Total Body Stores Of Vitamin Research Articles

Filipino Children with High Usual Vitamin A Intakes and Exposure to Multiple Sources of Vitamin A Have Elevated Total Body Stores of Vitamin A But Do Not Show Clear Evidence of Vitamin A Toxicity

ABSTRACTBackgroundYoung children exposed to high-dose vitamin A supplements (VAS) and vitamin A (VA)–fortified foods may be at risk of high VA intake and high VA total body stores (TBS).ObjectivesTBS and estimated liver VA concentration were compared among children with adequate or high VA intake and different timing of exposure to VAS, and associations between estimated liver VA concentrations and biomarkers of VA toxicity were examined.MethodsChildren 12–18 mo of age (n = 123) were selected for 3 groups: 1) retinol intake >600 µg/d and VAS within the past mo, 2) retinol intake >600 µg/d and VAS in the past 3–6 mo, and 3) VA intake 200–500 µg retinol activity equivalents (RAE)/d and VAS in the past 3–6 mo. Dietary intake data were collected to measure VA intakes from complementary foods, breast milk, and low-dose, over-the-counter supplements. TBS were assessed by retinol isotope dilution, and VA toxicity biomarkers were measured. Main outcomes were compared by group.ResultsMean (95% CI) VA intakes excluding VAS were 1184 (942, 1426), 980 (772, 1187), and 627 (530, 724) µg RAE/d, in groups 1–3, respectively; mean VA intake was higher in groups 1 and 2 compared with group 3 (P < 0.05). Geometric mean (GM) (95% CI) TBS were 589 (525, 661), 493 (435, 559), and 466 (411, 528) µmol, respectively. GM TBS and GM liver VA concentrations were higher in group 1 compared with group 3 (liver VA concentration: 1.62 vs. 1.33 µmol/g; P < 0.05). Plasma retinyl ester and 4-oxo-retinoic acid concentrations and serum markers of bone turnover and liver damage did not indicate VA toxicity.ConclusionsIn this sample, most children had retinol intakes above the Tolerable Upper Intake Level (UL) and liver VA concentrations above the proposed cutoff for “hypervitaminosis A” (>1 µmol/g liver). There was no evidence of chronic VA toxicity, suggesting that the liver VA cutoff value should be re-evaluated. This trial was registered at www.clinicaltrials.gov as NCT03030339.

Vitamin D: not all is bad.

Dr Reid recently published an ‘‘Opinion’’ in our journal [1] reconsidering some of the actions of vitamin D on the basis of recently published paper [2]. He reaches to the conclusion that vitamin D is not a tonic for bone and that, therefore, small amounts are needed to maintain bone health. Experimental investigation supporting this hypothesis showed that adequate intestinal calcium absorption is crucial for normal bone mass accrual and that 1,25(OH)2D signalling is crucial to secure this process, also during normal calcium intake [2]. The finding that the osteomalacia of the vitamin D receptor (VDR) knockout mouse is completely corrected by selective expression of VDR in the gut enterocytes is in line with previous observations [1, 2]. These data furthermore emphasize the relative importance of intestinal vitamin D receptor compared with skeletal VDR. Following these premises, the physiological role of VDR in bone in normal conditions should be better defined, also in light of the finding that selective knockout of this receptor in bone is paradoxically associated with an increase in bone mass [3]. Dr Reid postulates a critical effect of VDR in facilitating calcium absorption; it appears therefore intuitive that the most favourable meta-analyses, for example on the reduction of hip fractures, are those in which vitamin D is co-administered with calcium salts. We agree with the conclusion that vitamin D should be administered only to those who are insufficient or deficient, even though such thresholds are still an issue of discussion [4, 5]; similar to what happens in the field of other nutrients, a unique term should probably be used [6]. Concerning the three studies cited linking high doses of vitamin D to adverse effects on bone resorption and skeletal mass, we should observe that one of them used the active metabolite [1,25(OH)2D] which from a pharmacological point of view is different from its precursor [7]. The other studies utilized high doses of vitamin D [8, 9]; apart from possible biases [10], there is another study showing that the annual administration of vitamin D2 indeed decreased the incidence of fracture [11]. The statement that individuals living independently in the community and not dark skinned or veiled will not need supplements at all, is not universally applicable. Indeed, it is well known that sunlight is responsible for producing 80 % of the nutritional supply of vitamin D in the body and maximizes serum 25(OH)D levels only in summer and autumn. In Italy, for example, from late October till early March, we do not have enough UV light from the sun to make vitamin D in the skin; therefore, the possibility of being insufficient in the winter–spring season, it is not an unrealistic hypothesis. We do not entirely agree with Dr Reid’s suggestion that measuring serum 25(OH)D levels has no value [12–14]. Serum 25(OH)D is at present a satisfactory indicator of total body stores of vitamin D, even though problems with assay do exist [4]. To further complicate the issue, we still do not exactly know if the free fraction of 25(OH)D should be measured to obtain meaningful information with respect to what we presently know [15]. Therefore, because some issues are not fixed, we believe that a word of caution should be offered on the problems previously addressed. S. Minisola (&) C. Cipriani S. Piemonte J. Pepe Department of Internal Medicine and Medical Disciplines, ‘‘Sapienza’’ Rome University, Via del Policlinico 155, 00161 Rome, Italy e-mail: salvatore.minisola@uniroma1.it

