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Christine A Northrop-Clewes,1 David I Thurnham21Nutrition Consultant, Cambridge, UK; 2Northern Ireland Centre for Food and Health, School of Biomedical Sciences, University of Ulster, Coleraine, UKAbstract: The World Health Organization defines anemia as the point at which the amount of hemoglobin in the circulation falls below World Health Organization cutoffs for specific age and sex groups. Anemia is a worldwide problem of complex etiology and is associated with many factors. The purpose of this review was to describe the biomarkers used to identify the nature of anemia in patients and in the community. The important biomarkers are the automated red cell counts, tests for nutritional deficiencies, hemoglobinopathies, and inflammation. Diseases are important potential initiators of anemia, but biomarkers of specific diseases are not included in this review, only the underlying feature common to all disease – namely, inflammation.Keywords: iron deficiency, biological markers, blood cell count, inflammation, avitaminosis, hemoglobinopathies

Iron status is influenced by inflammation when the normal control of iron metabolism is reorganized by the primary mediators of the acute phase response, tumour necrosis factor-alpha and interleukin-1. The objective of this review is to show how indices of iron status, particularly haemoglobin, serum ferritin and soluble transferrin receptor concentrations relate to changes in the acute phase proteins during inflammation. The pattern of acute phase response after elective surgery, not preceded by infection, is used to demonstrate the time course of stimulation of the acute phase proteins. The changes in the concentrations of serum acute phase protein and markers of iron status during treatment for infection are used to demonstrate inter-relationships between the indicators. In many developing countries, asymptomatic malaria and human immunodeficiency virus (HIV) are common and may affect the interpretation of iron indicators during population assessments. Malaria produces an acute phase response and relationships between acute phase protein and indices of iron status indicate an influence of inflammation in both symptomatic and asymptomatic malaria, except when the parasitaemia is less than 1000/muL of blood when ferritin appears to be unaffected. HIV-1 impacts on haemopoiesis and anaemia. Anaemia increases in severity as the disease progresses and it is often a negative prognostic indicator. However, in individuals infected with HIV there may be an atypical acute phase response in the absence of opportunistic infections. Tentative conclusions are drawn concerning the inter-relationships between ferritin and the acute phase proteins, C-reactive protein and alpha-1-acid glycoprotein during an acute phase response. [ABSTRACT FROM AUTHOR]

Approximately 5-7% of all infants are born prematurely, and birth before 37 weeks is the most common cause of neonatal mortality, morbidity and long-term disability. Premature infants are poorly equipped for life outside the womb, and oxidant stress has been implicated in the aetiology of visual impairment in these infants, who are often exposed to increased O2 concentrations and high light intensity in neonatal units. The carotenoids lutein and zeaxanthin, which give the macular area of the eye its yellow colour, are located in the retinal pigment epithelium of the eye, and are believed to play a role in protecting it against oxidative and light damage. The macular pigments are of dietary origin, and green leafy vegetables are the primary source of lutein and zeaxanthin. Lutein is one of the five most common carotenoids found in the diet. There is current interest in the macular pigment in relation to age-related macular degeneration, but these pigments may also have a protective role in the retinal pigment epithelium of the newborn infant. Little information is available on blood lutein and zeaxanthin levels in neonates. Levels of lutein in human milk are two to three times higher than those of beta-carotene, whereas their concentrations in the mothers' blood are approximately the same. Human milk is the main dietary source of lutein and zeaxanthin for infants until weaning occurs. The biochemical mechanisms which mediate the transport of the macular carotenoids into the eye are not known, but tubulin has been identified as the major carotenoid-binding protein, and may play a role in the physiology of the macula. [ABSTRACT FROM AUTHOR]

The accurate estimation of vitamin A deficiency (VAD) is critical to informing programmatic and policy decisions that could have important public health implications. However, serum retinol and retinol binding protein (RBP) concentrations, two biomarkers often used to estimate VAD, are temporarily altered during the acute phase response, potentially overestimating the prevalence of VAD in populations with high levels of inflammation. In 22 nationally-representative surveys, we examined (1) the association between C-reactive protein (CRP) or α1-acid glycoprotein (AGP) and retinol or RBP, and (2) how different adjustment approaches for correcting for inflammation compare with one another. In preschool age children (PSC) and school age children (SAC), the association between inflammation and retinol and RBP was largely statistically significant; using the regression approach, adjustments for inflammation decreased the estimated prevalence of VAD compared to unadjusted VAD (range: -22.1 to -6.0 percentage points). In non-pregnant women of reproductive age (WRA), the association between inflammation and vitamin A biomarkers was inconsistent, precluding adjustments for inflammation. The burden of VAD can be overestimated if inflammation is not accounted for, and the regression approach provides a method for adjusting retinol and RBP for inflammation across the full range of concentrations in PSC and SAC.

Background: The accurate estimation of the prevalence of vitamin A deficiency (VAD) is important in planning and implementing interventions. Retinol-binding protein (RBP) is often used in population surveys to measure vitamin A status, but its interpretation is challenging in settings where inflammation is common because RBP concentrations decrease during the acute-phase response. Objectives: We aimed to assess the relation between RBP concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and to investigate adjustment algorithms to account for these effects. Design: Cross-sectional data from 8 surveys for PSC ( n = 8803) and 4 surveys for WRA ( n = 4191) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to adjust RBP concentrations in PSC in inflammation and malaria settings as follows: 1 ) the exclusion of subjects with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L, 2 ) the application of arithmetic correction factors, and 3 ) the use of a regression correction approach. The impact of adjustment on the estimated prevalence of VAD (defined as <0.7 μmol/L) was examined in PSC. Results: The relation between estimated VAD and CRP and AGP deciles followed a linear pattern in PSC. In women, the correlations between RBP and CRP and AGP were too weak to justify adjustments for inflammation. Depending on the approach used to adjust for inflammation (CRP+AGP), the estimated prevalence of VAD decreased by a median of 11-18 percentage points in PSC compared with unadjusted values. There was no added effect of adjusting for malaria on the estimated VAD after adjusting for CRP and AGP. Conclusions: The use of regression correction (derived from internal data), which accounts for the severity of inflammation, to estimate the prevalence of VAD in PSC in regions with inflammation and malaria is supported by the analysis of the BRINDA data. These findings contribute to the evidence on adjusting for inflammation when estimating VAD with the use of RBP.

