Vitamin C: prospective functional markers for defining optimal nutritional status.

Most species of plants and animals synthesize ascorbic acid, but human subjects cannot, making vitamin C an essential component of our diet. Relationships between vitamin C intake and status, and between status and health are not yet clear. There is evidence, however, that higher intake of vitamin C is associated with lower risk of disease, supporting the concept that optimal intake is needed for optimal vitamin C status, and that both factors are required for optimal health. Vitamin C has low toxicity in healthy subjects, but a clear definition of optimal status and the dietary intake required to meet and maintain this status is needed before a change in the current recommended intake can be considered. Available evidence suggests that intake of 200 mg vitamin C/d saturates tissues and maintains fasting plasma levels above the proposed threshold (50 mumol/l) for minimum risk of CHD. However, the issue of whether or not these levels produce 'optimal vitamin C status' awaits the clear and accepted definition of the term. This definition in turn awaits the development of reliable functional markers capable of assessing the effects of varying levels of vitamin C nutriture. In the present paper the relationship between intake and body stores of vitamin C and the role of vitamin C in human health are reviewed briefly. The requirements of a reliable functional marker of human vitamin C status are defined, three classes of functional markers (molecular, biochemical and physiological) are described, and possible candidate markers are examined.     

Clinical importance of vitamin E: a review

In 1922 Evans and Bishop described a fat soluble factor which was necessary for normal reproduction in the rat, and this factor subsequently became known as vitamin E. During the years that following the discovery and isolation of the vitamin, most of the work was concerned with the characterization of disorders found in experimental vitamin E deficient animals. It soon became apparent that vitamin E deficiency produces a wide variety of pathological conditions which differ not only amongst the various animal species but sometimes even within the same species (Wasserman & Taylor, 1972). The lesion, however, which predominates in most species is that of a chronic necrotising myopathy or dystrophy (Machlin, 1980). Even though vitamin E deficiency syndromes had been produced experimentally in animals, the role of the vitamin in human nutrition remained much disputed for a long time and little understood. Many ill-founded claims were made such as its ability to slow the ageing process or to increase virility and fertility, and even, as reported in the American press, to protect against the effects of atomic fallout. Not surprisingly this led some cynics to dub vitamin E as “E for Everything”. Nevertheless, some well documented evidence for a role in human nutrition was reported in the late 1950s. Oppenheimer (1956) and Blanc et al. (1958) showed that infants with cystic fibrosis had low serum vitamin E concentrations associated with widespread ceroid deposition in smooth muscle and focal necrosis of striated muscle. More recently evidence has accumulated indicating a pharmacological role for the vitamin in certain disorders affecting preterm infants (Aranda et al., 1986; Muller, 1987), and it has become clear that it has an important physiological role in maintaining normal neurological structure and function. It is accepted that it is an important biological antioxidant and is indeed the only significant fat soluble secondary antioxidant in mammalian tissues (Burton et al. 1983)     

Status of vitamin E as an erythropoietic factor

There is now convincing evidence that vitamin E is a specific erythropoietic factor for nonhuman primates and swine. There is no evidence, however, that vitamin E is normally required as an erythropoietic factor for humans and many species of animals. We propose that the lack of a requirement for vitamin E in erythropoiesis in humans is due to a metabolic adaptation that circumvents the need for the role that the vitamin otherwise would serve. There is reason to believe that this metabolic adaptation is deranged in patients with protein-calorie malnutrition. These patients respond with reticulocytosis and a limited increase in hemoglobin concentration when vitamin E is given before their metabolic derangement is reversed by correcting their other nutritional deficiencies. Given this information, we may predict that other acquired or congenital abnormalities of metabolism could impair the adaptation that circumvents the role of vitamin E in erythropoiesis. Therefore, vitamin E should be viewed as a potential erythropoietic factor for humans, and it should receive further carefully controlled therapeutic trials in patients with anemia of obscure etiology, particularly in those with erythroid hyperplasia and unexplained ineffective erythropoiesis.     

Does vitamin E supplementation prevent cardiovascular events?

