e vitamina D 3 (colecalciferol), encontrada em óleos de fígado de peixe e peixes gordos , incluindo o arenque, cavala e sardinha. The natural human diet can only be considered as a secondary source of the vitamin, when there is enough exposure to sunlight ( Fraser, 1995 ; Vieth, 1999 ; Heaney et al , 2003a ). A dieta humana natural pode ser considerada apenas como uma fonte secundária de vitamina A, quando há bastante exposição à luz solar (Fraser, 1995; Vieth, 1999; Heaney et al, 2003a). However, in winter when UV-B in sunlight is limited, or when sunlight exposure is not adequate, dietary factors become of vital importance and dietary compensation should occur. No entanto, no inverno, quando a radiação UV-B na luz solar é limitada, ou quando a exposição solar não for adequada, fatores dietéticos se de vital importância e compensação alimentar deve ocorrer.

Vitamin D 3 is biologically inactive. A vitamina D 3 é biologicamente inativo. It is either stored in fat or converted by 25-hydroxylase (25-OHase) enzyme in the liver to 25OHD. Ou é armazenado na gordura ou convertida pela 25-hidroxilase (25-OHase) enzima no fígado a 25OHD. Interestingly, the presence of 25-OHase activity has also been demonstrated outside the liver in kidney, in keratinocytes in skin, and in parathyroid cells ( Lehmann et al , 1999 ; Gascon-Barre et al , 2001 ; Correa et al , 2002 ). Curiosamente, a presença de 25-atividade OHase demonstrou, também fora do fígado nos rins, nos queratinócitos na pele e nas células da paratireóide (Lehmann et al, 1999; Gascon-Barre et al, 2001; Correa et al, 2002).

25OHD 25OHD

25OHD is the major circulating form of vitamin D. The serum half-life of 25OHD is approximately 10 days to 3 weeks. 25OHD é a principal forma circulante da vitamina D. A meia-vida sérica de 25OHD é de aproximadamente 10 dias a 3 semanas. Serum 25OHD concentration is the indicator of the vitamin D status, and provides a good reflection of cumulative effects of exposure to sunlight and dietary intake of vitamin D ( Food and Nutrition Board (FNB), Institute of Medicine, 1997 ). A concentração sérica de 25OHD é o indicador do status da vitamina D, e fornece um bom reflexo do efeito cumulativo da exposição ao sol e ingestão de vitamina D (Food and Nutrition Board (FNB), Instituto de Medicina, 1997). Its concentration is used as a diagnostic criterion of vitamin D deficiency. Sua concentração é usado como critério de diagnóstico da deficiência de vitamina D. 25OHD is either stored in the liver or further converted by the enzyme 1 25OHD ou é armazenado no fígado ou ainda transformado pela enzima 1 alfa -hydroxylase (1 -hidroxilase (1 alfa -OHase) to 1,25-(OH) 2 D in the kidney, as well as in extra-renal tissues, including the brain (cerebellum, cerebral cortex) and lymph nodes ( Hewison et al , 2000 ; Zehnder et al , 2001 ). -OHase) a 1,25 – (OH) 2 D no rim, bem como em tecidos extra-renais, incluindo o cérebro (cerebelo, córtex cerebral) e gânglios linfáticos (Hewison et al, 2000; Zehnder et al, 2001 ).

Renal 1,25-(OH) 2 D and extra-renal 1,25-(OH) 2 D Renal 1,25 – (OH) 2 D e extra-renal 1,25 – (OH) 2 D

1,25-(OH) 2 D is the hormonally active form of vitamin D. Accumulating reports have provided evidence that 1,25-(OH) 2 D is a pleiotropic hormone influencing a plethora of biological actions, including regulation of calcium homeostasis, control of cell differentiation and maturation, and modification of immune responses ( Casteels et al , 1995 ; Cantorna et al , 1996 ; Hayes et al , 1997 ; Verstuyf et al , 1998 ; Brown et al , 1999 ; Hewison et al , 2000 ; Hayes, 2000 ; Overbergh et al , 2000 ; Mathieu et al , 2001 ; Garcion et al , 2002 ). 1,25 – (OH) 2 D é a forma hormonal ativa da vitamina D. Acumulando relatórios forneceram provas de que 1,25 – (OH) 2 D é um hormônio pleiotrópicos influenciando um grande número de ações biológicas, incluindo a regulação da homeostase do cálcio, controle da diferenciação celular e na maturação, e modificação de respostas imunes (Casteels et al, 1995; Cantorna et al, 1996; Hayes et al, 1997; Verstuyf et al, 1998; Brown et al, 1999; Hewison et al, 2000; Hayes , 2000; Overbergh et al, 2000; Mathieu et al, 2001; Garcion et al, 2002). In addition, 1,25-(OH) 2 D induces cell death, making the hormone of potential interest in the management of breast, prostate, and colon cancer, including brain tumors ( Hewison et al , 2001 ; Garcion et al , 2002 ). Além disso, 1,25 – (OH) 2 D induz a morte celular, fazendo com que o hormônio de potencial interesse na gestão de mama, próstata e cancro do cólon, incluindo tumores cerebrais (Hewison et al, 2001; Garcion et al, 2002) . The serum half-life of 1,25-(OH) 2 D is 4–6 h ( Kumar, 1986 ). A meia-vida de 1,25 – (OH) 2 D é de 4-6 h (Kumar, 1986). The renal 1 O 1 renal alfa -hydroxylation of 25OHD to 1,25-(OH) 2 D is highly regulated by the serum concentrations of parathyroid hormone (PTH), calcium, and phosphate ( Lips, 2001 ). -hidroxilação de 25OHD a 1,25 – (OH) 2 D é altamente regulada pelas concentrações séricas de hormônio da paratireóide (PTH), cálcio e fosfato (Lips, 2001). Owing to its relatively short serum half-life and the tight regulation of the production of 1,25-(OH) 2 D, it has not been proven to be a valuable marker for vitamin D deficiency, adequacy, or excess ( FNB, Institute of Medicine, 1997 ). Devido à sua meia soro-vida relativamente curta e uma regulamentação mais estrita da produção de 1,25 – (OH) 2 D, não foi provado ser um marcador valioso para a deficiência de vitamina D, a adequação ou excesso (FNB, Instituto de Medicina, 1997).

It is now acknowledged that a wide variety of extra-renal cells can produce 1,25-(OH) 2 D from 25OHD by the enzyme 1 É hoje reconhecido que uma ampla variedade de células extra-renal pode produzir 1,25 – (OH) 2 D a partir de 25OHD pela enzima 1 alfa -OHase in vitro , including activated macrophages, keratinocytes, and CNS cells (neurons and microglial cells) ( Adams et al , 1985 ; Pillai et al , 1987 ; Neveu et al , 1994 ). -OHase in vitro, incluindo macrófagos ativados, queratinócitos e células do SNC (neurônios e células da microglia) (Adams et al, 1985; Pillai et al, 1987; Neveu et al, 1994). The extra-renal production of 1,25-(OH) 2 D is not regulated in the same way as its renal production. A produção extra-renal de 1,25 – (OH) 2 D não está regulamentada, da mesma forma como sua produção renal. The relationship between expression of 1 A relação entre a expressão de 1 alfa -OHase activity by 1,25-(OH) 2 D in a particular tissue probably involves two specific mechanisms, the first of these being substrate access, and the second being auto-regulation of 1 -OHase atividade por 1,25 – (OH) 2 D em um tecido especial, provavelmente envolve dois mecanismos específicos, o primeiro deles sendo o acesso do substrato, ea segunda a ser auto-regulação de 1 alfa -OHase activity by 1,25-(OH) 2 D itself ( Hewison et al , 2000 ). -OHase atividade por 1,25 – (OH) 2 D em si (Hewison et al, 2000).

Exceptional levels of circulating 1,25-(OH) 2 D are found in several clinical conditions. Níveis excepcionais de circulação de 1,25 – (OH) 2 D são encontrados em várias condições clínicas. Lower levels have been found in severe vitamin D deficiency ( Lips et al , 1982 , 1988 ; Bouillon et al , 1987 ), as well as in inherited vitamin D metabolic disorders and chronic renal failure. Os níveis mais baixos foram encontrados em situação de grave deficiência de vitamina D (Lips et al, 1982, 1988; Bouillon et al, 1987), bem como em distúrbios metabólicos da vitamina D herdado e insuficiência renal crônica. Higher levels, caused by excessive extra-renal production, have been observed in sarcoidosis, tuberculosis, or malignant lymphoproliferation ( Hewison et al , 2001 ). Níveis mais altos, causada pelo excesso de produção extra-renal, foram observados na sarcoidose, tuberculose, ou Linfoproliferação (Hewison et al, 2001). The gene encoding 1 O gene que codifica 1 alfa -OHase is located on chromosome 12q13 and abnormal gene expression is the cause of hereditary pseudovitamin D-deficiency rickets (PDDR) ( St-Arnaud et al , 1997 ). -OHase está localizado no cromossomo 12q13 e expressão do gene anormal é a causa hereditária pseudovitamin D-raquitismo (deficiência PDDR) (St-Arnaud et al, 1997).

Vitamin D catabolism Catabolismo da vitamina D

Ultimately, 25OHD and 1,25-(OH) 2 D are metabolized by 24-hydroxylase (24-OHase), an enzyme induced by 1,25-(OH) 2 D itself to control its own levels in circulation ( Brown et al , 1999 ). Em última análise, 25OHD e 1,25 – (OH) 2 D são metabolizados pelo 24-hidroxilase (24-OHase), uma enzima induzida por 1,25 – (OH) 2 D-se a controlar os seus próprios níveis em circulação (Brown et al , 1999). Finally, calcitroic acid is the major excretory form ( Esvelt and De Luca, 1981 ). Finalmente, o ácido calcitroic é a principal forma de excreção (Esvelt e De Luca, 1981).

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Vitamin D transport and function A vitamina D de transportes e na função

Vitamin D-binding protein (DBP) A vitamina D-binding protein (DBP)

Vitamin D-binding protein (DBP) is a serum globulin, which is mainly produced in the liver. A vitamina D-binding protein (DBP) é uma globulina do soro, que é produzido principalmente no fígado. DBP transports vitamin D metabolites to a large number of target organs. PAD transporta metabólitos da vitamina D para um grande número de órgãos-alvo. Under normal physiological conditions, most of the circulating vitamin D metabolites are bound to DBP and albumin. Sob condições fisiológicas normais, a maioria dos metabolitos circulantes de vitamina D são obrigados a PAD e albumina. DBP helps to regulate the bioavailability of 1,25-(OH) 2 D, as it buffers the levels of the free metabolites and thus affords a degree of protection against short-term seasonally or dietary induced fluctuations ( White & Cooke, 2000 ). PAD ajuda a regular a biodisponibilidade de 1,25 – (OH) 2 D, como ele protege os níveis de metabólitos livres e, portanto, proporciona um grau de proteção contra curto prazo, as flutuações sazonais ou de dieta induzida (White & Cooke, 2000). The DBP gene locus 4q12 is among the most polymorphic known. O gene DBP locus 4q12 está entre os mais polimórfico conhecido.