Background: The accurate estimation of iron deficiency is important in planning and implementing interventions. Ferritin is recommended as the primary measure of iron status, but interpretability is challenging in settings with infection and inflammation. Objective: We assessed the relation between ferritin concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and investigated adjustment algorithms to account for these effects. Design: Cross-sectional data from 15 surveys for PSC ( n = 27,865) and 8 surveys for WRA (24,844), from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to estimate depleted iron stores (ferritin concentration <12 μg/L in PSC and <15 μg/L in WRA) in inflammation and malaria settings as follows: 1 ) increase ferritin-concentration cutoff to <30 μg/L; 2 ) exclude individuals with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L; 3 ) apply arithmetic correction factors; and 4 ) use a regression correction approach. Results: Depleted iron-store estimates incrementally increased as CRP and AGP deciles decreased (4% compared with 30%, and 6% compared with 29% from highest compared with lowest CRP deciles for pooled PSC and WRA, respectively, with similar results for AGP). Depending on the approach used to adjust for inflammation (CRP plus AGP), the estimated prevalence of depleted iron stores increased by 7-25 and 2-8 absolute median percentage points for PSC and WRA, respectively, compared with unadjusted values. Adjustment for malaria in addition to CRP and AGP did not substantially change the estimated prevalence of depleted iron stores. Conclusions: Our results lend support for the use of internal regression correction to estimate the prevalence of depleted iron stores in regions with inflammation. This approach appears to mathematically reflect the linear relation of ferritin concentrations with acute-phase proteins. More research is warranted to validate the proposed approaches, but this study contributes to the evidence base to guide decisions about how and when to adjust ferritin for inflammation.

Background: Iron deficiency is thought to be one of the most prevalent micronutrient deficiencies globally, but an accurate assessment in populations who are frequently exposed to infections is impeded by the inflammatory response, which causes iron-biomarker alterations. Objectives: We assessed the relation between soluble transferrin receptor (sTfR) concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and investigated adjustment algorithms to account for these effects. Design: Cross-sectional data from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project from 11,913 PSC in 11 surveys and from 11,173 WRA in 7 surveys were analyzed individually and combined with the use of a meta-analysis. The following 3 adjustment approaches were compared with estimated iron-deficient erythropoiesis (sTfR concentration >8.3 mg/L): 1 ) the exclusion of individuals with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L, 2 ) the application of arithmetic correction factors, and 3 ) the use of regression approaches. Results: The prevalence of elevated sTfR concentrations incrementally decreased as CRP and AGP deciles decreased for PSC and WRA, but the effect was more pronounced for AGP than for CRP. Depending on the approach used to adjust for inflammation, the estimated prevalence of iron-deficient erythropoiesis decreased by 4.4-14.6 and 0.3-9.5 percentage points in PSC and WRA, respectively, compared with unadjusted values. The correction-factor approach yielded a more modest reduction in the estimated prevalence of iron-deficient erythropoiesis than did the regression approach. Mostly, adjustment for malaria in addition to AGP did not significantly change the estimated prevalence of iron-deficient erythropoiesis. Conclusions: sTfR may be useful to assess iron-deficient erythropoiesis, but inflammation influences its interpretation, and adjustment of sTfR for inflammation and malaria should be considered. More research is warranted to evaluate the proposed approaches in different settings, but this study contributes to the evidence on how and when to adjust sTfR for inflammation and malaria.

Background: In many settings, populations experience recurrent exposure to inflammatory agents that catalyze fluctuations in the concentrations of acute-phase proteins and certain micronutrient biomarkers such as C-reactive protein (CRP), α-1-acid glycoprotein (AGP), ferritin, and retinol. Few data are available on the prevalence and predictors of inflammation in diverse settings. Objective: We aimed to assess the relation between inflammation (CRP concentration >5 mg/L or AGP concentration >1 g/L) and covariates, such as demographics, reported illness, and anthropometric status, in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y). Design: Cross-sectional data from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project from 29,765 PSC in 16 surveys and 25,731 WRA in 10 surveys were used to model bivariable and multivariable relations. Results: The inflammation prevalence was 6.0-40.2% in PSC and 7.9-29.5% in WRA (elevated CRP) and 21.2-64.3% in PSC and 7.1-26.7% in WRA (elevated AGP). In PSC, inflammation was consistently positively associated with recent fever and malaria but not with other recent illnesses. In multivariable models that were adjusted for age, sex, urban or rural residence, and socioeconomic status, elevated AGP was positively associated with stunting (height-for-age z score <-2) in 7 of 10 surveys. In WRA, elevated CRP was positively associated with obesity [body mass index (in kg/m 2 ) ≥30] in 7 of 9 surveys. Other covariates showed inconsistent patterns of association with inflammation. In a pooled analysis of surveys that measured malaria, stunting was associated with elevated AGP but not CRP in PSC, and obesity was associated with both elevated CRP and AGP in WRA. Conclusions: Recent morbidity and abnormal anthropometric status are consistently associated with inflammation across a range of environments, whereas more commonly collected demographic covariates were not. Because of the challenge of defining a general demographic population or environmental profile that is more likely to experience inflammation, inflammatory markers should be measured in surveys to account for their effects.

Purpose of Review: Investigations to discover new biomarkers of nutrition highlighted the fact that inflammation and infection were cross-cutting issues complicating interpretation of status. Collaborative groups of nutritionists, immunologists, clinicians and statisticians were set up to investigate the issues, and some are now reporting their findings., Recent Findings: Recent work on the vitamins A, D, E and C and the elements iron, zinc and selenium are reported in this review. In clinical settings, experts emphasize the unreliability of nutritional biomarkers to reflect status, but some advocate the use of albumin to assist interpretation. In apparently healthy people with subclinical inflammation, one method to correct data on vitamin A and iron stores using C-reactive protein and alpha-1-acid glycoprotein is available, and two studies report on its use; others methods are currently being investigated., Summary: Biomarkers of most micronutrients are the plasma concentrations of the respective vitamins or minerals and, irrespective of nutritional status, many are reduced by inflammation; the main exception is ferritin which is increased. Different methods are being investigated to better interpret nutritional data in the presence of infection or inflammation, and nutritionists who work with apparently healthy people need to be aware of subclinical inflammation to avoid exaggerating or underreporting nutritional results.