Vitamin A and Bone Health: The Balancing Act

The role of vitamin A status as it relates to bone health is historical yet controversial. Population-based studies have linked high dietary intake of preformed vitamin A, which is obtained from animal-source foods, fortified foods, and some supplements, to greater risk of osteoporosis and hip fracture. In contrast, carotenoids, some of which are vitamin A precursors from plants, are associated with improved bone health. Carotenoids may be a biomarker that reflects a generally healthy lifestyle, which includes fruit and vegetable consumption. Current dietary recommendations to increase fruit and vegetable intake in the Dietary Guidelines for Americans will result in greater intakes of provitamin A carotenoids if consumers comply. This could lead to artificially high intakes of vitamin A in dietary analyses. However, multiple factors affect the bioconversion of provitamin A carotenoids to the active form of vitamin A. The human body will strive to maintain vitamin A balance by down-regulating provitamin A carotenoid bioconversion. If high preformed vitamin A intake is associated with poor bone health and provitamin A carotenoids are protective, future studies are needed to clarify the associations between total body stores of vitamin A, dietary intake of the pre- and pro-forms, and bone health throughout the life cycle.

Linking agriculture to nutrition – The harvest is near and how do we measure impact?

An emerging success story in linking agriculture to nutrition is the biofortification of staple crops with micronutrients, namely provitamin A carotenoids, iron, and zinc. As a case study, biofortification of staple crops with provitamin A carotenoids has included sweet potato, maize, and cassava using traditional breeding methods, while transgenic approaches have been utilized in Golden Rice. Human studies have included a variety of technologies, and stable isotope methods are among the most powerful to measure bioavailability and efficacy. Animal and human studies have demonstrated promising β‐carotene to retinol bioconversion factors. Long‐term intake studies in children have been completed or are underway to determine if these favorable bioconversion factors can translate into improved liver reserves of vitamin A. Using the naturally enriched, stable 13C‐signature of maize, the change in 13C‐enrichment in serum retinol was shifted in 3 to 5 year old children eating orange maize for 70 days. This shows that the β‐carotene is bioavailable and contributing to the vitamin A pool. Another study is evaluating changes in total body stores of vitamin A after 90 days of feeding orange maize to 5 to 7 year old children using the 13C2‐retinol isotope dilution test. Effectiveness studies after biofortified maize is broadly introduced are needed to investigate the feeding of β‐carotene enhanced staple crops to population groups. Biofortification of staple crops with provitamin A carotenoids is feasible and all results published to date point towards it being an effective method to improve long‐term vitamin A status of populations that adopt them.Supported by NIH‐5T32DK007665–20 and HarvestPlus

