Modeling tool for calculating dietary iron bioavailability in iron-sufficient adults.

Background: Values for dietary iron bioavailability are required for setting dietary reference values. These are estimated from predictive algorithms, nonheme iron absorption from meals, and models of iron intake, serum ferritin concentration, and iron requirements.Objective: We developed a new interactive tool to predict dietary iron bioavailability.Design: Iron intake and serum ferritin, a quantitative marker of body iron stores, from 2 nationally representative studies of adults in the United Kingdom and Ireland and a trial in elderly people in Norfolk, United Kingdom, were used to develop a model to predict dietary iron absorption at different serum ferritin concentrations. Individuals who had raised inflammatory markers or were taking iron-containing supplements were excluded.Results: Mean iron intakes were 13.6, 10.3, and 10.9 mg/d and mean serum ferritin concentrations were 140.7, 49.4, and 96.7 mg/L in men, premenopausal women, and postmenopausal women, respectively. The model predicted that at serum ferritin concentrations of 15, 30, and 60 mg/L, mean dietary iron absorption would be 22.3%, 16.3%, and 11.6%, respectively, in men; 27.2%, 17.2%, and 10.6%, respectively, in premenopausal women; and 18.4%, 12.7%, and 10.5%, respectively, in postmenopausal women.Conclusions: An interactive program for calculating dietary iron absorption at any concentration of serum ferritin is presented. Differences in iron status are partly explained by age but also by diet, with meat being a key determinant. The effect of the diet is more marked at lower serum ferritin concentrations. The model can be applied to any adult population in whom representative, good-quality data on iron intake and iron status have been collected. Values for dietary iron bioavailability can be derived for any target concentration of serum ferritin, thereby giving risk managers and public health professionals a flexible and transparent basis on which to base their dietary recommendations. This trial was registered at clinicaltrials.gov as NCT01754012.

EURRECA-Evidence-based methodology for deriving micronutrient recommendations.

The EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence explored the process of setting micronutrient recommendations to address the variance in recommendations across Europe. Work centered upon the transparent assessment of nutritional requirements via a series of systematic literature reviews and meta-analyses. In addition, the necessity of assessing nutritional requirements and the policy context of setting micronutrient recommendations was investigated. Findings have been presented in a framework that covers nine activities clustered into four stages: stage one "Defining the problem" describes Activities 1 and 2: "Identifying the nutrition-related health problem" and "Defining the process"; stage two "Monitoring and evaluating" describes Activities 3 and 7: "Establishing appropriate methods," and "Nutrient intake and status of population groups"; stage three "Deriving dietary reference values" describes Activities 4, 5, and 6: "Collating sources of evidence," "Appraisal of the evidence," and "Integrating the evidence"; stage four "Using dietary reference values in policy making" describes Activities 8 and 9: "Identifying policy options," and "Evaluating policy implementation." These activities provide guidance on how to resolve various issues when deriving micronutrient requirements and address the methodological and policy decisions, which may explain the current variation in recommendations across Europe. [Supplementary materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition for the following free supplemental files: Additional text, tables, and figures.].

EURRECA-Estimating iron requirements for deriving dietary reference values.

Currently, a factorial approach is used to derive reference values for iron. Calculations include the use of a bioavailability factor to convert the physiological requirement, derived from obligatory losses and requirements for growth and development, into a dietary intake value. A series of systematic reviews undertaken by the EURRECA Network of Excellence aimed to identify data that may increase the accuracy of factorial calculations across all population groups. The selection of robust data was guided by the use of standardized review methodology and the evidence-based selection of status biomarkers and dietary intake assessment techniques. Results corroborated the dearth of relevant factorial data, including whole-diet bioavailability data, and confirmed the need to continue extrapolating physiological requirements across population groups. Data were also unavailable that would allow reference values to be based on selected health outcomes associated with iron intake or status. Ideally, a series of observational and randomized controlled trial (RCT) studies need to be undertaken across all population groups and life stages to generate robust data for setting dietary reference values for iron. It will also be essential to include information on polymorphisms that potentially influence iron absorption and status in the derivation process.

EURRECA-Estimating selenium requirements for deriving dietary reference values.

Current reference values for selenium, an essential micronutrient, are based on the intake of selenium that is required to achieve maximal glutathione peroxidase activity in plasma or erythrocytes. In order to assess the evidence of relevance to setting dietary reference values for selenium, the EURRECA Network of Excellence focused on systematic searches, review, and evaluation of (i) selenium status biomarkers and evidence for relationships between intake and status biomarkers, (ii) selenium and health (including the effect of intake and/or status biomarkers on cancer risk, immune function, HIV, cognition, and fertility), (iii) bioavailability of selenium from the diet, and (iv) impact of genotype/single nucleotide polymorphisms on status or health outcomes associated with selenium. The main research outputs for selenium and future research priorities are discussed further in this review.

