Use of Compartmental Modeling and Retinol Isotope Dilution to Determine Vitamin A Stores in Young People with Sickle Cell Disease Before and After Vitamin A Supplementation.

BACKGROUND: Suboptimal plasma retinol concentrations have been documented in US children with sickle cell disease (SCD) hemoglobin SS type (SCD-HbSS), but little is known about vitamin A kinetics and stores in SCD. OBJECTIVES: The objectives were to quantify vitamin A total body stores (TBS) and whole-body retinol kinetics in young people with SCD-HbSS and use retinol isotope dilution (RID) to predict TBS in SCD-HbSS and healthy peers as well as after vitamin A supplementation in SCD-HbSS subjects. METHODS: Composite plasma [13C10]retinol response data collected from 22 subjects with SCD-HbSS for 28 d after isotope ingestion were analyzed using population-based compartmental modeling ("super-subject" approach); TBS and retinol kinetics were quantified for the group. TBS was also calculated for the same individuals using RID, as well as for healthy peers (n = 20) and for the subjects with SCD-HbSS after 8 wk of daily vitamin A supplements (3.15 or 6.29 µmol retinol/d [900 or 1800 µg retinol activity equivalents/d]). RESULTS: Model-predicted group mean TBS for subjects with SCD-HbSS was 428 µmol, equivalent to ∼11 mo of stored vitamin A; vitamin A disposal rate was 1.3 µmol/d. Model-predicted TBS was similar to that predicted by RID at 3 d postdosing (mean, 389 µmol; ∼0.3 µmol/g liver); TBS predictions at 3 compared with 28 d were not significantly different. Mean TBS in healthy peers was similar (406 µmol). RID-predicted TBS for subjects with SCD-HbSS was not significantly affected by vitamin A supplementation at either dose. CONCLUSIONS: Despite differences in plasma retinol concentrations, TBS was the same in subjects with SCD-HbSS compared with healthy peers. Because 56 d of vitamin A supplementation at levels 1.2 to 2.6 times the Recommended Dietary Allowance did not increase TBS in these subjects with SCD-HbSS, further work will be needed to understand the effects of SCD on retinol metabolism. This trial was registered as NCT03632876 at clinicaltrials.gov.

Use of Theoretical Subjects to Develop a Method for Assessing Equivalence of Dietary Vitamin A in a Mixed Diet.

BACKGROUND: Although the vitamin A (VA) equivalency of provitamin A carotenoids from single foods or capsules has been studied using several approaches, there is currently no reliable method to determine VA equivalency for mixed diets. OBJECTIVES: To reach the objective of identifying a method to determine the VA equivalency of provitamin A carotenoids in mixed diets, we tested a new approach using preformed VA as proxy for provitamin A. METHODS: We studied 6 theoretical subjects who were assigned physiologically plausible values for dietary VA intake, retinol kinetic parameters, plasma retinol pool size, and VA total body stores. Using features in the Simulation, Analysis and Modeling software, we specified that subjects ingested a tracer dose of stable isotope-labeled VA on day 0 followed by 0-µg supplemental VA or 200, 400, 800, 1200, 1600, and 2000 µg VA daily from day 14 to day 28; we assigned VA absorption to be 75%. For each supplement level, we simulated plasma retinol specific activity (SAp) over time and calculated the mean decrease in SAp relative to 0 µg. Group mean data were fitted to a regression equation to calculate predicted VA equivalency at each supplement level on day 28. RESULTS: For each subject, higher VA supplement loads resulted in lower SAp, with the magnitude of the decrease differing among subjects. The mean predicted amount of absorbed VA was within 25% of individual subjects' assigned amount for 4 of the 6 subjects, and the mean ratio of predicted to assigned amount of absorbed VA over all supplement loads ranged from 0.60 to 1.50, with an overall mean ratio of 1.0. CONCLUSIONS: Results for preformed VA suggest that this protocol may be useful for determining VA equivalency of provitamin A carotenoids in free-living subjects if mixed diets with known provitamin A content were substituted for the VA supplements.

Dietary retinoic acid alters vitamin A kinetics in both the whole body and in specific organs of rats with low vitamin A status.

To study the effects of exogenous retinoic acid on vitamin A (VA) metabolism, we analyzed previously collected tracer kinetic data on VA dynamics in rats with low vitamin A (LA) status either with (LA+RA) or without (LA) retinoic acid supplementation. In spite of low VA intake ( approximately 7 nmol/d), the LA+RA rats were in a slight positive VA balance (0.325 nmol/d vs. -0.168 for LA) for 35 d after administration of [(3)H]retinol-labeled plasma. Using the Windows version of the Simulation, Analysis and Modeling software, we determined that the VA disposal rate was lower in LA+RA than in LA rats (3.98 vs. 5.00 nmol/d) as was the system fractional catabolic rate (0.0548 vs. 0.110 d(-1)). Model-predicted traced mass and residence times (the average time that a molecule of retinol spends in an organ before irreversible loss) were higher for liver (19.4 vs. 1.8 nmol; 5.0 vs. 0.36 d), kidneys (7.0 vs. 2.1 nmol; 1.4 vs. 0.42 d), small intestine (2.1 vs. 0.42 nmol; 0.43 vs. 0.084 d), and lungs (3.2 vs. 0.10 nmol; 1.6 vs. 0.021 d) in the LA+RA compared with the LA rats; there were no major differences for eyes, testes, adrenal glands, or remaining carcass. We conclude that RA supplementation of rats with low VA status affects VA metabolism at both the whole-body level and in specific organs. These organs (liver, kidneys, small intestine, and lungs) have the enzymatic capability and an appropriate cell type to store retinyl esters.