Vitamin D receptor (VDR) Receptor da vitamina D (VDR)

When entering a target cell, 1,25-(OH) 2 D dissociates from DBP, diffuses across the plasma membrane, connects to the vitamin D receptor (VDR) and shuttles between the cytoplasm and the nucleus (nuclear VDR, nVDR). Ao entrar em uma célula-alvo, 1,25 – (OH) 2 D dissocia da PAD, difunde através da membrana plasmática, conecta-se ao receptor da vitamina D (VDR) e de ônibus entre o citoplasma eo núcleo (VDR nuclear, nVDR). Cellular action only follows after binding of 1,25-(OH) 2 D by the nVDR in the target cell. Ação celular só segue após a ligação de 1,25 – (OH) 2 D pelo nVDR na célula-alvo. The gene encoding the VDR is located on chromosome 12q14 and has several common allelic variants ( Zmuda et al , 2000 ). O gene que codifica o VDR está localizado no cromossomo 12q14 e tem diversas variantes alélicas comum (Zmuda et al, 2000).

The nVDR is a member of the nuclear steroid, retinoid, and thyroid hormone receptor superfamily, acts as a ligand-activated transcription regulator, and 1,25-(OH) 2 D is a ligand. O nVDR é um membro do esteróide nuclear, retinóide e superfamília do receptor da hormona tiroideia, age como um ligante ativado regulador de transcrição, e 1,25 – (OH) 2 D é um ligante. The activated VDR dimerizes with another nuclear receptor, the retinoic acid receptor (RXR). O activado dimerizes VDR com outro receptor nuclear, o receptor do ácido retinóico (RXR). The heterodimer RXR/VDR/1,25-(OH) 2 D binds to a vitamin D responsive element (VDRE), a specific sequence of DNA, in the promoter region of target genes, regulated by 1,25-(OH) 2 D. O RXR/VDR/1 heterodímero, 25 – (OH) 2 D se liga a um elemento responsivo da vitamina D (VDRE), uma seqüência específica de DNA, na região promotora dos genes-alvo, regulamentada por 1,25 – (OH) 2 D. Upon binding to the VDRE, the heterodimer RXR/VDR/1,25-(OH) 2 D activates or suppresses gene transcription, whereby synthesis of proteins is induced or repressed. Após a ligação para o VDRE, o RXR/VDR/1 heterodímero, 25 – (OH) 2 D ativa ou reprime a transcrição de genes, por meio da síntese de proteínas é induzida ou reprimida. 1,25-(OH) 2 D thus exerts biological actions through VDR-mediated gene expression dependent on the target cell ( Brown et al , 1999 ). 1,25 – (OH) 2 D, assim, exerce ações biológicas através da expressão do gene VDR-mediada dependentes da célula-alvo (Brown et al, 1999). VDR can also form homodimers, of which the functional significance is unknown ( Issa et al , 1998 ). VDR também pode formar homodímeros, do qual o significado funcional é desconhecido (Issa et al, 1998). Efficient transcription requires co-activator or co-repressor proteins ( Brown et al , 1999 ). Transcrição eficiente requer co-ativador ou co-repressor proteínas (Brown et al, 1999). For instance, Smad3, a downstream component of the transforming growth factor (TGF)- Por exemplo, Smad3, um componente a jusante do fator de crescimento transformador (TGF) — beta signaling pathway, acts as a co-activator of VDR, by potentiating ligand-induced transactivation of the VDR ( Yanagisawa et al , 1999 ). via de sinalização, atua como um co-ativador da VDR, por potencialização ligand-induced transativação do VDR (Yanagisawa et al, 1999). On the other hand, Smad-7 abrogates this Smad3-mediated VDR potentiation by inhibiting the Smad3–VDR complex. Por outro lado, Smad-7 revoga este Smad3 potenciação VDR mediada através da inibição da Smad3 complexo VDR. Thus, the interplay between the TGF- Assim, a interação entre o TGF – beta and vitamin D pathways can modulate the VDR transactivation both positively and negatively by involving different Smad proteins ( Yanagi et al , 1999 ). e vias de vitamina D pode modular a transativação VDR positivamente e negativamente, envolvendo diferentes proteínas Smad (Yanagi et al, 1999). 1,25-(OH) 2 D also mediates rapid responses via a putative membrane-bound receptor of the hormone ( Norman et al , 1992 ). 1,25 – (OH) 2 D é um mediador de resposta rápida através de uma membrana putative receptor do hormônio ligado (Norman et al, 1992).

Serum 1,25-(OH) 2 D concentration influences the number of VDR in the cells. Soro 1,25 – (OH) 2 D influencia a concentração do número de VDR em células. VDR in cells bind 1,25-(OH) 2 D and buffer 1,25-(OH) 2 D concentration in serum. VDR em células ligam 1,25 – (OH) 2 D e tampão 1,25 – (OH) 2 D concentração no soro. Action of 1,25-(OH) 2 D through the VDR can be hindered by low 1,25-(OH) 2 D levels, or by VDR underexpression, abnormal binding functions, and aberrant transcription ( Pike, 1991 ). Ação da 1,25 – (OH) 2 D através do VDR pode ser prejudicada pela baixa 1,25 – (OH) 2 níveis D, ou pelo VDR underexpression anormal, as funções de ligação, ea transcrição aberrante (Pike, 1991). The VDR has been identified in most nucleated cells of the body, involved in countless physiological functions ( Walters, 1992 ). O VDR tem sido identificado na maioria das células nucleadas do corpo, envolvido em inúmeras funções fisiológicas (Walters, 1992). VDR-containing cells, in autoimmune diseases, include VDR-células contendo, em doenças auto-imunes, incluem beta -cells in the pancreas in insulin-dependent diabetes mellitus (IDDM), chondrocytes in the joints in rheumatoid arthritis (RA), and oligodendrocytes in the brain in MS ( Casteels et al , 1995 ; Baas et al , 2000 ; DeLuca & Cantorna, 2001 ). As células do pâncreas no diabetes mellitus insulino-dependente (DMID), condrócitos nas articulações na artrite reumatóide (AR) e oligodendrócitos no cérebro em MS (Casteels et al, 1995; Baas et al, 2000; DeLuca & Cantorna, 2001). In parallel to oligodendrocytes, other CNS constituent cells (microglia, neurons, and astrocytes) are VDR-expressing cells responding directly to the hormone ( Garcion et al , 2002 ). Em paralelo com oligodendrócitos, CNS outras células constituintes microglia (, neurônios e astrócitos) são VDR-células que expressam a responder diretamente ao hormônio (Garcion et al, 2002). The VDR has also been identified in immune-competent cells, including macrophages and activated T-lymphocytes, which implies that 1,25-(OH) 2 D can exert effects on immune functions carried out by these cells ( Bhalla et al , 1983 ; Provvedini et al , 1983 ). O VDR também foi identificada em células imunes competentes, incluindo macrófagos e linfócitos T activados, o que significa que 1,25 – (OH) 2 D pode exercer efeitos sobre as funções imunológicas realizadas por essas células (Bhalla et al, 1983; Provvedini et al, 1983).

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Sunlight and vitamin D metabolism Luz solar e metabolismo da vitamina D

Sunlight and vitamin D 3 production in skin Luz solar e vitamina D na pele de produção 3

The production of vitamin D 3 in the skin depends on exposure to sunlight. A produção de vitamina D 3 na pele depende da exposição à luz solar. Yet, not all sunlight is intense enough to produce vitamin D 3 in the skin. Porém, nem toda a luz solar é intensa o suficiente para produzir a vitamina D 3 na pele. UV-B irradiance is the result of solar elevation, which in turn relies on three factors — latitude, time of year, and time of day. Irradiância UV-B é o resultado de elevação solar, que por sua vez, depende de três fatores – latitude, época do ano e hora do dia. UV-B irradiance, necessary for vitamin D 3 production, is less when the sun is lower and its path length through the atmosphere becomes longer; additional factors influencing its intensity include cloud cover, the amount of ozone, altitude, reflectivity of the earth’s surface, haze (aerosols), and other pollutions. Irradiância UV-B, necessárias para a produção de vitamina D 3, é menor quando o sol está mais baixo e seu comprimento do caminho através da atmosfera torna-se mais; fatores adicionais que influenciam a sua intensidade incluem cobertura de nuvens, a quantidade de ozônio, altitude, reflexibilidade da superfície da Terra , neblina (aerossóis), e outras poluições. In the tropics, sunlight is able to produce vitamin D 3 in the skin all year round. Nos trópicos, a luz solar é capaz de produzir a vitamina D 3 na pele durante todo o ano. Outside the tropics at latitudes between 23:5°, the sun is never at right angles relative to the earth’s surface and the seasonal influence becomes greater. Fora dos trópicos, em latitudes entre 23:5 °, o sol nunca se perpendicularmente em relação à superfície da terra e da influência sazonal torna-se maior. At latitudes higher than around 35°, sunlight is not able to produce previtamin D 3 in vitro all year round ( Holick, 2002 ). Em latitudes mais elevadas do que em torno de 35 °, a luz solar não é capaz de produzir pré-vitamina D 3, in vitro, durante todo o ano (Holick, 2002). In winter, the sun is not only weaker as its elevation is lower, but people also spend less time outdoors and cover their skin with clothing ( Webb & Holick, 1988 ). No inverno, o sol não é apenas mais fraca, pois sua elevação é menor, mas as pessoas também gastam menos tempo ao ar livre e cobrir sua pele com roupa (Webb & Holick, 1988). If one strives to achieve and maintain an optimal serum 25OHD concentration throughout the year, it is important to know when sunlight is able to produce vitamin D 3 in the skin and how long one needs to stay outdoors to produce a sufficient amount. Se alguém se esforça para alcançar e manter uma ótima 25OHD sérica concentração durante todo o ano, é importante saber quando a luz solar é capaz de produzir a vitamina D 3 na pele e em quanto tempo é necessário para ficar ao ar livre para produzir uma quantidade suficiente. Matters are being complicated, as UV-B irradiance has become a topic of increasing concern, because of its potential negative effects, including sunburn and skin cancer. Questões são complicadas, como irradiância UV-B tornou-se um tema de crescente preocupação, por causa de seus potenciais efeitos negativos, incluindo queimaduras solares e cancro da pele. Excessive UV-B irradiance needs to be avoided, without losing sight of its positive effect. Excesso irradiância UV-B deve ser evitado, sem perder de vista o seu efeito positivo.

The ability to synthesize previtamin D 3 in vitro has been published for a number of cities in the world ( Figure 1 ). A capacidade de sintetizar D previtamin 3 in vitro tem sido publicado por várias cidades do mundo (Figura 1). In Los Angeles, USA, at latitude 33:56°NL with an altitude (alt.) at 38 m above sea level, sunlight can produce previtamin D 3 in vitro all year round. Em Los Angeles, E.U.A., na latitude 33:56 ° NL com uma altitude (alt.) em 38 m acima do nível do mar, a luz solar pode produzir pré-vitamina D 3, in vitro, durante todo o ano. In Boston, USA (42:22° NL, alt. 6 m), little if any cutaneous vitamin D 3 production occurs in the four winter months from November to February, no matter how long one stays outdoors and in Edmonton, Canada (53:19° NL, alt. 715 m) the equivalent ‘vitamin D winter’ lasts 6 months, from October to March ( Webb & Holick, 1988 ). The influence of season and latitude on the synthesis of previtamin D 3 in vitro in the southern hemisphere was measured in Buenos Aires (34:50 SL°, alt. 20 m), Cape Town (33:58 SL°, alt. 42 m), Johannesburg (26:08° SL, alt. 1694 m) and Ushuaoa (54:48° SL, alt. 16 m) ( Holick, 2002 ). Only in Ushuaoa (54:48° SL, alt. 16 m) no previtamin D 3 was formed in the 6 winter months April–September. For Europe, no comparable data on cutaneous vitamin D 3 production have been reported, except for Bergen in Norway (60:17° NL, alt. 50 m). In Bergen the ‘vitamin D winter’ lasted 6 months, from October to March, but in the other months of the year the previtamin D 3 formation per month is less than in Edmonton and the hours of UV-B per day are also fewer ( Holick, 2002 ).