In recent years, vitamin E has been investigated as a cardioprotective agent. Experimental studies have identified potential mechanisms by which vitamin E may inhibit the development of atherosclerosis, and observational studies of individuals without coronary disease suggest that vitamin E intake may prevent future cardiovascular events. Secondary prevention trials to date have demonstrated little benefit from vitamin E supplementation. It remains possible, however, that supplementation may be useful among certain high-risk groups, including those with nutritional deficiencies. Limited data from completed primary prevention trials also indicate minimal cardioprotection from vitamin E, but large-scale trials now in progress may yet show benefit. Results from ongoing trials will contribute powerfully to the totality of evidence on which to formulate both appropriate clinical recommendations for individual patients and a rational public health policy for the population as a whole. At this time, there is insufficient evidence for issuing a public health recommendation to use vitamin E supplements to prevent cardiovascular disease (CVD). Rather, increased intake of fruits, vegetables, and other antioxidant-rich foods should be promoted as part of a healthy diet because they provide nutritional benefits beyond any potential antioxidant effect. Moreover, even if found to reduce CVD risk, vitamin supplement use should be considered an adjunct, not an alternative, to established cardioprotective measures, such as smoking abstention, avoidance of obesity, adequate physical activity, and control of high blood pressure and hyperlipidemia.     

Successful treatment of chronic erythema nodosum with vitamin B12

A 38-year-old woman presented with painful lesions on both shins that first appeared a few days earlier. Physical examination revealed multiple red tender nodules on both legs. The patient had been treated with nonsteroidal anti-inflammatory drugs for having a few months without any improvement. The patient was referred to a dermatologist and a rheumatologist, who confirmed our diagnosis of chronic erythema nodosum (EN). She returned to the clinic 3 months later complaining of having numbness in the soles of her feet for a few weeks. Her serum vitamin B12 level was 118 pg/mL (normal range 135 to 911). After 4 weeks of twice weekly injections of vitamin B12 at a dose of 1000 mcg, there was a clear alleviation of the numbness, and the EN completely resolved without evidence of recurrence on follow-up. Because it seems that vitamin B12 caused resolution of EN in this case, we recommend that physicians consider testing for vitamin B12 deficiency in patients with EN.     

Antioxidant micronutrients and breast cancer.

We reviewed epidemiologic evidence on the relationship between four antioxidant micronutrients (vitamin A, vitamin C, vitamin E, and selenium) and breast cancer risk. Available data support a modest protective effect of vitamin A, although more studies are needed to examine further this association and to assess the relative contributions of preformed vitamin A (retinol) and carotenoids. In addition, the possibility that some other component of vitamin A-rich foods may account for this observed association should be explored. Data on the relationship between vitamins C and E and breast cancer risk are limited and inconsistent, and further information is necessary. A substantial body of evidence indicates a lack of any appreciable effect of selenium intake on breast cancer risk, at least within the range of human diets. Future observational studies should ideally be prospective in design, as prospective studies are less prone to selection and recall bias than are case-control studies, and should address methodologic issues such as confounding by other micronutrients and appropriate storage conditions of blood specimens. Although hypotheses relating micronutrient intake to risk of breast cancer should be tested in randomized trials, ethical and logistical constraints make these studies difficult to perform.     

Vitamin D insufficiency in North America

Vitamin D insufficiency is a term that has been used to describe the finding of biochemical evidence of deficiency, without obvious clinical signs or symptoms, such as rickets or osteomalacia. The condition is most commonly diagnosed by a serum 25-hydroxyvitamin D below 40 nmol/L (16 microg/L). This paper reviews North American studies addressing the prevalence of the problem, and the growing body of evidence that vitamin D insufficiency predisposes individuals to poor bone and muscle health. The term insufficiency is somewhat misleading, as patients with this condition are really just part of the spectrum of vitamin D deficiency. If the more generous definition of this condition is used (serum 25-hydroxyvitamin D < 80 nmol/L), a much larger proportion of the population has the problem. The response to vitamin D supplementation in clinical trials suggests current recommendations for dietary intake of this vitamin are too low and that a higher adequate intake should be recommended.     