Establishment of vitamin A requirement for Chinese children

Adequate intake (AI) of vitamin A has not been established for Chinese children. To establish AI of vitamin A for Chinese children, we evaluated dietary intake in well‐nourished children, whose liver vitamin A levels were ≥0.07μmol/g and &lt;1.05μmol/g as determined by 3‐day and 18‐day deuterated‐retinol‐dilution (DRD) techniques. We found that the intake of dietary vitamin A and β‐carotene were significantly correlated with vitamin A stores in the body, but not with the serum concentration of retinol. The mean (±SD) vitamin A intake was 476.9±196.7 μg retinol equivalence (RE)/day for the 4~6 y and 529.1±87.2μg RE/d for the 7~9 y children. The total body stores of vitamin A derived from 3‐day DRD before the equilibrium of vitamin A was reached were similar to those derived from 18‐day DRD, when the vitamin A equilibrium was reached. Based on our results, we estimate the average dietary vitamin A intake in children with an appropriate vitamin A reserve as their adequate intake, that is, around 450 RE μg/d (95%CI 384~569 RE μg/d) for 4~6 y and 550 RE μg/d (95%CI 500~559 RE μg/d) for 7~9 y children.

Quantitative assessment of total body stores of vitamin A in adults with the use of a 3-d deuterated-retinol-dilution procedure

The conventional deuterated-retinol-dilution (DRD) technique provides a quantitative estimate of total body stores of vitamin A in humans. The procedure requires equilibration of serum deuterated retinol with nondeuterated retinol after administration of an oral dose of deuterated vitamin A. Equilibration takes approximately 3 wk to complete. Our goal was to develop a predictive mathematical formula for quantitative assessment of total body stores of vitamin A in adults by using a procedure that takes less time to perform because serum isotope equilibration is not required, so that blood drawing can be done 3 d, instead of approximately 3 wk, after isotope dosing. Ratios of serum deuterated to nondeuterated retinol (D:H retinol) were determined in Filipino adults (n = 68) 3 and 20 d after an oral dose of 0.015 mmol [(2)H(4)]retinyl acetate and in Guatemalan adults (n = 15) 3 and 21 d after a 0.030-mmol dose. D:H retinol values 20 or 21 d after the isotope dose were used in a mathematical formula to obtain quantitative estimates of total body stores of vitamin A that were then correlated with serum D:H retinol values 3 d after the isotope dose. The relation between these variables was nonlinear and was described by the following equation: total body stores of vitamin A (in mmol retinol) = 0.00468 x 10(37(isotope dose in mmol))/D:H retinol in serum 3 d after the isotope dose. A 3-d DRD technique could be used for quantitative assessment of total body stores of vitamin A; this technique takes less time than does the conventional DRD technique.

Reduced Spinal Bone Mineral Density in Adolescents of an Ultra-Orthodox Jewish Community in Brooklyn

Reduced Spinal Bone Mineral Density in Adolescents of an Ultra-Orthodox Jewish Community in Brooklyn

Bioconversion of plant carotenoids to vitamin A in Filipino school-aged children varies inversely with vitamin A status

It is important to understand the factors affecting strategies to improve the vitamin A status of populations. We reported previously that a 3-d deuterated-retinol-dilution (DRD) procedure might be used to indicate total body stores of vitamin A. We studied the ability of 3-d DRD to detect changes in the body pool size of vitamin A and the effect of vitamin A status on the bioconversion of plant carotenoids to vitamin A. Two separate, unrelated studies were conducted in 7-13-y-old children with poor or marginal serum retinol concentrations (0.32-0.93 micromol/L) by feeding them controlled diets daily for 5 d/wk for 12 wk, after treatment with an anthelmintic drug. In school 1 (n = 27), lunch and 2 snacks that were provided at school contained 2258 retinol equivalents/d (mostly from orange fruit and vegetables) and 5.3 MJ/d from 33 g fat, 37 g protein, and 209 g carbohydrates; in school 2 (n = 25), 2 snacks provided 2.5 MJ/d from 9.4 g fat, 9.6 g protein, and 119 g carbohydrates, but no carotenes. In school 1, mean serum beta-carotene increased from 0.12 to 0.62 micromol/L (P = 0.0001) and serum retinol increased from 0.68 to 1. 06 micromol/L (P = 0.0001). In school 2, serum beta-carotene increased from 0.06 to 0.11 micromol/L (P = 0.0001) and serum retinol increased from 0.66 to 0.86 micromol/L (P = 0.0001). In school 1, but not school 2, improvement in serum retinol varied inversely with baseline retinol (r = -0.38, P = 0.048). In both schools, 3-d DRD showed reductions in the ratio of serum deuterated to nondeuterated retinol (D:H retinol) postintervention, denoting improvements in vitamin A status; the higher D:H retinol (ie, the poorer the status) at baseline, the greater the reduction in D:H retinol postintervention (school 1: r = -0.99, P = 0.0001; school 2: r = -0.89, P = 0.0001). Three-day DRD can detect changes in the body pool size of vitamin A, although a predictive equation to quantitate total body stores of vitamin A with the use of 3-d data needs to be developed. Bioconversion of plant carotenoids to vitamin A varies inversely with vitamin A status; improvement in status after dietary interventions is strongly influenced by total body stores of vitamin A and is influenced little or not at all by serum retinol.