Figure 1. Figura 1.

Figura 1 - Infelizmente nós somos incapazes de fornecer um texto alternativo acessível para isso. Se precisar de ajuda para aceder a esta imagem, por favor help@nature.com contato ou o autorCities of the world, red dots, where the length of the ‘vitamin D winter’ has been measured: Bergen in Norway (60:17° NL, alt. 50 m), Boston (44:22° NL, alt. 6 m), Buenos Aires (34:50 SL°, alt. 20 m), Edmonton (59:19 NL°, alt. 715 m), Cape Town (33:58 SL°, alt. 42 m), Johannesburg (26:08° SL, alt. 1694 m), Ushuaoa (54:48° SL, alt. 16 m). Note: At latitudes higher than around 35°, sunlight is unable to produce previtamin D 3 in vitro all year round.

Full figure and legend (178 K )

In the United States the vitamin D intake is much higher than in Europe, due to fortification of milk with 10 Nos Estados Unidos, a ingestão de vitamina D é muito maior do que na Europa, devido à fortificação do leite com 10 mu g (400 IU) vitamin D per quart ( Norman, 2000 ). g (400 UI) de vitamina D por litro (Norman, 2000). Currently, in Europe, which is, by the way, much further away from the equator than the United States, milk is not fortified with vitamin D and recommended nutritional supplementation with vitamin D differs from country to country. Atualmente, na Europa, que é, aliás, muito mais longe do equador do que nos Estados Unidos, o leite não é fortificado com vitamina D e suplementação nutricional recomendada de vitamina D difere de país para país.

During the ‘vitamin D winter’, the body is dependent on its vitamin D 3 stores or on dietary intake from natural sources, food fortified with vitamin D, or supplements. Durante o “inverno vitamina D”, o corpo é dependente de sua vitamina D 3 lojas ou na ingestão de fontes naturais, alimentos fortificados com vitamina D ou suplementos. As vitamin D 3 barely occurs naturally in food, and food in most countries is not fortified with vitamin D, dietary supplementation with the vitamin may be necessary for certain groups in the ‘vitamin D winter’ to maintain an optimal 25OHD serum level throughout the year. Como a vitamina D 3 mal ocorre naturalmente nos alimentos, e alimentos, na maioria dos países não são fortificados com vitamina D, a suplementação com vitamina A pode ser necessário para certos grupos no ‘inverno vitamina D “para manter um nível sérico ideal 25OHD durante todo o ano .

Sunlight and 25OHD Luz solar e 25OHD

The approximate normal range for serum 25OHD values is 25–130 nmol/l ( Feldman et al , 1997 ). O intervalo de aproximadamente normal para soro 25OHD valores é 25-130 nmol / l (Feldman et al, 1997). Currently, there is no consensus on what represents an optimal serum 25OHD concentration. Atualmente, não há consenso sobre o que representa um ótimo soro 25OHD concentração. An increasing number of reports is available on 25OHD serum levels both in healthy and unhealthy populations, from which it has become apparent that serum 25OHD levels vary from winter to summer, with lower levels in winter ( Stamp, 1975 ; Bouillon et al , 1987 ; Lips et al , 1988 : McKenna, 1992 ; Scharla et al , 1996 ; Scharla, 1998 ). Um número crescente de relatórios está disponível em ambos os níveis séricos de 25OHD em populações saudáveis e insalubres, da qual tornou-se evidente que os níveis séricos de 25OHD variam de inverno a verão, com níveis mais baixos no inverno (Stamp, 1975; Bouillon et al, 1987; Lips et al, 1988: McKenna, 1992; Scharla et al, 1996; Scharla, 1998). Here we focus on two of these reports ( Bouillon et al , 1987 ; Scharla, 1998 ). Aqui nos concentramos em dois desses relatórios (Bouillon et al, 1987; Scharla, 1998).

In an age- and sex-stratified population-based sample of a normal population living in South Germany ( n =415, 206 women and 209 men, ranging from 50 to 80 y), serum 25OHD reached its nadir of 42.5 Em uma idade e sexo da população estratificada baseada em amostras de uma população que vive no sul da Alemanha normal (n = 415, 206 mulheres e 209 homens, variando de 50 a 80 y), 25OHD sérica atingiu seu ponto mais baixo de 42,5 plusminus 22.5 nmol/l in January, and its zenith of 67.5 22,5 nmol / l, em janeiro, e seu apogeu de 67,5 plusminus 25 nmol/l in the months August and September ( Scharla et al , 1996 ). 25 nmol / l no mês de agosto e setembro (Scharla et al, 1996). Of the women, 40% had a subclinical vitamin D deficiency in winter, defined as < 30 nmol/l 25OHD ( Scharla, 1998 ). Das mulheres, 40% tinham uma deficiência subclínica de vitamina D no inverno, definidas como <30 nmol / l 25OHD (Scharla, 1998). The serum 25OHD concentration of elderly subjects living in Belgium, who were consecutively admitted to one of the geriatric wards in Leuven ( n =240, 137 women and 103 men, ranging from 55 to 99 y), reached its nadir of 18 nmol/l in February. O soro 25OHD concentração de idosos residentes na Bélgica, que foram, consecutivamente admitidas em uma das enfermarias de geriatria em Leuven (n = 240, 137 mulheres e 103 homens, variando de 55 a 99 y), atingiu seu nadir de 18 nmol / l em fevereiro. The lowest levels were recorded in the 4 months from January to April (mean < 25 nmol/l), and its zenith of 30 nmol/l in July ( Bouillon et al , 1987 ). Os níveis mais baixos foram registrados nos 4 meses de janeiro a abril (média <25 nmol / l), e seu auge de 30 nmol / l em julho (Bouillon et al, 1987). It was found that the frequency of very low levels of 25OHD (< 12.5 nmol/l) was more pronounced in wheelchair-bound or institutionalized elderly subjects ( Bouillon et al , 1987 ). Verificou-se que a freqüência de níveis muito baixos de 25OHD (<12,5 nmol / l) foi mais pronunciada em cadeira de rodas ou idosos institucionalizados (Bouillon et al, 1987). From these reports, it could be concluded that the unhealthy elderly living in Belgium had lower 25OHD levels in winter than in summer. A partir destes relatórios, pode-se concluir que a vida não saudáveis idosos na Bélgica tinham níveis de 25OHD menores no inverno que no verão. Their monthly and yearly 25OHD levels were significantly lower than those of their healthy younger control subjects. Sua mensal e anual 25OHD níveis foram significativamente inferiores aos dos seus indivíduos saudáveis jovens controle. The unhealthy elderly living in Belgium also had lower monthly 25OHD levels than the healthy elderly living in South Germany. Os idosos saudáveis que vivem na Bélgica também tinham níveis de 25OHD mensal menor do que os idosos saudáveis que vivem no sul da Alemanha. Not only in unhealthy elderly, but also in young subjects a significant difference between winter and summer 25OHD has been found ( Guillemant et al , 1995 , 1999 ; Docio et al , 1998 ; Zittermann et al , 1999 ). Não só em idosos saudáveis, mas também em indivíduos jovens, uma diferença significativa entre o inverno eo verão 25OHD foi encontrado (Guillemant et al, 1995, 1999; Docio et al, 1998; Zittermann et al, 1999). Taken together, these results emphasize a widespread seasonal variation in 25OHD levels, with low 25OHD levels in winter. Em conjunto, estes resultados enfatizam uma ampla variação sazonal em níveis de 25OHD, com baixos níveis de 25OHD no inverno. This seasonal variation is reflected in the approximate normal range for serum 25OHD values 25–130 nmol/l. Esta variação sazonal é refletido no intervalo de aproximadamente normal para soro 25OHD valores de 25-130 nmol / l. This wide range is used to classify individuals in vitamin D deficient and sufficient. Esta gama é usada para classificar os indivíduos deficientes em vitamina D e suficiente.

The Royal Dutch Meteorological Institute (KNMI) publishes the monthly and yearly mean duration of sunlight in hours of different cities in the world ( Nellestijn & Dekker, 1998 ). O Instituto Meteorológico Real Holandês (KNMI) publica a duração mensal e anual médio de horas de luz solar em diferentes cidades do mundo (Nellestijn & Dekker, 1998). The monthly mean duration of sunlight in hours in Munich in south Germany (48:21° NL, alt. 527 m) and Brussels in Belgium (50:54° NL, alt. 55 m) published by Nellestijn and Dekker (1998) , as well as the monthly mean serum 25OHD concentration of healthy elderly in south Germany reported by Scharla (1998) and that of unhealthy elderly in Belgium reported by Bouillon et al (1987) , were used to calculate the correlations. A duração média mensal da luz do sol nas horas em Munique, no sul da Alemanha (48:21 ° NL, alt. 527 m) e Bruxelas, na Bélgica (50:54 ° NL, alt. 55 m), publicado pela Nellestijn e Dekker (1998), bem como o valor médio mensal do soro 25OHD concentração de idosos saudáveis no sul da Alemanha relatado por Scharla (1998) e de idosos saudáveis na Bélgica relatado por Bouillon et al (1987), foram utilizados para calcular as correlações. The author of the present paper compared 12 consecutive months of the year and found a significant correlation between sunlight and 25OHD, 2 months later, in healthy elderly in south Germany r =0.86 ( P < 0.001, n =12) and in unhealthy elderly in Belgium r =0.90 ( P < 0.001, n =12). O autor do presente trabalho em comparação de 12 meses consecutivos do ano e encontraram uma correlação significativa entre a luz solar e 25OHD, 2 meses depois, em idosos saudáveis no sul da Alemanha r = 0,86 (P <0,001, n = 12) e em idosos saudáveis em Bélgica r = 0,90 (P <0,001, n = 12). This finding is in line with the time lag of 2 months between sunlight and 25OHD reported in other studies ( Hine & Roberts, 1994 ; Need et al , 2000 ). Esta constatação está em consonância com o lapso de tempo de 2 meses entre a luz solar e 25OHD relatado em outros estudos (Hine & Roberts, 1994; Need et al, 2000). It has been stated that the concentration as found in healthy individuals at the end of summer or as found in healthy individuals in the tropics provides a physiological indication of what might be optimal to maintain throughout the year ( Vieth, 1999 ). Tem sido afirmado que a concentração, tal como encontrados em indivíduos saudáveis no fim do verão ou como encontrados em indivíduos saudáveis nos trópicos fornece uma indicação fisiológica do que poderia ser ideal para manter durante todo o ano (Vieth, 1999).