Anemia and micronutrient deficiencies are widespread in sub-Saharan Africa, but the impact of food fortification is still debated. The objective of this study was to estimate the iron and vitamin A status of preschool children (PSC) and women of reproductive age (WRA) in households consuming fortified oil and wheat flour. The survey was cross-sectional in a rural and an urban area. Data on demographics, socioeconomic status, and fortified foods were collected at households. Hemoglobin (Hb), retinol binding protein (RBP), ferritin, soluble transferrin receptors (sTfR), subclinical inflammation, and Plasmodium spp. infection data were collected. In PSC, vitamin A deficiency (VAD) was prevalent, but for each 1 mg retinol equivalents (RE)/kg of oil consumed, RBP increased by 0.37 μmol/L (p = 0.03). In WRA, there was no significant VAD in the population (0.7%). Anemia was found in 92.2% of rural and 56.3% of urban PSC (p < 0.001). PSC with access to adequately fortified flour had Hb concentrations 15.7 g/L higher than those who did not (p < 0.001). Hb levels increased by +0.238 g/L per mg/kg increase in iron fortification levels (p < 0.001). The national program fortifying vegetable oil with vitamin A and wheat flour with iron and folic acid may have contributed to improved micronutrient status of PSC from two areas in Côte d'Ivoire.

Many nutrient biomarkers are altered by inflammation. We calculated adjustment factors for retinol and ferritin by using meta-analyses of studies containing the respective biomarker and 2 acute phase proteins in serum, C-reactive protein (CRP), and α1-acid glycoprotein (AGP). With the use of CRP and AGP we identified 4 groups in each study: reference (CRP ≤5 mg/L, AGP ≤1 g/L), incubation (CRP >5 mg/L, AGP ≤1 g/L), early convalescence (CRP >5 mg/L, AGP >1 g/L), and late convalescence (CRP ≤5 mg/L, AGP >1 g/L). For each biomarker, ratios of the geometric means of the reference to each inflammation group concentration were used to calculate adjustment factors for retinol (1.13, 1.24, and 1.11) and ferritin (0.77, 0.53, and 0.75) for the incubation, early, and late convalescent groups, respectively. The application of the meta-analysis factors in more recent studies compares well with study-specific factors. The same method was used to calculate adjustment factors for soluble transferrin receptor (sTfR) and body iron stores (BISs) in Lao children. We found no advantage in adjusting sTfR for inflammation; in fact, adjustment decreased iron deficiency. Neither adjusted (10% <0 mg/kg) nor nonadjusted (12% <0 mg/kg) BISs detected as much iron deficiency as did ferritin (18% <12 μg/L) and adjusted ferritin (21% <12 μg/L) unless the cutoff for BISs was increased from 0 to <3 mg/kg. However, we could find no evidence that the larger number of children identified as having BISs <3 mg/kg had risks of anemia comparable to those identified by using ferritin <12 μg/L. In conclusion, both corrected and uncorrected ferritin concentrations <12 μg/L are associated with more iron deficiency and anemia than either sTfR >8.3 mg/L or BISs <0 mg/kg in Lao children., (© 2015 American Society for Nutrition.)

Background: The Uzbekistan 1996 Demographic Health Survey reported 60.4% of women of reproductive age (WRA) had low hemoglobin concentrations (<120 g/L), and anemia was an important public health problem. Fortification of wheat flour was identified as an appropriate intervention to address anemia due to the ubiquitous consumption of wheat flour. A National Flour Fortification Program (NFFP) was implemented in 2005., Methodology/principal Findings: After 3-years of the NFFP, a national survey using large country-lot quality assurance sampling was carried out to assess iron, folate, hemoglobin and inflammation status of WRA; the coverage and knowledge of the fortified first grade UzDonMakhsulot (UDM) flour/grey loaf program; and consumption habits of women to investigate the dietary factors associated with anemia. Estimated anemia prevalence was 34.4% (95% CI: 32.0, 36.7), iron depletion 47.5% (95% CI: 45.1, 49.9) and folate deficiency 28.8% (95% CI: 26.8, 30.8); the effect of inflammation was minimal (4% with CRP >5 mg/L). Severe anemia was more prevalent among folate deficient than iron depleted WRA. Presence of UDM first grade flour or the grey loaf was reported in 71.3% of households. Among WRA, 32.1% were aware of UDM fortification; only 3.7% mentioned the benefits of fortification and 12.5% understood causes of anemia. Consumption of heme iron-containing food (91%) and iron absorption enhancers (97%) was high, as was the consumption of iron absorption inhibitors (95%)., Conclusions/significance: The NFFP coincided with a substantial decline in the prevalence of anemia. Folate deficiency was a stronger predictor of severe anemia than iron depletion. However, the prevalence of iron depletion was high, suggesting that women are not eating enough iron or iron absorption is inhibited. Fortified products were prevalent throughout Uzbekistan, though UDM flour must be adequately fortified and monitored in the future. Knowledge of fortification and anemia was low, suggesting consumer education should be prioritized.

Background: Fortification of staple foods has been repeatedly recommended as an effective approach to reduce micronutrient deficiencies. With the increased number of fortification projects globally, there is a need to share practical lessons learned relating to their implementation and responses to project-related and external challenges., Objective: To document the achievements, challenges, lessons learned, and management responses associated with national fortification projects in Morocco, Uzbekistan, and Vietnam., Methods: Independent end-of-project evaluations conducted for each project served as the primary data source and contain the history of and project activities undertaken for, each fortification project. Other sources, including national policy documents, project reports from the Global Alliance for Improved Nutrition (GAIN) and other stakeholders, industry assessments, and peer-reviewed articles, were used to document the current responses to challenges and future project plans., Results: All projects had key achievements related to the development of fortification standards and the procurement of equipment for participating industry partners. Mandatory fortification of wheat flour was a key success in Morocco and Uzbekistan. Ensuring the quality of fortified foods was a common challenge experienced across the projects, as were shifts in consumption patterns and market structures. Adjustments were made to the projects' design to address the challenges faced., Conclusions: National fortification projects are dynamic and must be continually modified in response to specific performance issues and broader shifts in market structure and consumption patterns.