Protection of Vitamin A Status in Chinese Children by a Dietary Intervention with Vegetables

A study of seasonal fluctuation of serum vitamin A concentrations in children in northern China showed that the prevalence of low serum levels of vitamin A was due to seasonal changes in the intakes of carotenoids. to determine whether plant carotenoids could sustain or improve children's vitamin A status during the fall and winter seasons, we performed an intervention with vegetables starting in the fall in Shandong, China. At a kindergarten, the serum vitamin A concentration was less than 1.05 μmol/L in 39% of the children. for five days per week for 10 weeks, 22 children were each provided with approximately 238 g/day of green and yellow vegetables and 34 g/day of light-coloured vegetables. Nineteen children maintained their customary dietary intake in the fall season, which included 56 g/day of green and yellow vegetables and 224 g/day of light-coloured vegetables. Vitamins A-d 8 and Ad 4 were given before and after the interventions, respectively, and their enrichments in the circulation were determined by gas chromatography/mass spectrometry to investigate vitamin A body stores. the serum concentration of β-carotene improved in the group fed mainly green and yellow vegetables but decreased in the group fed mainly light-coloured vegetables. the serum concentration of retinol was sustained in the group fed mainly green and yellow vegetables but decreased in the group fed mainly light-coloured vegetables (p &lt; .01). the isotope dilution tests confirmed that total body stores of vitamin A were sustained in the group fed mainly green and yellow vegetables but decreased by 27 μmol (7,700 μg), on average, per child in the group fed mainly light-coloured vegetables (p &lt; .06). Dietary green and yellow vegetables can provide adequate vitamin A nutrition to kindergarten children and protect them from becoming vitamin A deficient during seasons when the provitamin A food source is limited.

Use of the deuterated-retinol-dilution technique to assess total-body vitamin A stores of adult volunteers consuming different amounts of vitamin A

The deuterated-retinol-dilution (DRD) technique provides a quantitative estimate of total body stores of vitamin A. However, it is not known whether the technique can detect changes in vitamin A pool size in response to different intakes of vitamin A. Our objective was to determine the responsiveness of the DRD technique to 3 different daily supplemental vitamin A intakes during a period of 2.5-4 mo. Two oral doses of [(2)H(4)]retinyl acetate [52.4 micromol retinol equivalent (RE)] were administered on study days 1 and 91 to 26 men (18-32 y of age) who were consuming controlled, low-vitamin A diets, and receiving daily either 0, 5.2, or 10.5 micromol RE of unlabeled supplemental retinyl palmitate during a 75- or 129-d period. Plasma isotopic ratios of [(2)H(4)]retinol to retinol on day 115 were used to estimate final vitamin A body stores per Furr et al (Am J Clin Nutr 1989;49:713-6). Final ( +/- SD) estimated vitamin A pool sizes were 0.048 +/- 0.031, 0.252 +/- 0.045, and 0.489 +/- 0.066 mmol in the treatment groups receiving 0, 5.2, and 10.5 micromol RE/d, respectively (P < 0.001). Estimated mean changes in vitamin A pool sizes were similar to those expected for the vitamin A-supplemented groups [estimated:expected (95% CI of change in pool size): 1.08 (0.8, 1.2) and 1.17 (1.0, 1.3)]. The DRD technique can detect changes in total body stores of vitamin A in response to different daily vitamin A supplements. However, abrupt changes in dietary vitamin A intake can affect estimates of total-body vitamin A stores.

