Marjorie J Haskell

Estimating the Potential for Vitamin A Toxicity in Women and Young Children

This paper describes usual intakes of vitamin A from diet plus low dose supplements, reviews methods for assessing vitamin A toxicity and applies a kinetic analysis of vitamin A turnover to estimate the effect of high dose supplements on vitamin A liver stores in infants and young children. In the United States, the 95th percentile of intake by preschoolers from foods and supplements exceeds the tolerable upper level (UL) but is below the no-observed-adverse-effect level (NOAEL). The 95th percentile of vitamin A intake from foods and supplements for nonpregnant, nonlactating women aged 19-30 y also exceeds the UL but is below the NOAEL for women of reproductive age. In low income populations in developing countries, vitamin A intakes of preschoolers and women consuming foods plus low dose supplements can also exceed the UL but are unlikely to exceed the NOAEL. There are few data on which to establish thresholds for excessive vitamin A intake or vitamin A concentrations in tissues. To assess the potential toxicity of the new recommendations (see article by Ross in this issue) for high dose vitamin A supplements for infants and children, we used a kinetic approach to estimate accumulation of the vitamin in liver. The new recommendations are unlikely to result in toxic levels (>300 microg per gram of liver) even if high dose supplements are inadvertently given monthly. The kinetic analysis also illustrates that a constant supply of vitamin A from breast milk (and/or complementary foods) is vital for preventing depletion of liver vitamin A stores between high dose supplements.

Maternal Vitamin A Nutriture and the Vitamin A Content of Human Milk

Because of the many functions of vitamin A inhuman physiology, deficiency or excess of the vitamin inlactating women or their infants can adversely affecttheir health. Infants are born with low body stores of vitamin A, and rely on vitamin A inmilk to meet their needs. The vitamin A content of milkis related to maternal vitamin A status and maternaldietary vitamin A intake during lactation. Low-income lactating women in non-industrialized countrieshave lower milk vitamin A concentrations than lactatingwomen in industrialized countries. Supplementation oflactating women in non-industrialized countries with vitamin A or beta-carotene has resulted inincreased milk vitamin A concentrations. However, theoptimal timing and dose for sustaining adequate levelsof vitamin A in milk throughout the lactation period has not been determined. Furtherresearch is needed to understand factors affecting thetransfer of vitamin A to milk, and to evaluate variousstrategies for improving the vitamin A status of mothers and infants.

The challenge to reach nutritional adequacy for vitamin A: β-carotene bioavailability and conversion—evidence in humans

β-Carotene is an important dietary source of vitamin A for humans. However, the bioavailability and vitamin A equivalency of β-carotene are highly variable and can be affected by food- and diet-related factors, including the food matrix, food-processing techniques, size of the dose of β-carotene, and the amounts of dietary fat, fiber, vitamin A, and other carotenoids in the diet as well as by characteristics of the target population, such as vitamin A status, nutrient deficiencies, gut integrity, and genetic polymorphisms associated with β-carotene metabolism. The absorption of β-carotene from plant sources ranges from 5% to 65% in humans. Vitamin A equivalency ratios for β-carotene to vitamin A from plant sources range from 3.8:1 to 28:1, by weight. Vitamin A equivalency ratios for β-carotene from biofortified Golden Rice or biofortified maize are 3.8:1 and 6.5:1, respectively, and are lower than ratios for vegetables that have more complex food matrices (10:1 to 28:1). The vitamin A equivalency of β-carotene is likely to be context-specific and dependent on specific food- and diet-related factors and the health, nutritional, and genetic characteristics of human populations. Although the vitamin A equivalency of β-carotene is highly variable, the provision of vegetable and fruit sources of β-carotene has significantly increased vitamin A status in women and children in community settings in developing countries; these results support the inclusion of dietary interventions with plant sources of β-carotene as a strategy for increasing vitamin A status in populations at risk of deficiency.