The approximate normal range for serum 1,25-(OH) 2 D values is 36–144 pmol/l ( Feldman et al , 1997 ). O intervalo de aproximadamente normal para soro 1,25 – (OH) 2 D é valores 36-144 pmol / l (Feldman et al, 1997). No seasonal variation in 1,25-(OH) 2 D levels was observed in healthy adults ( Chesney et al , 1981 ; Bouillon et al , 1987 ). Não houve variação sazonal em 1,25 – (OH) 2 níveis D foi observada em adultos saudáveis (Chesney et al, 1981; Bouillon et al, 1987). No association between 25OHD and concentrations of 1,25-(OH) 2 D was found in euthyroid patients, who previously had low 25OHD (<50 nmol/l) levels, but had been advised to take 25 Não houve associação entre 25OHD e as concentrações de 1,25 – (OH) 2 D foi encontrada em pacientes euthyroid, que anteriormente tinha 25OHD baixa (<50 nmol / l) níveis, mas tinham sido aconselhados a tomar 25 mu g (1000 IU)/day vitamin D 3 ( Vieth et al , 2003 ). g (1000 UI) / dia de vitamina D 3 (Vieth et al, 2003).

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Vitamin D nutrition Vitamina D nutrição

Dietary compensation should occur to overcome low 25OHD levels when cutaneous production of vitamin D 3 is inadequate. Dietary compensação deve ocorrer de baixo para superar os níveis de 25OHD, quando a produção cutânea de vitamina D 3 é inadequada. For their recommendations of vitamin D 3 intake, National Councils on Food and Nutrition have abandoned the older criterion of absence of disease as the definition of adequacy. Para que as suas recomendações de ingestão de vitamina D 3, Conselhos Nacionais de Alimentação e Nutrição, ter abandonado o antigo critério de ausência de doenças como a definição de adequação. Now they are confronted with two new questions, one: what concentration of serum 25OHD is adequate, and two: how much vitamin D 3 is needed each day to meet or sustain that concentration. Agora, eles são confrontados com duas novas perguntas, uma: que a concentração sérica de 25OHD é adequado, e dois: o quanto de vitamina D 3 é necessária a cada dia para atingir ou manter a concentração. The border between a vitamin D-deficient and -sufficient state is represented by reported cutoff levels for the 25OHD concentration which rang widely from 12.5 to 140 nmol/l, but seem to increase over the years ( Bouillon et al , 1987 ; Chapuy et al , 1997 ; Dawson-Hughes et al , 1997 ; Barger-Lux et al , 1998 ; Malabanan et al , 1998 ; Scharla, 1998 ; Thomas et al , 1998 ; Vieth, 1999 ; Need et al , 2000 ; Lips, 2001 ; Heaney et al , 2003a ). A fronteira entre uma deficiência de vitamina D e estado-suficiente é representada por níveis de corte relatado para a concentração 25OHD que tocou amplamente 12,5-140 nmol / l, mas parece aumentar ao longo dos anos (Bouillon et al, 1987; Chapuy et al , 1997; Dawson-Hughes et al, 1997; Barger-Lux et al, 1998; Malabanan et al, 1998; Scharla, 1998, Thomas et al, 1998; Vieth, 1999; Need et al, 2000; Lips, 2001; Heaney et al, 2003a). Serum levels of 25OHD between 30 and 100 nmol/l have been mentioned as necessary to ensure vitamin D sufficiency ( Barger-Lux et al , 1998 ; Lips, 2001 ; Heaney, 2003b ; Vieth et al , 2003 ). Os níveis séricos de 25OHD entre 30 e 100 nmol / l foram mencionadas como necessárias para garantir a suficiência de vitamina D (Barger-Lux et al, 1998; Lips, 2001; Heaney, 2003b; Vieth et al, 2003). In elderly nursing home residents, vitamin D 3 10 Em residentes de asilos de idosos, a vitamina D 3 10 mu g (400 IU)/day increased serum 25OHD from 22 to 62 nmol/l in 12 weeks ( Chel et al , 1998 ). g (400 UI) / dia 25OHD sérica de 22-62 nmol / l em 12 semanas (Chel et al, 1998). Others have observed higher doses to ensure adequate serum 25OHD levels ( Barger-Lux et al , 1998 ; Heaney et al , 2003a ; Vieth et al , 2003 ). Outros têm observado altas doses de soro adequada para assegurar níveis de 25OHD (Barger-Lux et al, 1998; Heaney et al, 2003a; Vieth et al, 2003). Recently, a daily supplement of 25 Recentemente, um suplemento diário de 25 mu g (1000 IU) vitamin D 3 has been advocated for all adults to ensure a serum 25OHD level of at least 40 nmol/l ( Vieth et al , 2001 , 2003 ). g (1000 UI) de vitamina D 3 tem sido defendida por todos os adultos para garantir um nível de 25OHD sérica de pelo menos 40 nmol / l (Vieth et al, 2001, 2003). There is no consensus on this, but this dose is well below the Tolerable Upper Intake Level (UL) of vitamin D for adults of 50 Não há consenso sobre isso, mas esta dose for bem abaixo do tolerável Upper Intake Level (UL) de vitamina D para adultos de 50 mu g (2000 IU)/day set by the FNB of the Institute of Medicine for the USA, as well as by the Scientific Committee on Food of the European Commission (SCF) for the European Union ( FNB, Institute of Medicine, 1997 ; SCF, 2002 ). g (2000 UI) / dia fixado pela FNB, do Instituto de Medicina para a E.U.A., bem como pelo Comité Científico da Alimentação Humana da Comissão Européia (SCF) para a União Europeia (FNB, Instituto de Medicina, 1997; SCF , 2002).

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MS and vitamin D MS e de vitamina D

MS prevalence and sunlight Prevalência e da luz solar

MS is more common in temperate climates than in the tropics, with a prevalence of 100/100 000 and 10/100 000, respectively ( Martyn, 1991 ; Gale & Martyn, 1995 ). MS é mais comum em climas temperados que nos trópicos, com uma prevalência de 100/100 000 e 10/100 000, respectivamente (Martyn, 1991; Gale & Martyn, 1995). Of all the climatic variables analyzed, insolation, in terms of annual and winter hours of sunlight, exhibited the strongest negative correlation with the prevalence of MS ( Acheson et al , 1960 ; Norman et al , 1983 ). De todas as variáveis climáticas analisadas, insolação, em termos de horas anuais de inverno e de luz solar, apresentaram a maior correlação negativa com a prevalência de MS (Acheson et al, 1960; Norman et al, 1983). The incidence of MS is low in areas with at least 3000 h sunlight annually or with sufficient vitamin D 3 intake ( Goldberg, 1974a ). A incidência de MS é baixa em áreas com luz solar, no mínimo, 3000 h anualmente ou com um número suficiente de vitamina D 3 de admissão (Goldberg, 1974a). Unlike mortality from skin cancer, mortality from MS was negatively associated with residential exposure to sunlight ( Freedman et al , 2000 ). Ao contrário da mortalidade por câncer de pele, a mortalidade de MS foi negativamente associado com a exposição à luz solar residencial (Freedman et al, 2000). A negative correlation between ultraviolet radiation (UVR) and MS prevalence was found in Australia ( Van der Mei et al , 2001 ). A correlação negativa entre a radiação ultravioleta (RUV) ea prevalência de SM foi encontrado na Austrália (Van der Mei et al, 2001). The suggestion that the risk of developing MS is largely determined before the age of 15 y has been questioned by Australian epidemiological data. A sugestão de que o risco de desenvolver esclerose múltipla é largamente determinado antes da idade de 15 y tem sido questionada pelo australiano dados epidemiológicos. The prevalence in the migrant population from the UK and Ireland in the different regions in Australia showed a significant correlation with latitude and was considerably less than in their countries of origin ( Hammond et al , 2000 ). A prevalência na população de migrantes provenientes do Reino Unido e na Irlanda em diferentes regiões da Austrália mostrou uma correlação significativa com a latitude e foi consideravelmente menor do que nos seus países de origem (Hammond et al, 2000). The epidemiological evidence suggests that UVR may play a protective role in three autoimmune diseases: MS, insulin-dependent diabetes mellitus, and rheumatoid arthritis has been reviewed ( Ponsonby et al , 2002 ). A evidência epidemiológica sugere que a RUV pode desempenhar um papel protetor em três doenças autoimunes: esclerose múltipla, diabetes mellitus insulino-dependente, e artrite reumatóide foi comentado (Ponsonby et al, 2002). New evidence has been reported that increased sun exposure during ages 6–15 y is associated with a decreased risk of multiple sclerosis ( Van der Mei et al , 2003 ). Novas evidências tem sido relatado que a exposição ao sol aumentou durante as idades 6-15 y está associado com um risco menor de esclerose múltipla (Van der Mei et al, 2003). Interestingly, the prevalence of MS among Sardinians presents evidence against the latitude gradient theory ( Pugliatti et al , 2001 ) and could be explained by a high susceptibility of the population to MS ( Montomoli et al , 2002 ). Curiosamente, a prevalência de SM entre Sardinians apresenta provas contra a teoria do gradiente de latitude (Pugliatti et al, 2001) e poderia ser explicada por uma alta suscetibilidade da população de MS (Montomoli et al, 2002).

MS and 25OHD serum concentration MS e da concentração de 25OHD sérica

Only a few reports have investigated the association between MS and 25OHD serum concentration. Somente alguns relatórios têm investigado a associação entre MS e concentração sérica de 25OHD. Vitamin D deficiency was detected in a group of female MS patients who were subjects of a study on osteoporosis. A deficiência de vitamina D foi detectado em um grupo de pacientes do sexo feminino de MS que participaram de um estudo sobre a osteoporose. Of these patients ( n =52), 70% had a subclinical vitamin D deficiency, defined as serum 25OHD <50 nmol/l ( Nieves et al , 1994 ). Destes pacientes (n = 52), 70% tinham uma deficiência subclínica de vitamina D, definida como 25OHD sérica <50 nmol / l (Nieves et al, 1994). This study consecutively recruited female MS patients who were admitted to a tertiary care hospital because of deterioration in their clinical status, and there was no appropriate control group. Este estudo consecutivamente recrutados pacientes do sexo feminino de MS que foram internados em um hospital terciário por causa da deterioração do seu estado clínico, e não havia um grupo controle adequado. Results suggested that low circulating 25OHD levels contributed to low bone mineral density (BMD) ( Nieves et al , 1994 ). Os resultados sugerem que baixos níveis circulantes 25OHD contribuiu para a baixa densidade mineral óssea (DMO) (Nieves et al, 1994).