Vitamin D and tuberculosis

Tuberculosis is highly prevalent worldwide, accounting for nearly two million deaths annually. Vitamin D influences the immune response to tuberculosis, and vitamin D deficiency has been associated with increased tuberculosis risk in different populations. Genetic variability may influence host susceptibility to developing active tuberculosis and treatment response. Studies examining the association between genetic polymorphisms, particularly the gene coding for the vitamin D receptor (VDR), and TB susceptibility and treatment response are inconclusive. However, sufficient evidence is available to warrant larger epidemiologic studies that should aim to identify possible interactions between VDR polymorphisms and vitamin D status.     

The Mary Sheridan Unit: an evaluation of the effects of a hospital unit on the development of visually-impaired multiply handicapped children

The evidence in this study appears to indicate that adopting a goal-planning approach can provide demonstrable and clear improvements in the developmental functioning of multiply handicapped blind children. However, while the improvements in functioning for self-help and sensorimotor abilities are quite significant, those for communication and language skills are much less so. Three possible hypotheses have been advanced as to why this should be so. The hypothesis that the setting might be an institutionalizing one was rejected on the grounds that some of the evidence did not fit with that from other populations. The second hypothesis referred to the lack of formal speech and communication training on the unit. The best possible test of this hypothesis would be to employ a speech therapist to work on the unit and support for such a scheme is being sought. Finally, it was hypothesized that the way in which the staff interacted with the children was not being sufficiently modified to take account of the children's handicaps.     

Vitamin supplement use and reduced risk of oral and pharyngeal cancer.

Use of vitamin and mineral supplements was assessed in a population-based case-control study of oral and pharyngeal cancer, conducted during 1984-1985 in four areas of the United States. There was no association with intake of multivitamin products, but users of supplements of individual vitamins, including vitamins A, B, C, and E, were at lower risk after controlling for the effects of tobacco, alcohol, and other risk factors for these cancers. After further adjustment for use of other supplements, vitamin E was the only supplement that remained associated with a significantly reduced cancer risk. The adjusted odds ratio of oral and pharyngeal cancer for "ever regularly used" vitamin E was 0.5 (95% confidence interval 0.4-0.6). To the authors' knowledge, this is the first epidemiologic study to show a reduced oral cancer risk with vitamin E use. Although it is not clear that the lower risk among consumers of vitamin E supplements is due to the vitamin per se, the findings are consistent with experimental evidence and should prompt further research on the role of vitamin E and other micronutrients as inhibitors of oral and pharyngeal cancer.     

Emerging relationships of vitamins and cancer risks

Evidence is emerging that at least some vitamins may play a role in reducing cancer risks. Over the past year, the best evidence for such effects has been presented for vitamins A, D and E; less consistent evidence has been presented for vitamin C. Although there are still many inconsistencies in our understanding of the anti-cancer roles and mechanisms of these vitamins, it is possible that they may account for at least some of the apparently cancer-protective effects associated with certain dietary patterns.     

Vitamin B6: a challenging link between nutrition and inflammation in CVD

The objective of the present review is to highlight the relationship between low vitamin B6 status and CVD through its link with inflammation. While overt vitamin B6 deficiency is uncommon in clinical practice, increasing evidence suggests that marginal vitamin B6 deficiency is rather frequent in a consistent proportion of the population and is related to an increased risk of inflammation-related diseases. Ample evidence substantiates the theory of atherosclerosis as an inflammatory disease, and low plasma vitamin B6 concentrations have been related to increased CVD risk. Several studies have also shown that low vitamin B6 status is associated with rheumatoid arthritis and chronic inflammatory bowel diseases, both of which hold an underlying chronic inflammatory condition. Furthermore, the inverse association observed between inflammation markers and vitamin B6 supports the notion that inflammation may represent the common link between low vitamin B6 status and CVD risk. In addition to the epidemiological evidence, there are a number of cell culture and animal studies that have suggested several possible mechanisms relating impaired vitamin B6 status with chronic inflammation. A mild vitamin B6 deficiency characterises, in most cases, a subclinical at-risk condition in inflammatory-linked diseases which should be addressed by an appropriate individually tailored nutritional preventive or therapeutic strategy.     