The first observation of a pigment in milk with yellow-green fluorescence can be traced to the English chemist Alexander Wynter Blyth in 1872, but it was not until the early 1930s that the substance was characterized as riboflavin. Interest in accessory food factors began in the latter half of the 19th century with the discovery of the first vitamin, thiamin. Thiamin was water soluble and given the name vitamin B(1). However, researchers realized that there were one or more additional water-soluble factors and these were called the vitamin B-2 complex. The search to identify these accessory food factors in milk, whole wheat, yeast, and liver began in the early 1900s. As there is no classical nutritional disease attributable to riboflavin deficiency, it was the growth-stimulating properties of the food extracts given to young rats that provided the tool with which to investigate and eventually extract riboflavin. Riboflavin was the second vitamin to be isolated and the first from the vitamin B-2 complex; the essential nature of the vitamin as a food constituent for man was shown in 1939., (Copyright © 2012 S. Karger AG, Basel.)

Background: The World Health Organization recommends serum ferritin concentrations as the best indicator of iron deficiency (ID). Unfortunately, ferritin increases with infections; hence, the prevalence of ID is underestimated., Objective: The objective was to estimate the increase in ferritin in 32 studies of apparently healthy persons by using 2 acute-phase proteins (APPs), C-reactive protein (CRP) and alpha(1)-acid glycoprotein (AGP), individually and in combination, and to calculate factors to remove the influence of inflammation from ferritin concentrations., Design: We estimated the increase in ferritin associated with inflammation (ie, CRP gt 5 mg/L and/or AGP gt 1 g/L). The 32 studies comprised infants (5 studies), children (7 studies), men (4 studies), and women (16 studies) (n = 8796 subjects). In 2-group analyses (either CRP or AGP), we compared the ratios of log ferritin with or without inflammation in 30 studies. In addition, in 22 studies, the data allowed a comparison of ratios of log ferritin between 4 subgroups: reference (no elevated APP), incubation (elevated CRP only), early convalescence (both APP and CRP elevated), and late convalescence (elevated AGP only)., Results: In the 2-group analysis, inflammation increased ferritin by 49.6% (CRP) or 38.2% (AGP; both P lt 0.001). Elevated AGP was more common than CRP in young persons than in adults. In the 4-group analysis, ferritin was 30%, 90%, and 36% (all P lt 0.001) higher in the incubation, early convalescence, and late convalescence subgroups, respectively, with corresponding correction factors of 0.77, 0.53, and 0.75. Overall, inflammation increased ferritin by ap 30% and was associated with a 14% (CI: 7%, 21%) underestimation of ID., Conclusions: Measures of both APP and CRP are needed to estimate the full effect of inflammation and can be used to correct ferritin concentrations. Few differences were observed between age and sex subgroups.

Background: Information about the zinc status of low-income minority children in the United States is lacking., Objective: The objective was to determine the prevalence of zinc deficiency and anemia and their interrelation among low-income African American and Hispanic preschool children., Design: This was a cross-sectional study in which a prospective 3-d food diary was completed, and hemoglobin, serum ferritin, zinc, copper, and C-reactive protein concentrations were measured. Children with elevated C-reactive protein concentrations were excluded from analysis., Results: Of 292 children recruited, 280 (mean +/- SD age: 2.5 +/- 1.2 y) qualified for analysis. One hundred forty-six (52%) children were African American and 134 (48%) were Hispanic; 202 (72%) were enrolled in the Women, Infants, and Children nutrition program. A low serum zinc concentration (<10.7 mumol/L) was present in 34 (12%) children, and 37 (13%) were anemic (hemoglobin < 110 g/L). African American (odds ratio: 3.47; 95% CI: 1.51, 7.96) and anemic (odds ratio: 2.92; 95% CI: 1.24, 6.90) children had an increased risk of zinc deficiency. Serum zinc correlated with hemoglobin (r = 0.24, P < 0.001). Children with a height/length less than the fifth percentile had significantly lower mean serum zinc concentrations than those with a height/length greater than the fifth percentile (12.4 +/- 1.8 compared with 13.0 +/- 2.2 micromol/L; P < 0.001). In a multiple logistic regression model, African American race-ethnicity was associated with zinc deficiency (odds ratio: 0.26; P = 0.02). The main sources of iron and zinc in the diets were meat products and cereals., Conclusions: The prevalence of zinc deficiency and anemia was high in this population of low-income minority children, especially among African Americans. Further investigation of the incidence of zinc deficiency and the ability of anemia to screen for it is warranted.

Smoking is associated with oxidative stress and increased risks of many chronic diseases that both shorten life and impair its quality. Low concentrations of several micronutrients, especially the antioxidants vitamin C and beta-carotene, are also associated with smoking, and there has been much interest in determining whether deficiencies in micronutrients are involved etiologically in smoking-related diseases. The objective of this review was to bring together reports on dietary intakes, biochemical indicators of micronutrient status, and results of some intervention studies on micronutrients where authors had compared outcomes in smokers and non-smokers. The micronutrients discussed are vitamins A, E, and C; the carotenoids; some of the B-vitamin group; and the minerals selenium, zinc, copper, and iron. The data were then examined to determine whether effects on the biochemical markers of micronutrient status were due to differences in dietary intakes between smokers and non-smokers or to the consequences of inflammatory changes caused by the oxidative stress of smoking. It was concluded that although smoking is associated with reduced dietary intake of vitamin C and carotenoid-containing foods, inflammatory changes increase turnover of these micronutrients so that blood concentrations are still lower in smokers than non-smokers even when there is control for dietary differences. In the case of vitamin E, there is some evidence for increased turnover of this nutrient in smokers, but this has little to no influence on blood concentrations, and there are no differences in dietary intake of vitamin E between smokers and non-smokers. Serum concentrations of vitamin A, folate, and vitamin B12 and B6 markers do not appear to be influenced by smoking, although there is some influence of dietary intake on concentrations of these nutrients in the body. In the case of the minerals examined, the main effects on biochemical markers of mineral status were attributed to inflammation and were therefore greater in heavy or long-term smokers. Serum concentrations of selenium and erythrocyte GPx activity were lower in smokers. Erythrocyte CuZn-SOD activity and serum ceruloplasmin concentrations were elevated, while serum zinc concentrations were depressed only in heavy smokers. Lastly, smoking appears to affect iron homeostasis mainly by changing hemoglobin concentrations, which were in general increased. Serum iron, TfR, and ferritin were mostly unaffected by smoking, except in pregnancy where there is evidence of increased erythropoiesis causing lower saturation of plasma transferrin and some evidence of lowering of iron stores.