Another group of MS patients ( n =54), of whom 64% had a subclinical vitamin D deficiency, defined as serum 25OHD < 50 nmol/l, had more rapid bone loss and more frequent fractures than healthy age- and gender-matched controls ( Cosman et al , 1998 ). Outro grupo de pacientes com esclerose múltipla (n = 54), dos quais 64% tinham uma deficiência subclínica de vitamina D, definida como 25OHD sérica <50 nmol / l apresentaram perda óssea mais rápida e mais freqüente de fraturas que a idade saudáveis e de sexo, controles pareados (Cosman et al, 1998). Levels of 25OHD were on average 20–37.5 nmol/l lower in MS patients than they were in the three control groups: men, pre- and postmenopausal women. Níveis de 25OHD foram, em média 20-37,5 nmol / l menor em pacientes com EM do que eram em três grupos de controle: homens, pré e pós-menopausa. In the analyses, lack of sunlight exposure, a vitamin D-deficient diet, immobility, and corticosteroid treatment contributed to the low 25OHD serum concentrations ( Cosman et al , 1998 ). Nas análises, a falta de exposição à luz solar, a vitamina D, dieta deficiente, imobilidade, uso de corticóide e contribuiu para a baixa concentrações séricas de 25OHD (Cosman et al, 1998). However, in this study, it was not clear whether the vitamin D deficiency was merely a result of immobility, as it has been reported that immobility may be the strongest risk factor for vitamin D deficiency ( Gloth et al , 1995 ). No entanto, neste estudo, ficou claro se a deficiência da vitamina D foi apenas uma conseqüência da imobilidade, como tem sido relatado que a imobilidade pode ser o maior factor de risco para a deficiência de vitamina D (Gloth et al, 1995).

Mahon et al (2003) reported that 48% of MS patients ( n =39) had a subclinical vitamin D deficiency at baseline, defined as serum 25OHD <50 nmol/l. Mahon et al (2003) relataram que 48% dos pacientes com EM (n = 39) tinha uma deficiência subclínica de vitamina D na linha de base, definido como 25OHD sérica <50 nmol / l.

No reports have been found on the 1,25-(OH) 2 D serum concentration in MS patients. Não foram encontrados relatos sobre a 1,25 – (OH) 2 D concentração do soro em pacientes com EM. Case–control studies with sufficient power on patients with MS with respect to serum 25OHD and 1,25-(OH) 2 D concentration are lacking. Estudos de caso-controle com potência suficiente em pacientes com EM com relação ao soro 25OHD e 1,25 – (OH) 2 D concentração estão faltando. Moreover, seasonal variation of 25OHD serum concentration has not yet been established in MS patients. Além disso, a variação sazonal da concentração sérica de 25OHD ainda não foi estabelecida em pacientes com EM.

MRI and season RM e temporada

Various studies have investigated the association between number of active magnetic resonance imaging (MRI) lesions and season ( Auer et al , 2000 ; Embry et al , 2000 ; Rovaris et al , 2001 ; Killestein et al , 2002 ). Vários estudos têm investigado a associação entre o número de imagens de ressonância magnética ativa (MRI) e lesões temporada (Auer et al, 2000; Embry et al, 2000; Rovaris et al, 2001; Killestein et al, 2002). Active MRI lesions are the gadolinium-enhancing lesions on MRI scans, which reflect subclinical disease activity. Lesões ativas são a ressonância magnética gadolínio-realçando lesões em varreduras de MRI, que refletem a atividade da doença subclínica. A statistical significant seasonal fluctuation, measured as active MRI lesions, has been demonstrated in MS patients ( n =53) living in south Germany. A flutuação estatística significativa sazonal, medido como lesões ativas de ressonância magnética, tem sido demonstrada em pacientes com EM (n = 53) que vivem no sul da Alemanha. The number of active MRI lesions was the highest in April and lowest in October ( Auer et al , 2000 ). O número de lesões ativas de ressonância magnética foi o maior em abril e menor em outubro (Auer et al, 2000). The seasonal variation of active MRI lesions in MS patients has since been re-addressed in other studies. A variação sazonal de lesões ativas de ressonância magnética em pacientes do MS, desde então, sido re-abordados em outros estudos. The monthly mean number of MRI lesions was pooled in four seasons: spring (March, April, May), summer (June, July, August), autumn (September, October, November), and winter (December, January, February). O número médio mensal de lesões de RM foi agrupada em quatro estações: primavera (março, abril, maio), verão (junho, julho, agosto), Outono (Setembro, Outubro, Novembro), e no inverno (dezembro, janeiro, fevereiro). No statistical significant difference could be detected between the number of active MRI lesions in these four seasons ( Rovaris et al , 2001 ; Killestein et al , 2002 ). Não houve diferença estatística significativa poderia ser detectada entre o número de lesões ativas de ressonância magnética nestes quatro temporadas (Rovaris et al, 2001; Killestein et al, 2002). However, these calendar months do not necessarily correspond with the ‘vitamin D winter’ and more importantly do not necessarily represent the circulating 25OHD levels of the individuals under investigation. No entanto, estes meses de calendário não corresponde necessariamente com a ‘Winter vitamina D “e, mais importante, não representam necessariamente a 25OHD níveis circulantes dos indivíduos sob investigação. In addition, Rovaris et al (2001) used data from MS patients living in different parts of the world. Além disso, Rovaris et al (2001) utilizou dados de pacientes com esclerose múltipla que vivem em diferentes partes do mundo.

Embry et al (2000) have graphically combined two separate studies and showed close correspondence between the curve representing monthly mean serum 25OHD concentrations in the group of non-MS individuals provided by Scharla and the curve representing the monthly number of MRI lesions, 2 months later, in MS patients provided by Auer ( Scharla, 1998 ; Auer et al , 2000 ). Of course, there exists an inherent weakness in combining data from different studies to reach a new conclusion. In this case, the 25OHD serum levels were measured in a group of non-MS individuals. These levels may not be representative of a cohort of MS patients, whose vitamin D metabolite levels may be influenced by their MS.

The monthly mean duration of sunlight in hours in Munich published by Nellestijn and Dekker (1998) and the monthly mean number of active MRI lesions reported by Auer et al (2000) were used to calculate the correlation. The author of the present paper compared the 12 consecutive months of the year and found a statistical significant inverse correlation between sunlight and active MRI lesions, 4 months later, r =-0.90 ( P <0.001, n =12).

Further research is required; currently no reports are available on mean serum 25OHD concentrations, and active MRI lesions by months of the year in patients with MS living in the same area.

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Neuro-immunology and vitamin D metabolites

The CNS as a target tissue for vitamin D metabolites is supported by discovery of VDR in the rat forebrain, hippocampus, cerebellum, brainstem, spinal cord, and perivascular tissue and the discovery of 1 alfa -OHase in cerebellum and cerebral cortex ( Neveu et al , 1994 , Issa et al , 1998 , Hewison et al , 2000 ; Zehnder et al , 2001 ). In addition, the possibility of a local synthesis of 1,25-(OH) 2 D in brain has been postulated ( Garcion et al , 2002 ). Profound alterations in the brain at birth have been demonstrated in rats born to vitamin D 3 -deficient mothers ( Eyles et al , 2003 ).

The influences of 1,25-(OH) 2 D on cells of the nervous system were recently reviewed by Garcion ( Garcion et al , 2002 ). It appeared that 1,25-(OH) 2 D had effects on neurons, oligodendrocytes, as well as astrocytes, but the exact pathways of these effects remain to be established. In general, the influences of 1,25-(OH) 2 D on these cells seem to be neuroprotective and anti-inflammatory ( Garcion et al , 2002 ).

Immune system and 1,25-(OH) 2 D

The active form of vitamin D, 1,25-(OH) 2 D, is a potent regulator of the immune system ( Bouillon et al , 1995 ; Casteels et al , 1995 ; Cantorna et al , 1996 , 1998 , 1999 ; Hayes et al , 1997 ; Nashold et al , 2000 , 2001 ; Gregori et al , 2001 ; Griffin et al , 2001 ). Here we focus on the autoimmune animal model for MS EAE. The preventive and curative effects of vitamin D-related treatment on the clinical course of EAE are described ( Table 1 ). The effects on the cellular level, which are relevant for EAE, and may have implications for MS and other autoimmune diseases, are summarized. The possible actions of vitamin D metabolites on immune cells relevant for EAE are portrayed in Figure 2 . Finally, the influences of vitamin D metabolites on the production of cytokines and nitric oxide (NO), and on the BBB are described.

Figure 2. Figura 2.

Figura 2 - Infelizmente nós somos incapazes de fornecer o texto alternativo acessível para isso. Se precisar de ajuda para aceder a esta imagem, por favor help@nature.com contato ou o autorDownregulation by 1,25-(OH) 2 D of pro-inflammatory dendritic cell and T-cell function and macrophage activity and migration, in experimental allergic encephalomyelitis (EAE, an animal model of MS). Effects on the CNS-constituting cells are not incorporated in this figure, but are reviewed in Garcion et al (2002) . The effect of 1,25-(OH) 2 D on the cells of the BBB is unknown, but EAE data suggest that cellular infiltration is inhibited ( Nashold et al , 2000 ). Further references on which this figure is based are mentioned in the text under Neuro-immunology and vitamin D metabolites. Dendritic cell, DC; monocyte, MO; T helper 1 lymphocyte, Th1; T helper 2 lymphocyte, Th2; interferon gamma, IFN gamma itálico ; interleukin, IL; nitric oxide, NO; transforming growth factor beta , TGF , TGF beta ; tumor necrosis factor alpha, TNF alfa . .

Full figure and legend (198 K )

Experimental autoimmune encephalomyelitis (EAE)

EAE is a useful (although not perfect) animal model of human MS ( Van Etten et al , 2003 ). EAE is induced by immunization of rodents or primates with myelin or myelin components. This results in the generation of autoreactive, myelin-specific T lymphocytes. In the CNS of EAE animals perivascular inflammatory lesions are present and, depending on the immunization protocol, a variable degree of demyelination is observed. The lesions in the brain and spinal cord are accompanied by transient clinical signs such as paralysis of the tail and hind limbs. EAE can also be induced by transferring T lymphocytes from rats immunized with myelin components into naïve rats, indicating the crucial role of T lymphocytes in this model ( Paterson & Hanson, 1969 ). In particular, the interferon-gamma (IFN- gamma itálico )-producing T helper 1 (Th1) lymphocytes are required for induction of EAE. Macrophages are crucial for the effector phase of EAE, the phase in which actual tissue damage is caused by an immune response. In EAE, macrophage depletion leads to complete suppression of clinical signs ( Huitinga et al , 1990 ; Tran et al , 1998 ).