Plasma Retinol-Binding Protein Predicts Plasma Retinol Concentration in Both Infected and Uninfected Cameroonian Women and Children

Variation in the relationship between plasma retinol-binding protein (RBP) and retinol (ROH) has implications for vitamin A (VA) status assessment using RBP. Our objectives were to identify factors affecting the RBP:ROH relationship and to derive and evaluate population-specific RBP cutoffs for VA deficiency (VAD) in Cameroon. Plasma RBP, C-reactive protein (CRP), α1-acid-glycoprotein (AGP), and ROH concentrations were compared in a subsample of women 15-49 y (n = 121) and children 12-59 mo (n = 123) included in a national survey conducted in 2009. Plasma RBP and ROH were highly correlated (r = 0.94 for women; r = 0.96 for children; P < 0.001). Pregnancy and lactation altered the RBP:ROH relationship in women, but obesity, elevated CRP and AGP, age, and VA status did not. Among children, age altered the RBP:ROH relationship, but sex, stunting, VA status, and elevated CRP and AGP did not. Cutoffs for VAD derived using regression analysis were <1.17 μmol RBP/L for women (corresponding to <1.05 μmol ROH/L) and <0.83 μmol RBP/L for children (corresponding to <0.70 μmol ROH/L). The sensitivity and specificity of derived cutoffs were 81.8 and 93.0% for women and 94.7 and 88.9% for children, respectively. The infection-adjusted prevalence of low VA status (<1.17 μmol RBP/L) was 21.9% (95% CI = 18.7-25.0%) among women. Among children, the infection-adjusted prevalence of VAD (<0.83 μmol RBP/L) was 35.0% (95% CI = 31.1-39.0%). In conclusion, VAD remains a public health problem in Cameroon. The RBP:ROH relationship should be considered in surveys using RBP to assess VA status, and use of population-specific cutoffs may be advisable.

Biomarkers of Nutrition for Development (BOND)—Vitamin A Review

The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-informed advice to anyone with an interest in the role of nutrition in health. The BOND program provides information with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect, which will be especially useful for readers who want to assess nutrient status. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutritional status at the individual and population levels. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, folate, zinc, iron, vitamin A, and vitamin B-12. This review of vitamin A is the current article in this series. Although the vitamin was discovered >100 y ago, vitamin A status assessment is not trivial. Serum retinol concentrations are under homeostatic control due in part to vitamin A’s use in the body for growth and cellular differentiation and because of its toxic properties at high concentrations. Furthermore, serum retinol concentrations are depressed during infection and inflammation because retinol-binding protein (RBP) is a negative acute-phase reactant, which makes status assessment challenging. Thus, this review describes the clinical and functional indicators related to eye health and biochemical biomarkers of vitamin A status (i.e., serum retinol, RBP, breast-milk retinol, dose-response tests, isotope dilution methodology, and serum retinyl esters). These biomarkers are then related to liver vitamin A concentrations, which are usually considered the gold standard for vitamin A status. With regard to biomarkers, future research questions and gaps in our current understanding as well as limitations of the methods are described.

Stable isotope dilution techniques for assessing vitamin A status and bioefficacy of provitamin A carotenoids in humans

Vitamin A deficiency is a major global public health problem. Among the variety of techniques that are available for assessing human vitamin A status, evaluating the provitamin A nutritional values of foodstuffs and estimating human vitamin A requirements, isotope dilution provides the most accurate estimates. Although the relative expense of isotope dilution restricts its applications, it has an important function as the standard of reference for other techniques. Mathematical modelling plays an indispensable role in the interpretation of isotope dilution data. This review summarises recent applications of stable isotope methodology to determine human vitamin A status, estimate human vitamin A requirements, and calculate the bioconversion and bioefficacy of food carotenoids.

Carrier affinity as a mechanism for the pH-dependence of folate transport in the small intestine.

A mildly acidic pH in the lumen of the small intestine markedly enhances the transport of folate. This study investigated the relationship between pH and the affinity between folic acid and the apical membrane transporter using brush border membrane vesicles from rat jejunum and differentiated monolayer cultures of the colon carcinoma cell line, CaCo-2. Uptake studies with BBMV were conducted at folic acid concentrations of 0.1 to 50 mumol/l, conditions which were suitable for analyzing uptake data based on the Michaelis-Menten equation modified to include a nonsaturable component. These analyses yielded apparent Km values of 0.6 and 12.3 microM at pH 5.5 and pH 7.4, respectively (P less than 0.05). Values for Vmax were lower at pH 5.5 than at pH 7.4 (0.8 vs. 1.6 pmol/mg protein per 10 s, P less than 0.05). The studies with CaCo-2 cells employed folic acid concentrations of 0.1 to 5 mumol/l. Under these conditions the apparent Km for folic uptake was lowest at pH 6.0, where the Km was 0.7 mumol/l. The apparent Km increased sharply as a neutral pH was approached; reaching a value of 13.9 mumol/l at pH 7.1. These data suggest that the prominent pH effect on intestinal folate transport is, in part, explained by an increased affinity of the folate substrate for its membrane transporter.