EURRECA-Estimating zinc requirements for deriving dietary reference values.

Zinc was selected as a priority micronutrient for EURRECA, because there is significant heterogeneity in the Dietary Reference Values (DRVs) across Europe. In addition, the prevalence of inadequate zinc intakes was thought to be high among all population groups worldwide, and the public health concern is considerable. In accordance with the EURRECA consortium principles and protocols, a series of literature reviews were undertaken in order to develop best practice guidelines for assessing dietary zinc intake and zinc status. These were incorporated into subsequent literature search strategies and protocols for studies investigating the relationships between zinc intake, status and health, as well as studies relating to the factorial approach (including bioavailability) for setting dietary recommendations. EMBASE (Ovid), Cochrane Library CENTRAL, and MEDLINE (Ovid) databases were searched for studies published up to February 2010 and collated into a series of Endnote databases that are available for the use of future DRV panels. Meta-analyses of data extracted from these publications were performed where possible in order to address specific questions relating to factors affecting dietary recommendations. This review has highlighted the need for more high quality studies to address gaps in current knowledge, in particular the continued search for a reliable biomarker of zinc status and the influence of genetic polymorphisms on individual dietary requirements. In addition, there is a need to further develop models of the effect of dietary inhibitors of zinc absorption and their impact on population dietary zinc requirements.

Effect of iron intake on iron status: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The response of status biomarkers to an increase in iron supply depends on several physiologic and environmental factors, which make it difficult to predict the outcome of an intervention. OBJECTIVE: We assessed effects of baseline iron status, sex, menopausal status, duration of intervention, iron form, and daily dose on the change in iron status in response to iron supplementation. DESIGN: A systematic review of randomized controlled trials (RCTs) of iron-supplementation and -fortification trials that assessed effects on hemoglobin, serum ferritin (SF), soluble transferrin receptor, or body iron was conducted. Subgrouping and straight-line and curved metaregression were used to describe the magnitude and dose-responsiveness of effect modifiers with respect to changes in status. RESULTS: Forty-one RCTs were included; none of the RCTs were judged at low risk of bias. Random-effects meta-analyses showed that iron supplementation significantly improved iron status but with high levels of heterogeneity. Metaregression explained approximately one-quarter of between-study variance in effect size. There were clear effects on SF with study duration (increase in SF concentration/wk: 0.51 µg/L; 95% CI: 0.02, 1.00 µg/L; P = 0.04) and dose (increase in SF concentration/g Fe: 0.10 µg/L; 95% CI: 0.01, 0.20 µg/L; P = 0.036) and on hemoglobin concentrations with baseline iron status [-0.08 g/dL (95% CI: 0.15, 0.00 g/dL) per 10-µg/L increase in baseline SF concentration; P = 0.02]. Insufficient data were available to assess effects on body iron, sex, or menopausal status. CONCLUSION: Quantitative relations between baseline iron status, study duration, and iron dose on changes in iron-status biomarkers, which were generated from the meta-analyses, can be used to predict effects of trials of iron supplementation and fortification and to design iron-intervention programs.

Selenium and prostate cancer: systematic review and meta-analysis.

BACKGROUND: Prostate cancer is a growing public health problem. Several human studies have shown a potentially protective effect of selenium, but the conclusions from published reports are inconsistent. OBJECTIVE: The objective was to examine the evidence for relations between selenium intake, selenium status, and prostate cancer risk. DESIGN: This was a systematic review and meta-analysis of randomized controlled trials, case-control studies, and prospective cohort studies. The World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project database was searched up to September 2010. The studies included reported measurements of selenium intake or status (plasma, serum, or toenail selenium), assessments of prostate cancer cases (number of events), and the RR in the adult population. Meta-analyses were performed, and study quality, heterogeneity, and small study effects were assessed. Dose-response meta-analyses were used, with restricted cubic splines and fractional polynomials for nonlinear trends, to investigate the association between selenium status and prostate cancer risk. RESULTS: Twelve studies with a total of 13,254 participants and 5007 cases of prostate cancer were included. The relation between plasma/serum selenium and prostate cancer in a nonlinear dose-response meta-analysis showed that the risk decreased with increasing plasma/serum selenium up to 170 ng/mL. Three high-quality studies included in the meta-analysis of toenail selenium and cancer risk indicated a reduction in prostate cancer risk (estimated RR: 0.29; 95% CI: 0.14, 0.61) with a toenail selenium concentration between 0.85 and 0.94 µg/g. CONCLUSION: The relation between selenium status and decreased prostate cancer risk was examined over a relatively narrow range of selenium status; further studies in low-selenium populations are required.

