A. Catharine Ross

Dietary Reference Intakes for Calcium and Vitamin D

Calcium and vitamin D are two essential nutrients long known for their role in bone health. Over the last ten years, the public has heard conflicting messages about other benefits of these nutrients—especially vitamin D—and also about how much calcium and vitamin D they need to be healthy. To help clarify this issue, the U. S. and Canadian governments asked the Institute of Medicine (IOM) to assess the current data on health outcomes associated with calcium and vitamin D. The IOM tasked a committee of experts with reviewing the evidence, as well as updating the nutrient reference values, known as Dietary Reference Intakes (DRIs). These values are used widely by government agencies, for example, in setting standards for school meals or specifying the nutrition label on foods. Over time, they have come to be used by health professionals to counsel individuals about dietary intake. The committee provided an exhaustive review of studies on potential health outcomes and found that the evidence supported a role for these nutrients in bone health but not in other health conditions. Further, there is emerging evidence that too much of these nutrients may be harmful.

The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

IOM Committee Members Respond to Endocrine Society Vitamin D Guideline

In early 2011, a committee convened by the Institute of Medicine issued a report on the Dietary Reference Intakes for calcium and vitamin D. The Endocrine Society Task Force in July 2011 published a guideline for the evaluation, treatment, and prevention of vitamin D deficiency. Although these reports are intended for different purposes, the disagreements concerning the nature of the available data and the resulting conclusions have caused confusion for clinicians, researchers, and the public. In this commentary, members of the Institute of Medicine committee respond to aspects of The Endocrine Society guideline that are not well supported and in need of reconsideration. These concerns focus on target serum 25-hydroxyvitamin D levels, the definition of vitamin D deficiency, and the question of who constitutes a population at risk vs. the general population.

The 2011 Dietary Reference Intakes for Calcium and Vitamin D: What Dietetics Practitioners Need to Know

The Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D comprehensively reviewed the evidence for both skeletal and nonskeletal health outcomes and concluded that a causal role of calcium and vitamin D in skeletal health provided the necessary basis for the 2011 Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for ages older than 1 year. For nonskeletal outcomes, including cancer, cardiovascular disease, diabetes, infections, and autoimmune disorders, randomized clinical trials were sparse, and evidence was inconsistent, inconclusive as to causality, and insufficient for Dietary Reference Intake (DRI) development. The EAR and RDA for calcium range from 500 to 1,100 and 700 to 1,300 mg daily, respectively, for ages 1 year and older. For vitamin D (assuming minimal sun exposure), the EAR is 400 IU/day for ages older than 1 year and the RDA is 600 IU/day for ages 1 to 70 years and 800 IU/day for 71 years and older, corresponding to serum 25-hydroxyvitamin D (25OHD) levels of 16 ng/mL (40 nmol/L) for EARs and 20 ng/mL (50 nmol/L) or more for RDAs. Prevalence of vitamin D inadequacy in North America has been overestimated based on serum 25OHD levels corresponding to the EAR and RDA. Higher serum 25OHD levels were not consistently associated with greater benefit, and for some outcomes U-shaped associations with risks at both low and high levels were observed. The Tolerable Upper Intake Level for calcium ranges from 1,000 to 3,000 mg daily, based on calcium excretion or kidney stone formation, and from 1,000 to 4,000 IU daily for vitamin D, based on hypercalcemia adjusted for uncertainty resulting from emerging risk relationships. Urgently needed are evidence-based guidelines to interpret serum 25OHD levels relative to vitamin D status and intervention.

β-Carotene Is an Important Vitamin A Source for Humans

Experts in the field of carotenoids met at the Hohenheim consensus conference in July 2009 to elucidate the current status of β-carotene research and to summarize the current knowledge with respect to the chemical properties, physiological function, and intake of β-carotene. The experts discussed 17 questions and reached an agreement formulated in a consensus answer in each case. These consensus answers are based on published valid data, which were carefully reviewed by the individual experts and are justified here by background statements. Ascertaining the impact of β-carotene on the total dietary intake of vitamin A is complicated, because the efficiency of conversion of β-carotene to retinol is not a single ratio and different conversion factors have been used in various surveys and following governmental recommendations within different countries. However, a role of β-carotene in fulfilling the recommended intake for vitamin A is apparent from a variety of studies. Thus, besides elucidating the various functions, distribution, and uptake of β-carotene, the consensus conference placed special emphasis on the provitamin A function of β-carotene and the role of β-carotene in the realization of the required/recommended total vitamin A intake in both developed and developing countries. There was consensus that β-carotene is a safe source of vitamin A and that the provitamin A function of β-carotene contributes to vitamin A intake.

Cytochrome P450s in the Regulation of Cellular Retinoic Acid Metabolism

The active metabolite of vitamin A, retinoic acid (RA), is a powerful regulator of gene transcription. RA is also a therapeutic drug. The oxidative metabolism of RA by certain members of the cytochrome P450 (CYP) superfamily helps to maintain tissue RA concentrations within appropriate bounds. The CYP26 family--CYP26A1, CYP26B1, and CYP26C1--is distinguished by being both regulated by and active toward all-trans-RA (at-RA) while being expressed in different tissue-specific patterns. The CYP26A1 gene is regulated by multiple RA response elements. CYP26A1 is essential for embryonic development, whereas CYP26B1 is essential for postnatal survival as well as germ cell development. Enzyme kinetic studies have demonstrated that several CYP proteins are capable of metabolizing at-RA; however, it is likely that CYP26A1 plays a major role in RA clearance. Thus, pharmacological approaches to limiting the activity of CYP26 enzymes may extend the half-life of RA and could be useful clinically in the future.