Vitamin A Requirements of Infants under Six Months of Age

Infants are born with negligible liver stores of vitamin A. to enable some storage of the vitamin, the infant needs to be predominantly breastfed with milk containing at least 30 μg/dl. Where vitamin A in breastmilk is low, maternal supplementation with a single postpartum high dose increases milk vitamin A for three to eight months. the current cutoff levels for serum retinol and the modified relative dose response (MRDR) ratio probably need to be revised for young infants. Kinetic analyses of infants’ retention of vitamin A from breastmilk and supplements indicate that the doses of vitamin A given with immunizations in the World Health Organization (WHO) multicenter trial were inadequate to maintain adequate normal stores for more than a few months. the recommendation to double the doses currently given to mothers and infants in the Expanded Program in Immunization should prevent the depletion of liver vitamin A stores for most of the first year of life.

Markers of Innate Immune Function Are Associated with Vitamin A Stores in Men

Recommendations for vitamin A intake and liver stores are based on maintaining normal vision. We propose that higher levels may be required to maintain normal innate immune function. To test this hypothesis, we conducted an 8-wk residential study among 36 healthy Bangladeshi men with low vitamin A stores. Subjects were randomized to receive vitamin A (240 mg in 4 doses) or placebo during study wk 2 and 3. They received 2 vaccines during wk 5 and vitamin A stores were estimated by isotopic dilution at wk 8. The serum concentration of the chemokine interferon-gamma-induced protein 10, a component of T-helper 1 (Th1) response, increased significantly after supplementation and was positively and significantly associated with vitamin A stores. Blood concentrations of natural killer (NK) and NK T-cells, which have anticancer and antiviral activity, were positively associated with stores (P < 0.05), as was monocyte oxidative burst (P < 0.05), a marker of bacterial killing ability. However, serum interleukin (IL)-6 and IL-17, cytokines that regulate the antibacterial Th17 response, were significantly and negatively associated with stores, as was production of the regulatory cytokine IL-10 by whole-blood cultures stimulated with bacterial lipopolysaccharide. In summary, vitamin A stores were positively associated with several measures of innate immune activity across a broad range of stores, suggesting that vitamin A enhances protection against diverse pathogens even at concentrations above those needed to maintain normal vision. The negative association of stores with serum IL-6 and IL-17 suggests that not all protective responses are similarly enhanced by vitamin A.

Lipid-based nutrient supplements do not decrease breast milk intake of Malawian infants

BACKGROUND The potential for small-quantity lipid-based nutrient supplements (LNS) to promote growth and development after 6 mo of age is currently being investigated. Because infants self-regulate energy intake, consumption of LNS may reduce breast milk intake and potentially decrease the beneficial effects of breast milk. OBJECTIVE The objective was to test the hypothesis that the breast milk intake of 9- to 10-mo-old rural Malawian infants receiving LNS would not be lower than that of infants receiving no supplementation. DESIGN This was a substudy of the International Lipid-based Nutrient Supplements (iLiNS) DOSE trial, in which 6-mo-old infants were randomly assigned to receive 10, 20, or 40 g LNS/d containing 56, 117, or 241 kcal/d, respectively, or no LNS until 18 mo of age. A subset was randomly selected to estimate breast milk intake at 9-10 mo of age with the dose-to-mother deuterium oxide dilution method. The noninferiority margin was <10% of total energy requirements. RESULTS Baseline characteristics (n = 376) were similar across groups. The mean (± SD) daily breast milk intake of unsupplemented infants was 730 ± 226 g. The differences (95% CIs) in mean intake of infants provided with 10, 20, or 40 g LNS/d, compared with controls, were +62 (-18, +143), +30 (-40, +99), and +2 (-68, +72) g/d, respectively. Non-breast milk oral water intake did not differ by group (P = 0.39) and was inversely (r = -0.22, P < 0.01) associated with breast milk intake. CONCLUSION In this rural Malawian population, breast milk intake at 9-10 mo of age was not reduced by supplementation with complementary foods with 10-40 g LNS/d.