Increased consumption of fatty and lean fish reduces serum C-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies.

Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA. Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (-0.5 mg/L; 95% CI -0.9, -0.2) and cod (-0.4 mg/L; 95% CI -0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish. In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.

Assessing potential biomarkers of micronutrient status by using a systematic review methodology: methods.

BACKGROUND: To explore the relation between micronutrient status and health, it is important to understand which markers of micronutrient status can be relied on and under what circumstances. OBJECTIVE: The objective of this article was to develop a common systematic review methodology for use in the assessment of micronutrient status for selenium, iodine, copper, zinc, riboflavin, vitamin B-12, vitamin D, and omega-3 (n-3) long-chain polyunsaturated fatty acids. DESIGN: We developed a methodology on the basis of defining studies that clearly altered micronutrient status and then pooled data on the effects of this intervention on each specific biomarker to assess objectively the response of various status markers to changes in intake. RESULTS: The generic methodology included defining, and systematically searching for, studies that resulted in a change in micronutrient status. Study inclusion, data extraction, and assessment of validity were conducted with a minimum of 10% independent duplication. For each study and each potential biomarker, the highest dose and longest duration intervention data were selected to assess the statistical significance of any change in intake on the status biomarker. The consistency of biomarker response was explored by subgrouping the studies according to baseline micronutrient status, sex, population group, supplementation type, dose, duration, and analytic method. CONCLUSION: This methodology allows systematic assessment of the usefulness of a number of biomarkers for a selection of micronutrients.

Methods of assessment of copper status in humans: a systematic review.

BACKGROUND: The assessment of dietary adequacy of copper is constrained by the absence of recognized copper status biomarkers. OBJECTIVES: The objectives were to systematically review the usefulness of copper status biomarkers and identify those that reflected changes in status over > or =4 wk. DESIGN: The methods included a structured search on Ovid MEDLINE, EMBASE (Ovid), and Cochrane databases to October 2007, followed by the use of formal inclusion/exclusion criteria, data extraction, validity assessment, and meta-analysis. RESULTS: A total of 16 studies (288 participants) were included in the review, with data on 16 possible copper biomarkers. All of the included studies were small and at high risk of bias. Data for serum copper suggested its value as a biomarker, reflecting changes in status in both depleted and replete individuals, although these changes were smaller in the latter. Total ceruloplasmin protein is related to copper status but reflects changes in highly depleted individuals only. Erythrocyte superoxide dismutase and urinary deoxypyridinoline are not useful biomarkers, but there were insufficient data to draw firm conclusions about plasma, erythrocyte, and platelet copper; leukocyte superoxide dismutase; erythrocyte, platelet, and plasma glutathione peroxidase; platelet and leukocyte cytochrome-c oxidase; total glutathione; diamine oxidase; and urinary pyridinoline. The paucity of data prevented detailed subgroup analysis. CONCLUSIONS: Despite limited data, serum copper appears to be a useful biomarker of copper status at the population level. Further large studies with low risk of bias are needed to explore the effectiveness of other biomarkers of copper status and the relation between biomarker responsiveness, dose, and period of supplementation.

Methods of assessment of selenium status in humans: a systematic review.

BACKGROUND: To understand the effect of selenium intake on health, it is important to identify sensitive and population-specific biomarkers of selenium status. OBJECTIVE: The objective of this systematic review was to assess the usefulness of biomarkers of selenium status in humans. DESIGN: The methods included a structured search strategy on Ovid MEDLINE, EMBASE (Ovid), and Cochrane databases; formal inclusion and exclusion criteria; data extraction into an Access database; validity assessment; and meta-analysis. RESULTS: The data from 18 selenium supplementation studies (of which 9 were randomized controlled trials and 1 was considered to be at low risk of bias) indicate that plasma, erythrocyte, and whole-blood selenium, plasma selenoprotein P, and plasma, platelet, and whole-blood glutathione peroxidase activity respond to changes in selenium intake. Although there is a substantial body of data for plasma selenium, more large, high-quality, randomized controlled trials are needed for this biomarker, as well as for the other biomarkers, to explore the reasons for heterogeneity in response to selenium supplementation. There was insufficient evidence to assess the usefulness of other potential biomarkers of selenium status, including urinary selenium, plasma triiodothyroxine:thyroxine ratio, plasma thyroxine, plasma total homocysteine, hair and toenail selenium, erythrocyte, and muscle glutathione peroxidase activity. CONCLUSIONS: For all potentially useful biomarkers, more information is needed to evaluate their strengths and limitations in different population groups, including the effects of varying intakes, the duration of intervention, baseline selenium status, and possible confounding effects of genotype.

