Development of a Compartmental Model to Investigate the Influence of Inflammation on Predictions of Vitamin A Total Body Stores by Retinol Isotope Dilution in Theoretical Humans

Abstract

Background Inflammation, both acute and chronic, is associated with reductions in the synthesis of retinol-binding protein (RBP) and the concentration of retinol in plasma. Consequently, it is currently recommended that the retinol isotope dilution (RID) method not be used to estimate vitamin A total body stores (TBS) in subjects with inflammation. Objectives To apply compartmental analysis to study the effects of inflammation on hepatic apo-RBP input, plasma retinol pool size, and RID-predicted TBS in theoretical subjects with known steady state values for these parameters. Methods We selected 6 previously generated hypothetical subjects who ingested a dose of stable isotope–labeled vitamin A (day 0). Starting with each subject's published steady state model for retinol tracer kinetics, we developed a parallel model for unlabeled retinol and RBP that incorporated links between these entities and tied liver retinol secretion to RBP availability. Then we perturbed the steady state model by initiating chronic or acute inflammation on day 0 or acute inflammation on day 3 or 9 and simulating results for RBP, plasma retinol, and TBS. Results Chronic inflammation led to substantial reductions in RID-predicted TBS for at least 2 weeks after tracer administration. In contrast, acute inflammation induced on day 0 or 3 resulted in less dramatic impacts on TBS (37% or 20% reduction, respectively, from steady state levels, with levels rebounding by 14 days). When inflammation was induced 9 days after administration of the tracer, the effects on predicted TBS were minimal. Overall, for acute inflammation initiated at 0, 3, or 9 days, accurate predictions of TBS were obtained by 2 weeks. Conclusions Compartmental analysis can be applied in the novel way described here to study the influence of perturbations such as inflammation on predictions of vitamin A status using RID. Such an approach has potential value for studying other perturbations and different nutrients.

Nutrition in chronic inflammatory conditions: Bypassing the mucosal block for micronutrients

“…Retinol is also closely linked to the immune system. Serum retinol declines 431,432 as CRP levels increases 80,433 in infections and inflammatory diseases. Retinoic acid directly impacts many immune cell subsets, such as innate lymphoid cells, dendritic cells, and lymphocytes, while the immunomodulatory mechanisms of specific microbial species include the induction of retinoic acid metabolism in host cells 434,435 .…”

Scientific opinion on the tolerable upper intake level for preformed vitamin A and β‐carotene

“…The RID method is currently considered the best available indirect method to assess total body vitamin A status in humans (Gannon & Tanumihardjo, 2015 ; Green et al., 2020 ; Lietz et al., 2016 ). A small dose of retinol tracer labelled with stable deuterium ( 2 H) or carbon ( 13 C) is given orally, and the dilution of the tracer in plasma is measured when the labelled dose has mixed with endogenous stores and equilibrium is reached (14–21 days after administration).…”

“…The total body exchangeable retinol pool can then be derived from an RID equation based on the measurement of the ratio of labelled retinol to total retinol in plasma at a specified time after dosing, i.e. usually after 14–21 days after dose administration (Gannon & Tanumihardjo, 2015 ; Green et al., 2020 ; Lietz et al., 2016 ). Liver stores can be further determined by considering that the amount of retinol stored in the liver is positively correlated with the size of the total body pool.…”

Lack of iron, zinc, and vitamins as a contributor to the etiology of atopic diseases

“…Retinol is also closely linked to the immune system. In the case of any infection or inflammatory process, serum retinol declines ( 164 , 165 ), and this decline is associated with an increase in CRP ( 166 ). Therefore, in the presence of inflammation, this can result in an overestimation of vitamin A deficiency.…”