EAE and vitamin D-related treatment

Table 1 summarizes the observed effects of vitamin D-related treatment on EAE. Exposure of mice to whole body (full spectrum) UV was effective in preventing EAE when administered before immunization, but was ineffective in modifying ongoing EAE or in preventing relapses of EAE induced by re-immunization ( Hauser et al , 1984 ). However, this report does not mention vitamin D metabolites at all. The first study on 1,25-(OH) 2 D treatment of EAE was by Lemire and Archer (1991) and showed that administration of 1,25-(OH) 2 D during the immunization phase in mice significantly prevented the onset and development of EAE. The preventive effect of 1,25-(OH) 2 D on EAE in mice given before EAE induction was complete ( Cantorna et al , 1996 ). When treatment with 1,25-(OH) 2 D on EAE was started after the appearance of clinical signs, progression and severity was decreased in mice ( Cantorna et al , 1996 ) and rats ( Nataf et al , 1996 ). A vitamin D-deficient diet resulted in an increased susceptibility to EAE, an accelerated onset of paralytic symptoms and aggravated clinical symptoms ( Cantorna et al , 1996 ). In rats deprived of vitamin D, the clinical signs of EAE increased ( Garcion et al , 2003 ). Withdrawal of 1,25-(OH) 2 D after EAE induction resulted in a resumption of clinical signs ( Cantorna et al , 1996 ). The effect of 1,25-(OH) 2 D can be potentiated by cyclosporine, sirolimus (Rapamycin, RAP), and calcium ( Branisteanu et al , 1995 , 1997 ; Cantorna et al , 1999 ). In EAE in mice, calcium was required in addition to 1,25-(OH) 2 D to prevent the appearance of this disease, and the higher the calcium intake the lower the 1,25-(OH) 2 D dose needed ( Cantorna et al , 1999 ). These results suggest that 1,25-(OH) 2 D and dietary calcium are both involved in the prevention of symptomatic EAE ( Cantorna et al , 1999 ; DeLuca & Cantorna, 2001 ). Interestingly, changes in dietary calcium and phosphate levels resulted in changes in target tissue VDR expression ( Issa et al , 1998 ). VDR itself is essential for the immunosuppressive ability of 1,25-(OH) 2 D during EAE ( Meehan & DeLuca, 2002 ). From studies on vitamin D deficiency in the elderly, it is understood that a low calcium intake causes secondary hyperparathyroidism, which increases vitamin D turnover and aggravates vitamin D deficiency and its consequences, while high calcium intake may reduce vitamin D requirement ( Lips, 2001 ).

Treatment with synthetic 1,25-(OH) 2 D analogs has also been reported ( Lemire et al , 1994 ; Mattner et al , 2000 ; Van Etten et al , 2000 , 2003 ; Garcion et al , 2003 ). Curative treatment of vitamin D-deprived rats with the nontoxic-1,25-(OH) 2 D analog MC1288 strongly inhibited EAE symptoms, thus suggesting that these compounds may be a suitable treatment for MS ( Garcion et al , 2003 ). The 1,25-(OH) 2 D analog TX527 decreased disease severity and postponed onset in mice with EAE, and adding the bisphosphonate pamidronate prevented the side effects of this analog ( Van Etten et al , 2003 ).

Cellular effects

T lymphocytes and dendritic cells

The effect of 1,25-(OH) 2 D on the acquired, antigen-specific immune response is initiated by exposure of antigen in the groove of MHC class II molecules to T lymphocytes. This so-called antigen presentation results in proliferation and cytokine production by antigen-specific T lymphocytes. Based on the cytokine production profile, two populations of T lymphocytes can be distinguished. Th1 cells produce IFN- gamma itálico , a pro-inflammatory cytokine that promotes macrophage activation and MHC class II expression. T helper 2 (Th2) cells produce interleukin (IL)-4 and IL-5, promoting antibody production in particular IgE. Antigen-presenting cells can influence the cytokine production profile of T lymphocytes upon antigen recognition. By production of the cytokine IL-12, antigen-presenting cells can induce a shift towards the Th1 cytokine profile. Classical antigen-presenting cells are the so-called dendritic cells, which are derived from monocytes. They occur in almost all tissues of the body and in large numbers in lymphoid organs where they present antigen to T lymphocytes. 1,25-(OH) 2 D inhibits antigen-induced T-lymphocyte proliferation ( Bhalla et al , 1984 ; Lemire & Adams, 1992 ) and prevents Th1 development in EAE ( Mattner et al , 2000 ). Various reports have shown that 1,25-(OH) 2 D exerts major effects on dendritic cells (DC), by inhibition of DC maturation ( Penna & Adorini, 2000 ; Griffin et al , 2001 ). Accordingly, DC of VDR-deficient mice fail to respond to maturational stimuli ( Griffin et al , 2001 ). Mature DC are required for the induction of an efficient Th1 response, in particular by their production of the pro-inflammatory cytokine IL-12. The production of IL-12 by DC is downregulated by 1,25-(OH) 2 D, whereas the production of the anti-inflammatory cytokines IL-10 is enhanced ( Penna & Adorini, 2000 ) and the production of TGF- beta is unaffected ( Griffin et al , 2001 ). Thus, by reduction of IL-12 production by DC, 1,25-(OH) 2 D may inhibit the development of pro-inflammatory Th1 cells.

Furthermore, 1,25-(OH) 2 D treatment results, alone or when combined with the selective inhibitor of lymphocyte proliferation mycophenolate mofetil (MMF), in the generation of a population of CD4+CD25-regulatory T cells ( Gregori et al , 2001 ). The potency of this effect of 1,25-(OH) 2 D is illustrated by the fact that tolerance is induced by 1,25-(OH) 2 D/MMF treatment to fully mismatched pancreatic islet allografts in mice ( Gregori et al , 2001 ). Altogether, these data show that 1,25-(OH) 2 D inhibits DC maturation and inhibits the induction of pro-inflammatory Th1 cells. In addition, the formation of tolerogenic T cells, an active mechanism for natural immune suppression, and the production of anti-inflammatory cytokine IL-10 are promoted by 1,25-(OH) 2 D.

Macrophages Macrófagos

In addition to its effect on T lymphocytes, the effect of 1,25-(OH) 2 D on macrophages contributes to its immunomodulatory potential. Almost two decades ago, it has been reported that 1,25-(OH) 2 D promoted the induction of (pro)monocytic differentiation to macrophages ( Koeffler et al , 1984 ). 1,25-(OH) 2 D increases the antigen-presenting activity of macrophages and enhances the phagocytic activity of macrophages ( Goldman, 1984 ; Amento & Cotter, 1988 ).

Cytokines and nitric oxide (NO)

The cellular effects of 1,25-(OH) 2 D include effects on production of immunoregulatory molecules such as cytokines and NO. 1,25-(OH) 2 D decreases the production of pro-inflammatory cytokines IL-2, IFN- gamma itálico and TNF- alfa in vitro and in vivo ( Manolagas et al , 1985 ; Reichel et al , 1989 ; Lemire & Adams, 1992 ), and IL-12 in vivo ( Lemire et al , 1994 ; D’Ambrosio et al , 1998 ; Mattner et al , 2000 ). On the other hand, it promotes the in vivo production of anti-inflammatory cytokines such as IL-4 and TGF- beta ( Cantorna et al , 1998 ). An increase of TGF- beta 1 expression in lymph nodes at the periphery may explain the beneficial effect of 1,25-(OH) 2 D in EAE and has been re-emphasized in MS ( Cantorna et al , 1998 ; Mahon et al , 2003 ). In contrast, TGF- beta 1 increase was not found in the rat CNS ( Garcion et al , 2003 ), suggesting that the effects of 1,25-(OH) 2 D in EAE are due to effects on the peripheral immune system rather than on local immune suppression. 1,25-(OH) 2 D triggers the production of inducible nitric oxide synthase (iNOS) by a human macrophage cell line in vitro ( Figure 2 ) ( Rockett et al , 1998 ), but decreases iNOS expression during rat EAE ( Garcion et al , 1997 , 1998 , 2003 ). The macrophage enzyme iNOS is required for the inducible production of NO by macrophages. The role of NO in EAE and MS is not yet fully clarified, but several studies indicate a worsening effect due to NO production in the brain ( Cross et al , 1994 , 2000 ; Zhao et al , 1996 ). Others indicate that NO has an immune-downregulating effect in EAE ( Ruuls et al , 1996 ; Willenborg et al , 1999 ).

Blood–brain barrier (BBB)

Inflammatory cells can only cause damage in the CNS after they have migrated from the peripheral blood into the CNS parenchyma. This involves passage of these cells across the BBB. A direct effect of 1,25-(OH) 2 D on the BBB has, to our knowledge, not been described thus far. In 1,25-(OH) 2 D-treated EAE rats, a reduced number of infiltrated macrophages in the CNS was observed ( Nataf et al , 1996 , Nashold et al , 2000 ), suggesting that 1,25-(OH) 2 D suppresses the transendothelial migration of monocytes ( Nashold et al , 2000 ).

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MS and vitamin D supplementation

Only few reports are available on the effect of vitamin D supplementation in MS patients. A group of MS patients ( n =16) was treated with dietary supplements containing vitamin D 125 mu g (5000 IU), calcium (16 mg/kg/day), and magnesium (10 mg/kg/day) ( Goldberg et al , 1986 ). The results after 1 y showed that exacerbations were not eliminated, but their number was reduced by 59% compared with the number of the previous year(s). Vitamin D was given in the form of cod liver oil (20 g/day). Apart from vitamin D, cod liver oil may contain vitamin A and the amount of vitamin A in cod liver oil 20 g/day is six times its toxic dose. The limited number of patients in this study and the methodological bias (six out of 16 patients dropped out) do not allow conclusions.

Mahon et al (2003) studied the cytokine profile in patients with MS following 6 months supplementation with calcium 800 mg/day and vitamin D 25 mu g (1000 IU)/day ( n =17) or calcium 800 mg/day and placebo ( n =22). The serum 25OHD levels in the vitamin D treatment group significantly increased from 42.5 plusminus 15 to 70 plusminus 20 nmol/l. Vitamin D supplementation also significantly increased serum TGF- beta 1 levels.

Double-blind randomized placebo-controlled studies on vitamin D supplementation in patients with MS with sufficient power are lacking.

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Future prospects: MS and 1,25-(OH) 2 D treatment

Given its immune-modulatory and anti-inflammatory effects, treatment with 1,25-(OH) 2 D, or its analogs, may be valuable in the management of MS ( Cantorna et al , 1996 ; Hayes et al , 1997 ; Verstuyf et al , 1998 ; Mathieu et al , 2001 ; Mathieu & Adorini, 2002 ). The calcemic side effects of 1,25-(OH) 2 D make its use in high doses, needed for immunomodulation, unattractive. 1,25-(OH) 2 D analogs, which might block MS without affecting the blood calcium level, have been identified and synthesized ( DeLuca et al , 2000 ). Until now, only one of these 1,25-(OH) 2 D analogs, 19-nor-1,25-dihydroxyvitamin D 2 (19-nor), was given in an oral dose for more than 9 months to 11 newly diagnosed MS patients with RRMS. This analog, however, did not reduce the number of active MRI lesions ( Flemming et al , 2000 ). More research and clinical trials are needed to assess the usefulness of vitamin D compounds for the treatment of MS.

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Conclusion Conclusão

This review provides some epidemiological and ecological evidence for the preventive role that vitamin D nutrition may play in decreasing susceptibility to MS. The putative preventive effect of adequate supply of vitamin D 3 is supported by results obtained in EAE. In EAE 1,25-(OH) 2 D prevents the onset when administered before EAE induction and ameliorates the severity and duration of EAE when given after EAE induction ( Table 1 ).