Serum prohepcidin concentration: no association with iron absorption in healthy men; and no relationship with iron status in men carrying HFE mutations, hereditary haemochromatosis patients undergoing phlebotomy treatment, or pregnant women.

Hepcidin plays a major role in iron homeostasis, but understanding its role has been hampered by the absence of analytical methods for quantification in blood. A commercial ELISA has been developed for serum prohepcidin, a hepcidin precursor, and there is interest in its potential use in the clinical and research arena. We investigated the association between serum prohepcidin concentration and iron absorption in healthy men, and its relationship with iron status in men carrying HFE mutations, hereditary haemochromatosis patients, and pregnant women. Iron absorption was determined in thirty healthy men (fifteen wild-type, fifteen C282Y heterozygote) using the stable isotope red cell incorporation technique. Iron status was measured in 138 healthy men (ninety-one wild-type, forty-seven C282Y heterozygote), six hereditary haemochromatosis patients, and thirteen pregnant women. Mean serum prohepcidin concentrations were 214 (SD 118) ng/ml [208 (SD 122) ng/ml in wild-type and 225 (SD 109) ng/ml in C282Y heterozygotes] in healthy men, 177 (SD 36) ng/ml in haemochromatosis patients, and 159 (SD 59) ng/ml in pregnant women. There was no relationship between serum prohepcidin concentration and serum ferritin in any subject groups, nor was it associated with efficiency of iron absorption. Serum prohepcidin is not a useful biomarker for clinical or research purposes.

Effect of high-dose iron supplements on fractional zinc absorption and status in pregnant women.

BACKGROUND: Women have an increased risk of iron deficiency during pregnancy because of the demands of the developing fetus. Iron supplements are commonly advocated as a prophylactic treatment and are generally taken with meals to reduce side effects, but iron can interfere with the absorption of zinc. OBJECTIVE: The aim was to determine the effect of consuming an iron supplement (100 mg Fe/d as ferrous gluconate) with meals from 16 wk gestation to term on zinc status and absorption. DESIGN: Stable-isotope techniques were used to measure zinc status (exchangeable zinc pool, EZP) and fractional zinc absorption (FZA) in early and late pregnancy from a meal consumed at a different time from that of iron supplement or placebo consumption in 6 women given iron supplements and 7 given a placebo. RESULTS: FZA increased during pregnancy, independent of iron supplementation. FZA was significantly higher (P < 0.001) at week 34 than at weeks 16 and 24, and urinary zinc excretion was higher at week 34 than at week 16 (P = 0.02). The size of the EZP remained unchanged throughout pregnancy and was unaffected by iron supplementation. The iron status of iron-supplemented women was higher than that of the placebo group. CONCLUSIONS: In iron-replete pregnant women who consumed a Western diet, no detectable adverse effects on zinc metabolism were observed after ingestion of 100 mg Fe/d. An increase in the efficiency of zinc absorption was observed during late pregnancy.

Adaptive responses in men fed low- and high-copper diets.

The study of Cu metabolism is hampered by a lack of sensitive and specific biomarkers of status and suitable isotopic labels, but limited information suggests that Cu homeostasis is maintained through changes in absorption and endogenous loss. The aim of the present study was to employ stable-isotope techniques to measure Cu absorption and endogenous losses in adult men adapted to low, moderate and high Cu-supplemented diets. Twelve healthy men, aged 20-59 years, were given diets containing 0.7, 1.6 and 6.0 mg Cu/d for 8 weeks, with at least 4 weeks intervening washout periods. After 6 weeks adaptation, apparent and true absorption of Cu were determined by measuring luminal loss and endogenous excretion of Cu following oral administration of 3 mg highly enriched (65)Cu stable-isotope label. Apparent and true absorption (41 and 48 % respectively) on the low-Cu diet were not significantly different from the high-Cu diet (45 and 48 % respectively). Endogenous losses were significantly reduced on the low- (0.45 mg/d; P<0.001) and medium- (0.81 mg/d; P=0.001) compared with the high-Cu diet (2.46 mg/d). No biochemical changes resulting from the dietary intervention were observed. Cu homeostasis was maintained over a wide range of intake and more rapidly at the lower intake, mainly through changes in endogenous excretion.