Assessment of total body stores of vitamin A in Guatemalan elderly by the deuterated-retinol-dilution method

Deuterated retinol dilution (DRD) gives quantitative estimates of total body stores of vitamin A. In elderly people, we studied 1) the time when an oral dose of deuterated vitamin A equilibrates with body stores, 2) whether serum ratios of deuterated to nondeuterated retinol (D:H) at 3 or 6 d postdosing predicted body stores, and 3) the ability of DRD to detect changes in the size of the body vitamin A pool. A 10-mg oral dose of [2H4]retinyl acetate was administered to 60-81-y-old Guatemalans (n = 47); percentage enrichment of serum retinol with deuterated retinol was determined at 1-3 time points per subject at 3, 6, 7, 14, 20, 21, and 54 d. In subjects from whom blood was obtained at 3 and 21 d (n = 15) and at 6 and 20 d (n = 9), total body stores were calculated by using the formula of Furr et al (Am J Clin Nutr 1989;49:713-6) with 21- or 20-d data and correlated with serum D:H at 3 or 6 d postdosing. Nine subjects received diets containing 982+/-20 microg RE (x+/-SEM) plus 800 microg RE as retinyl acetate supplements for 32 d. DRD, serum retinol, and relative dose response were used to assess vitamin A status before and after the intervention. Deuterated retinol equilibrated with the body pool by 20 d postdosing. Vitamin A supplementation for 32 d increased body stores, although unexplained exaggerated increases were seen in some subjects. An inverse linear relation was found between estimates of body stores and serum D:H at 3 d postdosing (r = -0.75, P = 0.002); at 6 d postdosing, the correlation was weaker. DRD can detect changes in total body stores of vitamin A, although factors affecting serum D:H need to be elucidated. Serum D:H 3 d postdosing might be used as an early indicator of total body stores of vitamin A, although a predictive equation will need to be developed.

Plasma kinetics of an oral dose of [2H4]retinyl acetate in human subjects with estimated low or high total body stores of vitamin A

The deuterated retinol dilution technique is an indirect method for quantitatively estimating total body stores of vitamin A by using the postequilibration plasma isotopic ratio [2H4]retinol:retinol and the prediction model described by Furr et al (Am J Clin Nutr 1989;49:713-6). Limited data are available on the time required for an oral dose of labeled vitamin A to mix with vitamin A body stores in human subjects. This article describes the plasma retinol kinetics of an oral dose of [2H4] retinyl acetate in 4 healthy adults (2 men and 2 women) and 1 healthy female child in the United States and in 4 Bangladeshi women. After an oral dose of [2H4]retinyl acetate was administered, plasma samples were collected at 6, 12, and 24 h postdose during the first day and at 15 time points during the subsequent 90-d period for measurement of plasma [2H4]retinol:retinol. The mean respective plasma isotopic ratios on day 20 for US and Bangladeshi subjects (0.02 ± 0.02 and 0.17 ± 0.12, P = 0.03) and estimated total body vitamin A reserves (1.03 ± 0.45 and 0.10 ± 0.11 mmol, P = 0.003) were significantly different. The fraction of dose in plasma was plotted against time, and biexponential equations were fit to the kinetic data by using the time points from 24 h through day 90. The mean equilibration time (time required for the fraction of dose in plasma to reach a plateau) for all subjects was 16.6 ± 3.8 d (11-23 d). There was no difference in estimated equilibration time between the group of US and Bangladeshi adult subjects (17.5 ± 4.4 and 16.3 ± 3.9 d, respectively, P = 0.69). Thus, the size of hepatic vitamin A reserves does not appear to affect equilibration time within the range of values observed. Am J Clin Nutr 1998;68:90–5.

Vitamin A relative dose response test: validation by intravenous injection in children with liver disease

The relative dose response (RDR) test has been proposed as a tool for estimation of total body stores of vitamin A. In this study we have validated a variation of this test in children with or without liver disease. Administration of vitamin A was done by intravenous injection of 1000 micrograms of retinyl palmitate. We conclude that the RDR test by intravenous injection performed after 5 h is a reliable and sensitive indicator of vitamin A status. Values found were greater than 20% when liver vitamin A concentration is less than 20 micrograms/g liver and less than 10% when liver vitamin A concentration is greater than 20 micrograms/g liver. We also conclude that the RDR test can be applied to evaluate the efficiency of vitamin A therapy and we confirm that plasma retinol levels should not be used to screen vitamin A status.