Background: Two carotenoids, lutein and zeaxanthin are found in the retinal pigment epithelium of the eye where they are believed to protect it against oxidative and light damage. The amounts of these carotenoids consumed by premature infants are not known., Objective: The objective of the investigation was to measure these carotenoids in human and formulae milks., Design: In all, 28 human milk samples were obtained at various times between days 1 and 41 of lactation from 13 mothers. Six formula milks commonly used in hospitals were also analysed., Setting: Mothers who provided the milk samples had infants in the neonatal ward at the Royal Maternity Hospital, Belfast., Results: Median lutein and zeaxanthin concentrations in human milk were 4.79 (range 0.42-9.98) nmol/g fat and 0.55 (0.00-1.70) nmol/g fat, respectively. Five of the six formula milks also contained lutein and zeaxanthin with concentrations that varied over a wide range (0.7-9.7 and 0.1-1.2 nmol/g fat, respectively)., Conclusions: Carotenoid concentrations usually decreased with the duration of lactation. Some formula milks that were specially formulated for premature infants contained high concentrations of the lutein and zeaxanthin and the source may be egg yolk., Sponsorship: These studies were supported by the University of Ulster and the Northern Ireland Mother and Baby Appeal.

Many indicators of micronutrient status change during infection because of the acute phase response. In this study, relationships between the acute phase response, assessed by measuring concentrations of C-reactive protein (CRP), alpha(1)-antichymotrypsin (ACT) and alpha(1)-acid glycoprotein (AGP), and indicators of micronutrient status were analyzed in 418 infants who completed a 6-mo randomized, double-blind, placebo-controlled, supplementation trial with iron, zinc and/or beta-carotene. The acute phase response, defined by raised CRP (plasma concentration >10 mg/L), raised AGP (>1.2 g/L), or both raised CRP and AGP, significantly affected indicators of iron, vitamin A and zinc status, independently of the effects of supplementation. Plasma ferritin concentrations were higher by 15.7 (raised AGP) to 21.2 (raised CRP and AGP) micro g/L in infants with elevated acute phase proteins compared with infants without acute phase response (P < 0.001). In contrast, plasma concentrations of retinol were lower by 0.07 (P < 0.05, raised AGP) to 0.12 (P < 0.01, raised CRP) micro mol/L, and of zinc lower by 1.49 (P < 0.01, raised AGP) to 1.89 (P < 0.05, raised CRP and AGP) micro mol/L. Hemoglobin concentrations and the modified relative dose response were not affected. Consequently, the prevalence of iron deficiency anemia was underestimated in infants with raised acute phase proteins by >15%, whereas the prevalence of vitamin A deficiency was overestimated by >16% compared with infants without acute phase response. Hence, using indicators of micronutrient status without considering the effects of the acute phase response results in a distorted estimate of micronutrient deficiencies, whose extent depends on the prevalence of infection in the population.

Vitamin A supplements are reported to reduce febrile episodes of malaria and parasite counts, especially in children aged 12-36 months. Red palm oil (RPO) is a good source of vitamin A, is rich in alpha- and beta-carotene and is as effective as high-dose retinyl palmitate supplements in improving vitamin A status. In western Nigeria, where malaria is endemic, RPO is widely used and consumption can be measured using plasma alpha-carotene as a proxy biomarker since there are few other prominent sources of this carotene in the diet. The influence of RPO consumption on malaria was investigated in 207 children (aged 0-60 months) who presented with fever in August-October 1999 at several hospital clinics around Ile-Ife. Medical and anthropometric data, body temperature, parasitaemia and plasma C-reactive protein (CRP), retinol, carotenoids and tocopherols were measured in the children. Mothers were interviewed on usage of cooking oil and mosquito nets in the home, education and occupation. Most families used RPO and median plasma concentrations of both alpha-carotene (0.518 mumol/L) and beta-carotene (0.698 mumol/L) in the children were high. Using body temperature, parasite density and plasma CRP as markers of disease severity, multiple linear regression analysis was carried out on those for whom complete data were available (n = 138), separated into 3 age-groups of < 12 months (n = 37), 12-36 months (n = 68) and > 36 months (n = 33). In the absence of plasma retinol, plasma alpha-carotene explained 13.9% of the variance in parasite density (P = 0.013) but only in children aged > 36 months. The relationship with disease severity was negative, i.e., there was some evidence that RPO usage protected against malaria, and other dietary indices generally indicated that better nutritional status was associated with a lower severity of malaria.

Background: The effect of helminth infestation on the nutrition, growth, and physiology of the host is still poorly understood. Anthelmintic treatment of children in developing countries has had varying success in terms of growth improvements., Objective: The objective of this study was to assess the effect of regular deworming on child growth, physiology, and biochemical status., Design: The study was a 12-mo longitudinal intervention in 123 Bangladeshi children aged 2-5 y. Treatment (mebendazole) or placebo tablets were administered every 2 mo for 8 mo and again at 12 mo. Weight, height, midupper arm circumference, intestinal permeability, plasma albumin, alpha(1)-antichymotrypsin, and total protein concentration were assessed every 2 mo., Results: Treatment with mebendazole reduced the prevalence of Ascaris lumbricoides from 78% to 8%, of Trichuris trichiura from 65% to 9%, and of hookworm from 4% to 0%. There was no significant difference in the growth of treated children compared with those given placebo tablets. No changes in intestinal permeability or plasma albumin were observed after deworming. Significant decreases in total protein (P<0.001) and alpha(1)-antichymotrypsin (P<0.001) were observed in the treatment group, indicating possible reductions in inflammation and immunoglobulin concentration after deworming. A significant increase in the prevalence of Giardia intestinalis (from 4% to 49%) in the treatment group was associated with a short-term reduction in weight (P = 0.02) and higher intestinal permeability (P <0.001) in infected subjects. No long-term effects of G. intestinalis on growth were observed., Conclusion: Low-intensity helminth infections, predominantly of A. lumbricoides and T. trichiura, do not contribute significantly to the poor growth and biochemical status of rural Bangladeshi children.

