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

Reina Engle-Stone, Jody C Miller, Maria Fatima Dolly Reario, Charles D Arnold, Ame Stormer, Eleanore Lafuente, Anthony Oxley, Mario V Capanzana, Carl Vincent D Cabanilla, Jennifer Lynn Ford, Adam Clark, Thirumalaisamy P Velavan, Kenneth H Brown, Georg Lietz, Marjorie J Haskell, Reina Engle-Stone, Jody C Miller, Maria Fatima Dolly Reario, Charles D Arnold, Ame Stormer, Eleanore Lafuente, Anthony Oxley, Mario V Capanzana, Carl Vincent D Cabanilla, Jennifer Lynn Ford, Adam Clark, Thirumalaisamy P Velavan, Kenneth H Brown, Georg Lietz, Marjorie J Haskell

Abstract

Background: Young 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).

Objectives: TBS 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.

Methods: Children 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.

Results: Mean (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.

Conclusions: In 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.

Keywords: Philippines; children; dietary intake; fortified foods; retinol isotope dilution; supplements; total body stores; toxicity; vitamin A.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Enrollment and losses to follow-up of children by study group. CRP, C-reactive protein; Hb, hemoglobin; VAS, vitamin A supplements; WHZ, weight-for-height z score.
FIGURE 2
FIGURE 2
Distribution of liver vitamin A concentrations by study group. Box plots (p25, median, p75) are shown for each group. Dots are individual data points. GM (95% CI) liver vitamin A concentration differed between groups 1 and 3 (P < 0.05) controlling for child age. GM, geometric mean; p25, 25th percentile; p75, 75th percentile; VAS, high-dose vitamin A supplement.
FIGURE 3
FIGURE 3
Serum ALT activity vs. estimated liver vitamin A concentration in relation to age- and sex-specific cutoff values for serum ALT activity. The dashed lines represent the age- and sex-specific cutoff values for serum ALT activity for children 2 y of age (42). *Boys: r = 0.429; P = 0.005; girls: r = 0.302; P = 0.0739; boys and girls combined: r = 0.351; P = 0.002. ALT, alanine aminotransferase; VA, vitamin A.
FIGURE 4
FIGURE 4
Serum AST activity vs. estimated liver vitamin A concentration in relation to age- and sex-specific cutoff values for serum AST activity. The dashed lines represent the age- and sex-specific cutoff values for serum AST activity for children 2 y of age (43). *Boys: r = 0.170; P = 0.307; girls: r = 0.007; P = 0.972; boys and girls combined: r = 0.105; P = 0.397). AST, aspartate aminotransferase; VA, vitamin A.

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