Sun exposure and vitamin D sufficiency

Ultraviolet radiation is a carcinogen that also compromises skin appearance and function. Because the ultraviolet action spectra for DNA damage, skin cancer, and vitamin D(3) photosynthesis are identical and vitamin D is readily available from oral supplements, why has sun protection become controversial? First, the media and, apparently, some researchers are hungry for a new message. Second, the controversy is fueled by a powerful special interest group: the tanning industry. This industry does not target the frail elderly or inner-city ethnic minorities, groups for whom evidence of vitamin D(3) insufficiency is strongest, but rather fair-skinned teenagers and young adults, who are at highest risk of ultraviolet photodamage. Third, evolution does not keep pace with civilization. When nature gave humans the appealing capacity for cutaneous vitamin D(3) photosynthesis, life expectancy was <40 y; long-term photodamage was not a concern; and vitamin D(3) deficiency, with its resulting skeletal abnormalities (rickets), was likely to be fatal in early life. In the 21st century, life expectancy approaches 80 y in developed countries, vitamin D(3) is available at the corner store, and the lifetime risk of skin cancer is 1 in 3 among white Americans. Medical and regulatory groups should avoid poorly reasoned, sensationalistic recommendations regarding unprotected ultraviolet exposure. Instead, they should rigorously explore possible cause-and-effect relations between vitamin D(3) status and specific diseases while advocating the safest possible means of ensuring vitamin D(3) sufficiency.     

Ex Vivo Evaluation of the Sepsis Triple Therapy High-Dose Vitamin C in Combination with Vitamin B1 and Hydrocortisone in a Human Peripheral Blood Mononuclear Cells (PBMCs) Model

Sepsis is an extremely complex clinical syndrome, usually involving an excessive inflammatory response including an overshooting cytokine release that damages tissue and organs of the patient. Due to the severity of this condition, it is estimated that over 11 million people die from sepsis each year. Despite intensive research in the field, there is still no specific therapy for sepsis. Many sepsis patients show a marked deficiency of vitamin C. 9 out of 10 sepsis patients have a hypovitaminosis C, and every third patient even shows a clinical deficiency in the scurvy range. In addition, low vitamin C levels of intensive care sepsis patients correlate with a higher need for vasopressors, higher Sequential Organ Failure Assessment (SOFA) scores, and increased mortality. Based on this observation and the conducted clinical trials using vitamin C as sepsis therapy in intensive care patients, the aim of the present ex vivo study was to evaluate the effects of high-dose vitamin C alone and in a triple combination supplemented with vitamin B1 (thiamine) and hydrocortisone on the lipopolysaccharide (LPS)-induced cytokine response in peripheral blood mononuclear cells (PBMCs) from healthy human donors. We found that all corticosteroid combinations strongly reduced the cytokine response on RNA- and protein levels, while high-dose vitamin C alone significantly diminished the PBMC mediated secretion of the cytokines interleukin (IL)-10, IL-23, and monocyte chemo-attractant protein (MCP-1), which mediate the inflammatory response. However, vitamin C showed no enhancing effect on the secretion of further cytokines studied. This data provides important insights into the possible immunomodulatory function of vitamin C in an ex vivo setting of human PBMCs and the modulation of their cytokine profile in the context of sepsis. Since vitamin C is a vital micronutrient, the restoration of physiologically adequate concentrations should be integrated into routine sepsis therapy, and the therapeutic effects of supraphysiological concentrations of vitamin C in sepsis patients should be further investigated in clinical trials.     

Dietary influences on chronic obstructive lung disease and asthma: a review of the epidemiological evidence.