Background: Plasma retinol concentrations are depressed by infection but are commonly used to assess vitamin A status., Objective: We measured 2 acute phase proteins, alpha(1)-antichymotrypsin (ACT) and alpha(1)-acid glycoprotein (AGP), to determine whether they could be used to assist in interpreting vitamin A status., Design: In 1997, a 2-stage cluster-sampling procedure was used to select 3074 apparently healthy, 6-60-mo-old children from rural and urban areas of North West Frontier Province, Pakistan. Plasma retinol, ACT, AGP, and ferritin measurements and anthropometric measurements were obtained for 2519 children., Results: Median plasma retinol, ACT, AGP, and ferritin concentrations were 0.86 micromol/L, 0.39 g/L, 1.14 g/L, and 5.5 microg/L, respectively. There were no significant (P: > 0.05) differences in retinol, ACT, or AGP by sex or age. Some 797 children (32%) had retinol concentrations <0.7 micromol/L and 87 (4%) had retinol concentrations <0.35 micromol/L; 274 children (11%) had elevated ACT (>0.6 g/L) and 1141 (45%) had elevated AGP (>1.2 g/L). Retinol concentration correlated with ACT (r = -0.141), AGP (r = -0.138), and ferritin (r = -0.09) (all P: < 0.001), but stepwise multiple regression indicated that these 3 variables made a minimal although quantifiable contribution to the variance of retinol (ACT, r(2) = 0.02; all 3 variables, r(2) = 0.03)., Conclusions: The transient depression in plasma retinol produced by subclinical infection increased the number of at-risk children by 10% (76 of 797) and 56% (49 of 87) for plasma retinol concentrations <0.7 and <0.35 micromol/L, respectively. In addition, dietary inadequacy may be responsible for retinol concentrations being approximately 16% lower in Pakistani children than in children in the United Kingdom, where dietary vitamin A is adequate.

Gut integrity, which can be measured by the urinary lactulose:mannitol excretion test, deteriorates with the introduction of weaning foods. In The Gambia, gut integrity measured monthly over 15 months in 119 infants (aged 2-15 months) was least impaired from April to June. This coincides with the time of year of maximum vitamin A (VA) intake-the mango season. Subsequently, two VA intervention studies were done in infants in India. Eighty infants attending a community health center received 16,700 IU weekly or placebo. In another study, 94 hospitalized infants were given 200, 000 IU VA or placebo: 31 received VA on admission, while the rest (32 VA, 31 placebo) received treatment on discharge. All VA-treated groups had more rapid improvement in gut integrity than the placebo groups, but no group had gut integrity normalized by Western standards. The data suggest that VA status may influence gut integrity.

Ill health related to food-borne infection transcends all geographical, political and cultural boundaries. The incidence of food-borne diseases continues to adversely affect the health and productivity of populations in most countries, especially non-industrialised ones. However, since the 1950s, the emphasis in the industrialised world had shifted away from addressing public health problems, to problems of chemical contaminants etc., but recently food-borne infections have again become of increasing concern to governments and the food industry. Improvements in international transportation means food can be distributed throughout the world, but so can the parasitic pathogens which contaminate foods. Alternatively, tourists are being affected abroad and possibly transmitting the pathogen to others at home. Thus, an increasing number of food-related illnesses are international in scope. In this review parasitic contamination of foods of animal origin, particularly meat and fish, will be discussed together with potential problems associated with water and unwashed fruits and vegetables.

There are two major dietary sources of vitamin A: easily absorbed retinyl palmitate in foods of animal origin, and poorly bioavailable carotenoids from plant foods. Plasma retinol is tightly controlled, probably by regulation of retinol-binding protein (RBP) formation in the liver, and only hormonal factors (e.g. oral contraceptives) and infection will alter the homeostasis. Delivery of retinol to the tissues is facilitated by the RBP-retinol complex; however, there is evidence that this mechanism can be bypassed when very high doses of vitamin A are given. Some retinyl ester may be released to tissues from chylomicrons when the latter bind to tissue lipoprotein receptors during their passage from the gut to the liver following a meal. High-dose vitamin A therapy is a means of rapidly improving vitamin A status in persons with sub-optimal vitamin A nutrition but there are dangers of toxic symptoms (e.g. teratogenicity) from excess vitamin A usage. Evidence is presented to suggest that the plasma retinol: RBP may be a guide to optimal vitamin A status, since values less than one frequently occur in less-developed countries and during infection. In contrast to plasma retinol, plasma carotenoids reflect the dietary intake of plant foods. However, absorption is limited by poor bioavailability and a saturable uptake mechanism in competition with other phytochemicals. Recent work on bioavailability suggests that the calculation of plant food vitamin A activity should be re-examined. Illness has little influence on plasma levels except by suppressing appetite. Carotenoids are generally regarded as non-toxic yet intervention studies with beta-carotene in smokers have been associated with increased lung cancer and heart disease. Some carotenoids are important as vitamin A precursors, but the physiological importance of their antioxidant properties is not known and consequently the amount needed for optimal nutrition is uncertain.

Vitamin A is the generic term for a variety of fat-soluble substances including retinol, retinyl palmitate and the provitamin A carotenoids such as all-trans-beta-carotene. Vitamin A is commonly known as the anti-infective vitamin and has an essential role in vision and cellular differentiation, the latter providing a unique core mechanism helping to explain the influence of vitamin A on epithelial barriers. Alterations in the epithelial lining of vital organs occur early in deficiency, suggesting a potentially important role for the barrier function. Vitamin A deficiency (VAD) is most commonly recognized in the eye. The conjunctival-impression cytology test detects the presence of larger irregular keratinized cells and the absence of mucous-secreting goblet cells, indicative of VAD. The method is simple, quick and sensitive in populations where VAD is present. In the respiratory tract, observational studies all show an association with VAD, although vitamin A supplementation studies appear to have little effect on respiratory disease. Organ-specific targeting may improve success rates. The dual-sugar intestinal-permeability test allows the effect of vitamin A supplementation to be monitored on the gastrointestinal tract. Two vitamin A supplementation studies were carried out recently in Orissa State, India. Healthy infants of weaning age were administered orally eight weekly doses of 5.0 mg retinol equivalents and hospitalized infants received one large oral dose 60 mg retinol equivalents in the form of retinyl palmitate. Improvements in gut integrity and haematological status were observed in both studies. In summary, the response of the eye to vitamin A supplementation is well established; the present review highlights some of the more recent observations examining the effects of vitamin A.