Vitamin A and retinoic acid in T cell–related immunity

Interest in vitamin A as a regulator of immune function goes back to the early 1900s. Recently, several lines of evidence have converged to show that retinoic acid (RA), a major oxidative metabolite of vitamin A, plays a key role in the differentiation of T cell subsets, the migration of T cells into tissues, and the proper development of T cell-dependent antibody responses. This review discusses evidence from experimental studies that RA promotes the differentiation of regulatory T cells, which help to suppress inflammatory reactions, and plays a significant role in normal mucosal immunity by modulating T cell activation and regulating cell trafficking. RA also promotes antibody responses to T cell-dependent antigens. Conversely, in a state of vitamin A deficiency, inflammatory T cell reactions may be inadequately opposed and therefore become dominant. Although data from human studies are still needed, the framework now developed from studies in mice and rat models suggests that adequate vitamin A status, whether derived from ingestion of preformed retinol or β-carotene, is important for maintaining a proper balance of well-regulated T cell functions and for preventing excessive or prolonged inflammatory reactions.

Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE)

An increasing recognition has emerged of the complexities of the global health agenda—specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence-based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; 3) evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use; and 5) the presentation of new approaches to the study of these relations. Each WG was tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations.

Cloning of rat cytochrome P450RAI (CYP26) cDNA and regulation of its gene expression by all-trans-retinoic acid in vivo.

A novel retinoic acid (RA)-inducible cytochrome P450 (P450 RAI or CYP26), previously cloned from human, zebra fish, and mouse, functions in the metabolism of all-trans-RA to polar metabolites including 4-hydroxy-RA and 4-oxo-RA. To further study CYP26 in the rat model, we first cloned rat CYP26 cDNA. The nucleotide sequence predicts a 497-amino-acid protein whose sequence is 95% identical to mouse and 91% homologous to human CYP26. Animal studies showed that CYP26 mRNA expression is very low (0.01+/-0.008;P<0.05) in vitamin-A-deficient rats compared to pair-fed vitamin-A-sufficient rats (defined as 1.0). In a kinetic study, vitamin-A-deficient rats were treated with approximately 100 microg of all-trans-RA and liver was collected after 3-72 h for analysis of CYP26 mRNA by quantitative real-time PCR. Liver CYP26 mRNA increased to nearly 10-fold above control after 3 h (P<0.01), reaching a peak of about 2000-fold greater around 10 h (P<0.001) and then decreased rapidly. The CYP26 dose response to RA was nearly linear (R(2)=0.9638). Additionally, significant regulation of CYP26 gene expression was observed in the vitamin-A-deficient, control, and RA-treated condition in lung, testis, and small intestine. We conclude that CYP26 mRNA expression is dynamically regulated in vivo by diet and RA in hepatic and extrahepatic tissues. The long-term down-regulation of CYP26 in retinoid deficiency may be critical for conserving RA, while the acute up-regulation of CYP26 may be important for preventing a deleterious overshoot of RA derived from either dietary or exogenous sources.

Retinoic Acid and Polyriboinosinic:Polyribocytidylic Acid Stimulate Robust Anti-Tetanus Antibody Production while Differentially Regulating Type 1/Type 2 Cytokines and Lymphocyte Populations

Retinoic acid (RA), a bioactive retinoid, and polyriboinosinic:polyribocytidylic acid (PIC) are known to promote immunity in vitamin A-deficient animals. In this study, we hypothesized that RA, PIC, and the combination can provide significant immunoadjuvant activity even in the vitamin A-adequate state. Six-week-old C57BL/6 mice were immunized with tetanus toxoid (TT) and treated with RA and/or PIC at priming in three independent studies of short and long duration. RA and PIC differentially regulated both primary and secondary anti-TT IgG isotypes, whereas the combination of RA + PIC stimulated the highest level of anti-TT IgG production and, concomitantly, a ratio of IgG1 to IgG2a similar to that of the control group. The regulation of Ab response was strongly associated with type 1/type 2 cytokine gene expression. Whereas RA reduced type 1 cytokines (IFN-γ and IL-12), PIC enhanced both type 1 and type 2 cytokines (IL-4 and IL-12) and cytokine-related transcription factors. Despite the presence of PIC, the IL-4:IFN-γ ratio was significantly elevated by RA. In addition, RA and/or PIC modulated NK/NKT cell populations and the level of expression of the costimulatory molecules CD80/CD86, evident 3 days after priming. Notably, the NKT:NK and CD80:CD86 ratios were correlated with the IL-4:IFN-γ ratio, indicative of multiple converging modes of regulation. Overall, RA, PIC, and RA + PIC rapidly and differentially shaped the anti-tetanus Ig response. The robust, durable, and proportionate increase in all anti-TT IgG isotypes induced by RA + PIC suggests that this combination is promising as a means to enhance the Ab response to TT and similar vaccines.