The epidemiological evidence for a relationship between diet and indicators of asthma and chronic obstructive pulmonary disease (COPD) is evaluated. The review focuses on the intake of Na, n-3 fatty acids, and antioxidant vitamins as well as fruit and vegetables. Experimental studies suggest that a high-Na diet has a small adverse effect on airway reactivity in asthma patients. However, observational studies provide no clear evidence that high Na intake has adverse effects on airway reactivity or asthma symptoms in open populations. n-3 Polyunsaturated fatty acids, which are present in fish oils, are metabolized into less broncho-constricting and inflammatory mediators than n-6 polyunsaturated fatty acids. Studies in the general adult population suggest that a high fish intake has a beneficial effect on lung function, but the relationship with respiratory symptoms and clinically-manifest asthma or COPD is less evident. Also, experimental studies in asthma patients have not demonstrated an improvement in asthma severity after supplementations with fish oil. Several studies showed a beneficial association between fruit and vegetable intake and lung function, but the relationship with respiratory symptoms and the clinically-manifest disease was less convincing. A similar pattern was found for vitamin C in relation to indicators of asthma and COPD, but there are still conflicting results with respect to vitamin E and beta-carotene. In conclusion, the epidemiological evidence for a beneficial effect on indicators of asthma and COPD of eating fish, fruit and vegetables is increasing. However, the effectiveness of dietary supplementation in open-population samples is often not demonstrated. Several unresolved questions are raised, which should be addressed in future studies on the relationship between diet and respiratory disease.     

Nutrition and bone growth and development

The growth and development of the human skeleton requires an adequate supply of many different nutritional factors. Classical nutrient deficiencies are associated with stunting (e.g. energy, protein, Zn), rickets (e.g. vitamin D) and other bone abnormalities (e.g. Cu, Zn, vitamin C). In recent years there has been interest in the role nutrition may play in bone growth at intakes above those required to prevent classical deficiencies, particularly in relation to optimising peak bone mass and minimising osteoporosis risk. There is evidence to suggest that peak bone mass and later fracture risk are influenced by the pattern of growth in childhood and by nutritional exposures in utero, in infancy and during childhood and adolescence. Of the individual nutrients, particular attention has been paid to Ca, vitamin D, protein and P. There has also been interest in several food groups, particularly dairy products, fruit and vegetables and foods contributing to acid-base balance. However, it is not possible at the present time to define dietary reference values using bone health as a criterion, and the question of what type of diet constitutes the best support for optimal bone growth and development remains open. Prudent recommendations (Department of Health, 1998; World Health Organization/Food and Agriculture Organization, 2003) are the same as those for adults, i.e. to consume a Ca intake close to the reference nutrient intake, optimise vitamin D status through adequate summer sunshine exposure (and diet supplementation where appropriate), be physically active, have a body weight in the healthy range, restrict salt intake and consume plenty of fruit and vegetables.     

Proceedings of the Rank Forum on Vitamin D

The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25?nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations>75?nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.     

Is vitamin A consumption a risk factor for osteoporotic fracture?

Severe vitamin A toxicity is known to have adverse effects on skeletal health. Studies involving animal models and case reports have documented that hypervitaminosis A is associated with bone resorption, hypercalcaemia and bone abnormalities. More recently, some epidemiological studies have suggested that high habitual intake of vitamin A could contribute to low bone mineral content and fracture risk. The evidence relating to the possible deleterious role of vitamin A in bone health is of variable quality and is potentially confounded by collinearity of nutrient intake and difficulties in assessing vitamin A exposure. Furthermore, because intake of vitamin A varies between studies it is not possible to define an intake threshold associated with harm.     

Maternal Obesity Increases Congenital Malformations

There has been growing evidence that maternal obesity is associated with an increased risk of congenital malformations, particularly of neural tube defects. Two new studies confirm this relationship and indicate that it is independent of possible covariant confounders such as maternal age, socioeconomic status, education, smoking, and vitamin intake, including folic acid. There is a suggestion that folic acid loses its protective benefit in overweight and obese mothers. These new findings add to a long list of obstetric morbidities, and show a steep gradient with increasing maternal fatness and point to the urgent need to prevent excess weight gain in young women.