Parasite-specific plasma immunoglobulins have been used to indicate the presence of Giardia intestinalis infection in 60 infants living in a rural area of The Gambia. Infants were studied longitudinally between 2 and 8 mo of age. The median age for first exposure to G. intestinalis was between 3 and 4 mo, and by 8 mo all but 3 infants (95%) showed a positive titer on at least one occasion. Raised Giardia-specific IgM titers were associated with reduced weight gain in the 2 wk preceding a positive titer, but catch-up growth occurred in the following 2 wk. IgM antibody titers were also positively associated with intestinal permeability (lactulose/mannitol ratio), urinary lactose excretion, plasma concentrations of alpha1-antichymotrypsin and total IgM, IgA and IgG immunoglobulins. However, infant growth over the whole 6-mo period (i.e., between 2 and 8 mo of age) was not related to mean Giardia-specific antibody titers, nor the time of first exposure to the parasite. The data suggest that giardiasis in these very young breast-fed children occurs as a mild, acute disease, and its presence could not explain the marked, long-term growth faltering observed in many of the subjects.

Background: The ability of breast-feeding infants to utilize lactose, the major carbohydrate in breast-milk, is dependent on the presence of the enzyme lactase (E.C.3.2.1.108). Lactase is located in the brush border of the small intestine and because of its exposed position it is extremely vulnerable to pathogenic damage. Breast-fed Gambian infants have poor growth associated with intestinal damage beyond 3-4 months. The aim of this study was to assess the ability of Gambian infants aged 2-15 months (N = 113) to digest lactose and to see how this varied with age, intestinal permeability, and growth performance., Methods: Lactose maldigestion was estimated by monthly measurements of urinary lactose and lactulose following an oral dose of the latter., Results: Both urinary lactose excretion and lactulose maldigestion increased with age (p < 0.0001 ANOVA). Up to 6 months the mean urinary lactose: lactulose excretion ratio was within the quoted normal range (< 0.4). Beyond this age, mean values were hypolactasic. Lactose maldigestion was related to poor growth in both weight and length (r = -0.04, p < 0.0001, after age correction). Although a major part of this relationship was a reflection of the previously reported correlation between intestinal permeability and growth, more than 30% of the association was in addition to the permeability effect. Possible explanations are discussed., Conclusions: Moderate-to-severe hypolactasia does occur in breast-fed Gambian infants and is related to poorer-than-expected growth. However, this does not mean that breast milk intake should be reduced as the nutritional and immunological benefits of breast milk continue to outweigh any disadvantages.

There is no doubt that at high intensity of infection, intestinal parasites can cause severe illness and the death of their hosts. Even with the high prevalence of these infections, however, such severe cases are rare and the norm is for low to moderate numbers of parasites which cause few if any overt symptoms. Nevertheless, it has been argued that by causing subtle reductions in appetite, absorption, digestion and acute-phase status and increasing intestinal nutrient losses, these low-level but long-term infections could be responsible for the persistent, poor nutritional status of so many children in Third World communities. Although geographically, high parasite prevalence occurs in conjunction with high levels of protein-energy malnutrition, attempts to establish a cause and effect relationship have had very limited success with many investigators being unable to demonstrate any detrimental consequence of infection. The unimpressive results might be explained to some extent by the unusual features of helminth infections such as rapid reinfection, the overdisperse distribution pattern and the uncertainty of a host inflammatory response, but they also suggest that A. lumbricoides (on which most studies have concentrated) may be of little nutritional importance. It seems likely that the more invasive parasites, e.g. the hookworms, S. stercoralis, T. trichiura and perhaps G. lamblia may have a greater impact and clearly more studies are required here. Safe, cheap and effective anthelmintics are now available and, on the grounds of disease prevention, there is a case for their nationwide use. However, from the available evidence, it would be unwise to expect that such programmes would make a significant impact on the nutritional status of children in Third World communities.

The present study tested the hypothesis that inadequate Zn intake might be responsible for failure to thrive and impaired catch-up growth in young rural Gambian children, and that Zn supplements might be beneficial. Gambian children might be deprived of Zn because of its poor availability from their predominantly plant-based diet. Rural Gambian children (110; fifty boys, sixty girls) aged between 0.57 and 2.30 years were divided into two matched groups, one to receive 70 mg Zn twice weekly for 1.25 years, and the other a placebo. Growth and mid-upper-arm circumference were measured at weekly intervals throughout the study and illnesses were monitored. Capillary blood and urine samples were collected at 0, 2 and 8 weeks. Body weights and arm circumferences showed a linear increase, plus a seasonal effect (rainy season faltering). For body weight there was no significant overall effect of the supplement. For arm circumference, a very small (2%) but significant (P < 0.01) difference favoured the supplemented group. Plasma thymulin was much lower at the first clinic than at the second and third clinics, and in vitro Zn stimulation was greater at the first clinic. There was, however, no effect of Zn in vivo. Likewise, Zn did not significantly benefit T-cell numbers or ratios, secretory IgA in urine, circulating hormone levels or biochemical indices of Zn status. One index of intestinal permeability, i.e. lactulose: creatinine, was improved (P < 0.02) by the supplement, but the lactulose: mannitol value was not; this requires further investigation. Dietary Zn deficiency is, thus, unlikely to be of major overall importance for rural Gambian children's ability to thrive, and blanket Zn supplementation is not justified. There may, however, be vulnerable sub-groups who would benefit from Zn supplements.