Widespread seasonal variation in serum 25OHD levels has been reported especially in temperate climates, with low 25OHD levels in winter. A vitamin D-deficient diet in mice and rats resulted in an increased susceptibility to EAE, and 1,25-(OH) 2 D deprivation aggravated the clinical signs of EAE ( Cantorna et al , 1996 ; Garcion et al , 2003 ). Likewise, once MS is apparent, low 25OHD levels may aggravate its severity. Living in a temperate climate may cause annually recurring seasonal low serum 25OHD concentrations in MS patients. Low serum 25OHD concentrations may be responsible for upsetting the balance in the neuro-immune system of MS patients, causing reversible and irreversible neuro-immunological damage aggravating RRMS. The cumulative negative effects over the years may contribute to the secondary progressive course of MS. Further studies are required to establish the seasonal fluctuations in serum concentrations of vitamin D metabolites in MS patients. The effects of sunlight on the clinical manifestations of MS may be influenced by the fact that this may not be a direct effect, but indirect. There might be a time lag of 2 months between sunlight and 25OHD and a time lag of 4 months between sunlight and MRI lesions. A 25OHD reference interval may need to be determined to distinguish inadequate from adequate levels. The quantitative relation between vitamin D 3 input and the resulting serum 25OHD concentration needs to be investigated, as it has been speculated that patients with MS may have a higher vitamin D requirement ( Goldberg, 1974a ; Cantorna et al , 1996 ; Hayes et al , 1997 ; Hayes, 2000 ; Vieth, 1999 ; DeLuca & Cantorna, 2001 ; Holick, 2002 ; Mahon et al , 2003 ). More research is also needed to address the question if MS might be aggravated by a vitamin D-related metabolic or genetic disorder. It is hypothesized that vitamin D deficiency might only lead to MS in susceptible individuals, and a poor vitamin D status might expose an unknown, possibly gene-related, etiology.

Finally, we need to answer the question: ‘Do we need 1,25-(OH) 2 D analogs for the treatment of MS, as pharmacological doses of 1,25-(OH) 2 D are accompanied by adverse side effects, or is it simply a matter of enough vitamin D 3 all year round and enough time for it to take effect?’

Until more evidence is provided, it is suggested that MS patients living in temperate climates should have their serum 25OHD concentration checked in winter, January–March in the northern and July–September in the southern hemisphere, respectively, or use a vitamin D 3 supplement and follow the recommendations for vitamin D 3 and calcium published by their National Council on Food and Nutrition. The dietary reference intakes on vitamin D and calcium for the USA and Europe have been published by the FNB, Institute of Medicine in 1997 and by the SCF of the European Commission in 2002, respectively, and have since been updated ( FNB, Institute of Medicine, 1997 ; SCF, 2002 ; Heaney et al , 2003a ). Alternatively, the reader is referred to the most recent recommendations for the required daily intake of vitamin D 3 and calcium given for bone loss, osteoporosis, and fractures ( Chapuy et al , 1992 ; Lips, 2001 ). For the moment, it would be wise to aim at a serum 25OHD level >50 nmol/l either by augmenting sunlight exposure or by a vitamin D 3 supplement of 10 mu g (400 IU) per day. Such a dose is safe, and side effects are virtually nonexistent ( Lips, 2001 ). Further studies should be done to evaluate if higher levels of 25OHD are necessary in the management of MS to prevent exacerbations. In contrast, the use of the active metabolite 1,25-(OH) 2 D carries the danger of hypercalcemia, hypercalciuria, and renal failure, and should be restricted to clinical investigational use under close supervision.

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Acknowledgements Agradecimentos

The authors thank Jolijn Kragt, Arie van Nieuw Amerongen, Michael Eddleston, Pat Lee and I-Jin Chew for reading and commenting on draft versions and Adriana Dusso for always answering vitamin D queries.

disponível em

Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial — Trivedi et al. 326 (7387): 469 — BMJ

BMJ2003;326:469 ( 1 March )

Papers

Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial

Daksha P Trivedi, research fellowa Richard Doll, emeritus professorb Kay Tee Khaw, professor of clinical gerontologya

a Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge CB2 2QQ, b Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford

Correspondence to: K T Khaw kk101@medschl.cam.ac.uk // <![CDATA[
var u = “kk101”, d = “medschl.cam.ac.uk”; document.getElementById(“em0”).innerHTML = ‘‘ + u + ‘@’ + d + ”
// ]]>

Objective: To determine the effect of four monthly vitaminD supplementation on the rate of fractures in men and women aged65 years and over living in thecommunity.
Design: Randomised double blind controlled trial of100 000 IU oral vitamin D3 (cholecalciferol) supplementation ormatching placebo every four months over fiveyears.
Setting and participants: 2686 people (2037 men and 649 women) aged65-85 years living in the general community, recruited from theBritish doctors register and a general practice register inSuffolk.
Main outcome measures: Fracture incidence and total mortality bycause.
Results: After five years 268 men and women had incidentfractures, of whom 147 had fractures in common osteoporotic sites(hip, wrist or forearm, or vertebrae). Relative risks in the vitaminD group compared with the placebo group were 0.78 (95% confidenceinterval 0.61 to 0.99, P=0.04) for any first fracture and 0.67(0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebralfracture. 471 participants died. The relative risk for total mortalityin the vitamin D group compared with the placebo group was 0.88(0.74 to 1.06, P=0.18). Findings were consistent in men and womenand in doctors and the general practicepopulation.
Conclusion: Four monthly supplementation with 100 000IU oral vitamin D may prevent fractures without adverse effectsin men and women living in the generalcommunity.

What is already known in this topic
Vitamin D and calcium supplements are effective in preventing fractures in elderly women

Whether isolated vitamin D supplementation prevents fractures is not clear

What this paper adds
Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community

Total fracture incidence was reduced by 22% and fractures in major osteoporotic sites by 33%


© 2003 BMJ Publishing Group Ltd

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  • Kuchuk, N. O., Pluijm, S. M. F., van Schoor, N. M., Looman, C. W. N., Smit, J. H., Lips, P. (2009). Relationships of Serum 25-Hydroxyvitamin D to Bone Mineral Density and Serum Parathyroid Hormone and Markers of Bone Turnover in Older Persons. J. Clin. Endocrinol. Metab. 94: 1244-1250 [Abstract] [Full text]
  • Bischoff-Ferrari, H. A., Willett, W. C., Wong, J. B., Stuck, A. E., Staehelin, H. B., Orav, E. J., Thoma, A., Kiel, D. P., Henschkowski, J. (2009). Prevention of Nonvertebral Fractures With Oral Vitamin D and Dose Dependency: A Meta-analysis of Randomized Controlled Trials. Arch Intern Med 169: 551-561 [Abstract] [Full text]
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  • Aloia, J. F., Talwar, S. A., Pollack, S., Yeh, J. (2005). A Randomized Controlled Trial of Vitamin D3 Supplementation in African American Women. Arch Intern Med 165: 1618-1623 [Abstract] [Full text]
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  • Holick, M. F., Siris, E. S., Binkley, N., Beard, M. K., Khan, A., Katzer, J. T., Petruschke, R. A., Chen, E., de Papp, A. E. (2005). Prevalence of Vitamin D Inadequacy among Postmenopausal North American Women Receiving Osteoporosis Therapy. J. Clin. Endocrinol. Metab. 90: 3215-3224 [Abstract] [Full text]
  • Bischoff-Ferrari, H. A., Willett, W. C., Wong, J. B., Giovannucci, E., Dietrich, T., Dawson-Hughes, B. (2005). Fracture Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized Controlled Trials. JAMA 293: 2257-2264 [Abstract] [Full text]
  • Porthouse, J., Cockayne, S., King, C., Saxon, L., Steele, E., Aspray, T., Baverstock, M., Birks, Y., Dumville, J., Francis, R., Iglesias, C., Puffer, S., Sutcliffe, A., Watt, I., Torgerson, D. J (2005). Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 330: 1003- [Abstract] [Full text]
  • Dawson-Hughes, B. (2005). The Role of Vitamin D in Fracture Prevention. IBMS BoneKEy 2: 6-10 [Full text]
  • Venning, G. (2005). Recent developments in vitamin D deficiency and muscle weakness among elderly people. BMJ 330: 524-526 [Full text]
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  • Calvo, M. S., Whiting, S. J., Barton, C. N. (2005). Vitamin D Intake: A Global Perspective of Current Status. J. Nutr. 135: 310-316 [Abstract] [Full text]
  • Hollis, B. W. (2005). Circulating 25-Hydroxyvitamin D Levels Indicative of Vitamin D Sufficiency: Implications for Establishing a New Effective Dietary Intake Recommendation for Vitamin D. J. Nutr. 135: 317-322 [Abstract] [Full text]
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Rapid Responses:

Read all Rapid Responses

Vitamin D deficiency, lack of sunlight, multiple sclerosis
Peter K. Tun
bmj.com, 1 Mar 2003 [Full text]
Level of vitamin D (3) supplementation 100,000IU
Anne Woo
bmj.com, 1 Mar 2003 [Full text]
Re: Level of vitamin D (3) supplementation 100,000IU
Robert D Toon
bmj.com, 2 Mar 2003 [Full text]
Why no funding for a community trial?
Jim Page
bmj.com, 2 Mar 2003 [Full text]
100,000 IU of Vitamin D is a Lethal Dose for Many in our Community
Trevor G Marshall, PhD
bmj.com, 3 Mar 2003 [Full text]
How can Trivedi et al, Overlook the Possibility of Hypervitaminosis-D?
Belinda J Fenter
bmj.com, 3 Mar 2003 [Full text]
Safety of Vitamin D dose in used in fracture trial
Kay-Tee Khaw
bmj.com, 3 Mar 2003 [Full text]
A Therapy is Only Safe if it “Does No Harm”
Trevor G Marshall, PhD
bmj.com, 4 Mar 2003 [Full text]
Could vitamin D be of potential benefit in epileptic patients?
Mohammed S Rashid (BPharm MRPharmS)
bmj.com, 5 Mar 2003 [Full text]
Make sure to measure the correct ‘Vitamin D’- there are four of them
Trevor G Marshall
bmj.com, 6 Mar 2003 [Full text]
Potential Confounding Factors May Have Impacted on the Results
Henry Zeimer
bmj.com, 7 Mar 2003 [Full text]
Re: How can Trivedi et al, Overlook the Possibility of Hypervitaminosis-D?
Reinhold Vieth
bmj.com, 9 Mar 2003 [Full text]
Podiatrists administering vitamin D
Peter J Elton
bmj.com, 10 Mar 2003 [Full text]
Vitamin D, falls and fractures
Jugdeep K Dhesi, et al.
bmj.com, 16 Mar 2003 [Full text]
Vitamin D status in the population
Haakon E. Meyer
bmj.com, 18 Mar 2003 [Full text]
frail elderly patients and vitamin D
Michael D Stone
bmj.com, 22 Mar 2003 [Full text]
Annual injection
Mark D Oliver
bmj.com, 22 Mar 2003 [Full text]
Vitamin D for the over 65s
Lisa A Dunkley, et al.
bmj.com, 22 Mar 2003 [Full text]
Re: Vitamin D, falls and fractures
Andrew Herxheimer
bmj.com, 28 Mar 2003 [Full text]
Dose of vitamin D
John J Cannell, MD
bmj.com, 12 Apr 2003 [Full text]
The effect and administration of vitamin D.
Rauno J. Heikinheimo, et al.
bmj.com, 26 Apr 2003 [Full text]
Vitamin D and fractures
Montserrat Romera, et al.
bmj.com, 5 May 2003 [Full text]
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http://www.bmj.com/cgi/content/abstract/326/7387/469

NHS Evidence – Complementary and alternative medicine – Guest editorial: Vitamin D to prevent MS?

NHS Evidence – complementary and alternative medicine

formerly a Specialist Library of the National Library for Health

Guest editorial: Vitamin D to prevent MS?

Could supplementation of something as safe as vitamin D prevent MS? A series of studies offer the suggestion that this may be the case and following significant media coverage clinicians running MS clinics know that this is becoming a familiar theme. What is the background?

The striking variation in MS prevalence with latitude – increasing further from the equator  – has exercised epidemiologists for the majority of the 20th century. The first suggestion that this might relate to sunlight was made in 1960 and gained ground with the understanding of the relationship between sunlight exposure and vitamin D production. Limited vitamin D in the western diet (oily fish, sealion and polar bear are good sources…) means that production in the skin is the major source. A significant proportion of populations in temperate regions are deficient, particularly in winter months.

The discovery that vitamin D influences immune function – exerting anti-inflammatory influence on immune function (Smolders et al, 2008) – offered biological plausibility.

Circumstantial support comes from the observation of seasonal variation in birth rate, more patients with MS are born in May than November (Willer CJ, 2005), suggesting a seasonal environmental factor influencing disease risk in utero. Additional studies have shown children and adults with MS to be relatively deficient in vitamin D (Ascherio A, 2007) and that supplementation may reduce disease risk (Munger KL, 2004).

Further data comes from two recent publications. Ramagopalan and colleagues looked for evidence to link genetic predisposition to MS, driven by the association with HLA, to vitamin D (Ramagopalan SV, 2009). They screened the MHC class II region for genetic sequences coding for vitamin D response elements (VDRE) and found one such region, in the promoter region of HLA-DRB1. Sequencing of this region revealed absolute conservation in the MS associated haplotype (HLA-DRB1*15) with variation only in non-MS associated haplotypes. Further studies confirmed the VDRE to be functional and that vitamin D was able to increase expression of HLA-DRB1 on lymphoid cells. The study provides the first biological link between the strongest epidemiological and genetic features of the disease.

Correale and colleagues reported that patients with relapsing remitting MS (N=92), in relapse and remission, had lower vitamin D levels than controls (60) and patients with primary progressive MS (40) and that levels were lowest in relapse (Correale J, 2009). They also studied the effect of vitamin D on CD4+ T cells and showed that vitamin D has the potential to down-regulate auto-immune activity in vitro, suggesting that supplementation may have a role not only in reducing disease risk but also activity.

So how to advise patients? The case for vitamin D supplementation undoubtedly gets stronger, though is far from proven. For who, when and by how much are far from clear.

Supplementation is straightforward and safe – though current RDA (200-400IU/day) are insufficient to reliably maintain adequate levels. No significant problems have been associated with supplementation of 1000IU in children and 4000IU in adults.

Parents with MS, whose children have a 2-4% risk of the disease, will be motivated to consider interventions that may reduce this risk. Should we advise supplementation in pregnancy? Possibly – the seasonal variation in birth rate argues for such an intervention – and again supplementation appears safe. It is difficult to see how large scale, long term, intervention studies can be undertaken to generate the proof that some may require.

For patients with MS the evidence is weakest; here replication of the study from Correale would be welcome. A simple intervention which influences disease risk and outcome would be very welcome – polar bear anyone?

References

Ascherio A, Munger KL. (2007) Environmental risk factors for multiple sclerosis. Part II: Noninfectious factorsAnn Neurol. 61(6):504-13.

Correale J, Ysrraelit MC, Gaitán MI. (2009) Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 132 (Pt 5):1146-60.

Munger KL, Zhang SM, O’Reilly E, Hernán MA, Olek MJ, Willett WC, Ascherio A. (2004) Vitamin D intake and incidence of multiple sclerosis. Neurology 62(1):60-5.

Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA, Deluca GC, Herrera BM, Chao MJ, Sadovnick AD, Ebers GC, Knight JC. (2009) Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 5(2):e1000369. Epub 2009 Feb 6.

Smolders J, Damoiseaux J, Menheere P, Hupperts R. (2008) Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 194(1-2):7-17.

Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC; Canadian Collaborative Study Group. (2005) Timing of birth and risk of multiple sclerosis: population based study. BMJ. Jan 15;330(7483):120.

  • Publication Date: 12 Jun 2009
  • Publication Type: Editorial or Opinion Piece
  • Creator: NHS Evidence – neurological conditions Project Team
  • Contributor: Mike Boggild
  • Next Review Date: 12 Jun 2010
Disponível em

A vitamina D pode cortar o risco de desenvolver esclerose múltipla

A vitamina D pode cortar o risco de desenvolver esclerose múltipla

Study: Low Levels of Vitamin D May Boost Multiple Sclerosis Gene Risk Estudo: baixos níveis de vitamina D pode impulsionar o gene para risco de esclerose múltipla
By Miranda Hitti Por Miranda Hitti
WebMD Health News WebMD Health News
Reviewed by Louise Chang, MD Avaliado por Louise Chang, MD

Feb. 6, 2009 — Getting enough vitamin D early in life may cut the odds of developing multiple sclerosis , researchers report. 6 de fevereiro de 2009 – começando bastante vitamina D cedo na vida pode reduzir as chances de desenvolver esclerose múltipla, relatório dos investigadores.

Multiple sclerosis (MS) is more common in parts of the world far from the equator, where the sun wanes during winter. A esclerose múltipla (MS) é mais comum em algumas partes do mundo, longe do equador, onde o sol diminui durante o inverno. During that seasonal sunshine shortfall, it’s harder for the body to make vitamin D when exposed to sunlight. Durante esse défice sol sazonal, é mais difícil para o organismo a produzir vitamina D quando exposta à luz solar.

With that in mind, British and Canadian scientists studied a gene variant that triples the risk of multiple sclerosis — and they found that that gene is sensitive to vitamin D. Com isso em mente, os cientistas britânicos e canadenses estudaram uma variante do gene que triplica o risco de esclerose múltipla – e descobriram que esse gene é sensível à vitamina D.

“If too little of the vitamin is available, the gene may not function properly,” making multiple sclerosis more likely, Julian Knight, MBChB, DPhil, says in a news release. “Se muito pouco da vitamina está disponível, o gene pode não funcionar corretamente”, tornando mais provável a esclerose múltipla, Julian Knight, MBChB, DPhil, diz em uma nota de imprensa. Knight works at the Wellcome Trust Centre for Human Genetics at England’s University of Oxford. Knight trabalha no Wellcome Trust Centre para Genética Humana da Universidade de Oxford da Inglaterra.

Knight and colleagues suggest that because vitamin D deficiency is common, taking vitamin D supplements early in life might cut MS risk. Knight e colegas sugerem que, por deficiência de vitamina D é comum, tomar suplementos de vitamina D cedo na vida pode reduzir risco de esclerose múltipla. But they didn’t test that theory, and they’re not recommending certain vitamin D doses for MS prevention. Mas eles não testar essa teoria, e não estamos recomendando certas doses de vitamina D para prevenção MS.

The study appears in PLoS Genetic s. O estudo aparece na PLoS S. Genetic “PLoS” is short for “Public Library of Science.” “PLoS” é a abreviação de “Public Library of Science”.

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Vitamin D is ray of sunshine for multiple sclerosis patients

A vitamina D é uma luz para os pacientes de esclerose múltipla

O consumo de vitamina D elimina o risco de desenvolver esclerose multipla. Aos pacientes que apresentam baixos níveis de vitamina D no sangue, são administradas altas doses deste suplemento, evitando o aumento do número de pessoaas doentes.

Vitamin D is ray of sunshine for multiple sclerosis patients

Melanie Reid and Oliver Gillie
February 5, 2009

A scan image of the brain of a multiple sclerosis sufferer

An MRI scan of the brain of a multiple sclerosis sufferer

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Multiple sclerosis could be prevented through daily vitamin D supplements, scientists told The Times last night.The first causal link has been established between the “sunshine vitamin” and a gene that increases the risk of MS, raising the possibility that the debilitating auto-immune disease could be eradicated.George Ebers, Professor of Clinical Neurology at the University of Oxford, claimed that there was hard evidence directly relating both genes and the environment to the origins of MS.

His work suggests that vitamin D deficiency during pregnancy and childhood may increase the risk of a child developing the disease.

He has also established the possibility that genetic vulnerability to MS, apparently initiated by lack of vitamin D, may be passed through families.

These risks might plausibly be reduced by giving vitamin D supplements to pregnant woman and young children.

“I think it offers the potential for treatment which might prevent MS in the future,” Professor Ebers said.

“Our research has married two key pieces of the puzzle. The interaction of vitamin D with the gene is very specific and it seems most unlikely to be a coincidence of any kind.”

Warnings over sun exposure could now also be called into question – sunlight allows the body to produce the vitamin.

Professor Ebers said: “Serious questions now arise over the wisdom of current advice to limit sun exposure and avoid sunbathing. We also need to give better advice and help to the public on vitamin D supplements, particularly pregnant and nursing mothers.”

The news has momentous implications for Scotland and other northern countries, where the incidence of multiple sclerosis is the highest in the world. It will give added urgency to recent moves by Scotland’s Chief Medical Officer to consider recommending vitamin D supplements.

Deficiency in vitamin D, caused by lack of exposure to sunshine, has been increasingly linked to the cloudier climate in Scotland and other northern latitudes. The deficiency is twice as common among the Scots as it is amongst the English – and Orkney and Shetland have among the highest rates.

Studies have also shown that fewer people with MS are born in November and more in May, implicating a lack of sunshine during pregnancy.

The breakthrough comes after a groundswell of expert belief in the importance of vitamin D. Last November, at a conference organised by the Scottish Government, international experts urged vitamin D supplements for Scots to be tested “sooner rather than later” to find whether they could improve the nation’s health.

Researchers for the World Health Organisation said there should be large, randomised trials as there was strong evidence that increased daily intake of vitamin D could significantly improve health.

The seminar followed evidence, revealed in The Times, that Scotland’s poor health record has close links to vitamin D deficiency. Last September this newspaper reported evidence from scientists in Canada that children with early symptoms of multiple sclerosis have low levels of vitamin D.

Until now there has been no scientific proof of the links. However, Professor Ebers and his team have shown that vitamin D affects a particular genetic variant, identified as the one that increases the risk of developing MS threefold.

They suggest that a shortage of the vitamin alters this variant, thus preventing the immune system from functioning normally.

Professor Ebers said: “Whether it’s at the core of MS is going to take some further work, but it does look like a reasonably good chance.”

Last October Professor Ebers, in an article in The Times, backed the idea of distributing vitamin D supplements in Scotland to guard against conditions that may be linked to a deficiency, including MS.

“It is plausible that some 200 cases a year of MS might be prevented in Scotland alone by giving vitamin D to mothers and children,” he wrote.

“Over a trial duration of 25 years, 5,000 cases of this disease might be otherwise prevented.

“The economic impact of each person with MS is at least an extra million pounds during a lifetime.

“Over 25 years £5 billion is at issue in this disease without factoring in the human cost, the increasing rate of MS or inflation. A large-scale programme providing vitamin D could provide scientific evidence.”

Disease of the North: MS rates per 100,000 of the population

Canada 240

Scotland 150 – 200

Norway 110

England and Wales 90 – 110

Australia 78

Spain 59

Brazil 18

Sources: Atlas of Multiple Sclerosis; bandolier.com

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http://www.timesonline.co.uk/tol/life_and_style/health/article5663483.ece

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