Parasitic infection of the gut is highly prevalent in developing countries and contributes to the severe malnutrition associated with persistent diarrhoea in children. Using random faecal alpha 1-antitrypsin measurements as an index of protein-losing enteropathy, we examined children with and without parasitic infection of the gut. Seventeen percent of children with persistent diarrhoea had evidence of protein-losing enteropathy. This was found to be associated with hypoalbuminaemia in children infected with Strongyloides stercoralis. Only a minority (2 of 17) of children infected with Giardia lamblia had raised faecal alpha 1-antitrypsin excretion and this was not associated with hypoalbuminaemia. This study emphasises the need for rapid diagnosis and treatment of Strongyloides infection in children with persistent diarrhoea and severe nutrition.

This study aimed to characterise the clinical condition of Gambian children presenting with persistent diarrhoea and severe protein energy malnutrition and to evaluate the effects of short term in-patient treatment in terms of long-term outcome. Twenty-two children (aged 6 to 36 months) with persistent diarrhoea (greater than or equal to four loose stools/day for more than two weeks) and severe malnutrition (weight-for-height less than 75% of the National Center for Health Statistics median value) were assessed prior to in-patient treatment for three weeks with antibiotics and high nutrient-density milk. Initial assessment included biochemical and immunological status together with stool microbiology. Criteria for discharge--cessation of diarrhoea for five consecutive days and steady weight gain--were met in all subjects within four weeks. Progress was assessed clinically and anthropometrically at weekly intervals and 6 and 12 months following discharge. Results showed a steady improvement in growth during the period of in-patient treatment. Continuing improvement in weight-for-age and mid-upper arm circumference was observed after 6 and 12 months and weight-for-height continued to improve up to 6 months but fell back by 12 months. This study has demonstrated that, in the treatment of persistent diarrhoea in the tropics, relatively short periods of in-patient rehabilitation, whilst leading to a resolution of diarrhoeal symptoms and weight gain in the short term, do not lead to complete recovery. Persistent diarrhoea and malnutrition are likely to recur when the child returns to his village.(ABSTRACT TRUNCATED AT 250 WORDS)

There is controversy over whether children in developing countries can catch up on their growth rates after bouts of diarrhoea. A factor influencing catch-up growth is the extent and duration of mucosal injury. To explore the relation between intestinal disease and growth performance, a non-invasive test of intestinal integrity, the lactulose:mannitol permeability test, was done regularly on children aged 2-15 months, whose growth was monitored over a mean of 7.5 months. The study revealed persistent abnormalities in the small bowel mucosa of 2-15 month old Gambian infants and a negative correlation between these abnormalities and growth. Up to 43% of observed growth faltering can be explained on the basis of these long-term intestinal lesions.

Intestinal permeability was assessed (within 24-48h of admission to hospital) in 7 patients suffering from acute infections, mainly pneumonia. The permeability test involved administering an oral solution containing a mixture of lactulose (10 g) mannitol (5 g and 0.5 microCi) and (51)Cr-EDTA (30 microCi), and collecting urine samples before, and between 0-6, 6-12 and 12-24 h after dosing. The excretion of the markers was compared with the results obtained from 24 normal or control subjects and 15 patients with coeliac disease. None of the markers were excreted in significantly different amounts in the infected patients compared to the control subjects. In contrast, the coeliac patients excreted (0-6 h) four-fold more lactulose, three-fold more (51)Cr-EDTA and two-fold less mannitol than the normal subjects. The ratio of lactulose: mannitol and (51)Cr-EDTA: mannitol were therefore six- to eight-fold greater in the coeliac patients than in the normal subjects. The results confirm the sensitivity of the test for detecting the presence of an enteropathy but provide no evidence of a change in intestinal permeability in systemic infections studied under the stated conditions.

Intestinal permeability in 4-week-old rats has been assessed by the dual sugar (lactulose/mannitol) permeability test before and for two days after induction of systemic inflammation by various endotoxins and turpentine. Evidence of an inflammatory response to these agents was provided by marked reductions in food consumption and growth rate, hypoalbuminaemia, and a large increase in the plasma concentration of the acute-phase protein alpha-2-macroglobin. Abnormal values for intestinal permeability occurred only in animals which had been injected with E. coli 0111:B4 endotoxin. Neither turpentine nor the other endotoxins produced any detectable effect. Within 2-7h of the first exposure to a low dose, (3mg/kg) of either phenol or trichloroacetic extracts of E. coli 0111:B4 endotoxin, the lactulose:mannitol (L M ) ratio was elevated by 32% and 50% respectively (p < 0.05), but the rise was not sustained despite continued twice-daily injections of endotoxin. Administration of a higher dose, (10 mg/kg twice daily, phenol extract) resulted in diarrhoea, and a greater more persistent increase in the L M ratio; 115% (p < 0.05) 2-7h after the first injection, and 49% above control values, (p < 0.01) 24h later. The increase in L M ratio appeared to be due to a decrease in mannitol excretion. Total urinary lactulose also tended to fall, especially in rats given the high dose of endotoxin. It is concluded that a systemic inflammatory response does not necessarily lead to a change in intestinal permeability as measured by the dual sugar permeability test. The transient permeability changes observed following E. coli 0111:B4 administration may be a specific reaction to this material rather than to a more general systemic stimulus.

Secretory IgA outputs in urine have been measured in 24 malnourished Gambian children who had been admitted to hospital with chronic diarrhoea and in 43 children from a rural Gambian village. Village children of poor nutritional state (less than or equal to 74% weight for age compared with the National Center for Health Statistics reference curve) had secretory IgA outputs that were only one third of those of better nourished individuals. In contrast, the patients with chronic diarrhoea had secretory IgA outputs that were significantly raised compared with village children, regardless of nutritional state. These results demonstrate that secretory IgA production in the urinary tract can be stimulated by intestinal disease, suggesting that malnourished children are able to mount a response to mucosal infection and supporting the hypothesis of a common secretory immune system.

Chronic diarrhoea and malnutrition in Gambian children is associated with persisting damage to the mucosa of the small intestine. Intestinal permeability tests suggest that mucosal status gradually deteriorates with age throughout the first year of life in tandem with increasingly severe growth faltering. The ability of the dual sugar permeability test to assess intestinal mucosal status frequently in a non-invasive way makes the technique a valuable tool for future studies into the aetiology of this syndrome.