scholarly journals International Experiences in Assessing Vitamin A Status and Applying the Vitamin A-Labeled Isotope Dilution Method

2014 ◽  
Vol 84 (Supplement 1) ◽  
pp. 40-51 ◽  
Author(s):  
Veronica Lopez-Teros ◽  
Justin Chileshe ◽  
Nicole Idohou-Dossou ◽  
Tetra Fajarwati ◽  
Gabriel Medoua Nama ◽  
...  
Keyword(s):  
Vitamin A ◽  
Dose Response ◽  
Isotope Dilution ◽  
Qualitative Assessment ◽  
Isotope Dilution Method ◽  
Dilution Method ◽  
Serum Retinol ◽  
Retinyl Acetate ◽  
Positive Effects ◽  
Vitamin A Status

Inadequate vitamin A (VA) nutrition continues to be a major problem worldwide, and many interventions being implemented to improve VA status in various populations need to be evaluated. The interpretation of results after an intervention depends greatly on the method selected to assess VA status. To evaluate the effect of an intervention on VA status, researchers in Cameroon, India, Indonesia, Mexico, Senegal and Zambia have used serum retinol as an indicator, and have not always found improvement in response to supplementation. One problem is that homeostatic control of serum retinol may mask positive effects of treatment in that changes in concentration are observed only when status is either moderately to severely depleted or excessive. Because VA is stored mainly in the liver, measurements of hepatic VA stores are the “gold standard” for assessing VA status. Dose response tests such as the relative dose response (RDR) and the modified relative dose response (MRDR), allow a qualitative assessment of VA liver stores. On the other hand, the use of the vitamin A-labeled isotope dilution (VALID) technique, (using 13C or 2H-labeled retinyl acetate) serves as an indirect method to quantitatively estimate total body and liver VA stores. Countries including Cameroon, China, Ghana, Mexico, Thailand and Zambia are now applying the VALID method to sensitively assess changes in VA status during interventions, or to estimate a population’s dietary requirement for VA. Transition to the use of more sensitive biochemical indicators of VA status such as the VALID technique is needed to effectively assess interventions in populations where mild to moderate VA deficiency is more prevalent than severe deficiency.

scholarly journals Use of a short-term isotope-dilution method for determining the vitamin A status of children

2002 ◽  
Vol 76 (2) ◽  
pp. 413-418 ◽  
Author(s):  
Guangwen Tang ◽  
Jian Qin ◽  
Lan-ying Hao ◽  
Shi-an Yin ◽  
Robert M Russell
Keyword(s):  
Vitamin A ◽  
Isotope Dilution ◽  
Isotope Dilution Method ◽  
Dilution Method ◽  
Short Term ◽  
Vitamin A Status

Influence of Vitamin A Status on the Choice of Sampling Time for Application of the Retinol Isotope Dilution Method in Theoretical Children

2021 ◽  
Author(s):  
Veronica Lopez-Teros ◽  
Michael H Green ◽  
Marjorie J Haskell ◽  
Joanne Balmer Green
Keyword(s):  
Vitamin A ◽  
Isotope Dilution ◽  
Specific Activity ◽  
Geometric Mean ◽  
Sampling Time ◽  
Percentage Error ◽  
Isotope Dilution Method ◽  
Dilution Method ◽  
Individual Subject ◽  
Vitamin A Status

ABSTRACT Background Vitamin A status may influence the choice of a blood sampling time for applying the retinol isotope dilution (RID) equation to predict vitamin A total body stores (TBS) in children. Objectives We aimed to identify time(s) after administration of labeled vitamin A that provide accurate estimates of TBS in theoretical children with low or high TBS. Methods We postulated 2- to 5-y-old children (12/group) with low (<200 μmol) or high TBS (≥700 μmol) and used compartmental analysis to simulate individual subject values for the RID equation TBS =   FaS/SAp (Fa, fraction of dose in stores; S, retinol specific activity in plasma/in stores; SAp, retinol specific activity in plasma). Using individual SAp and group geometric mean FaS values from 1–28 d, we calculated individual and group mean TBS and compared them to assigned values. Results Mean TBS was accurately predicted for both groups at all times. For individuals, predicted and assigned TBS were closest when the CV% for FaS was low [12–14%; 4–13 d (low), 12–28 d (high)]. The mean percentage error for TBS was <10% from 2–19 d (low) and 7–28 d (high). Predicted TBS was within 25% of assigned TBS for ≥80% of children from 3–23 d (low) and 9–28 d (high). Within groups, RID tended to overestimate lower TBS and underestimate higher TBS. Conclusions Using a good estimate for FaS, accurate RID predictions of TBS for individuals will be obtained at many times. If vitamin A status is low, results indicate that early sampling (e.g., 4–13 d) is optimal; if vitamin A status is high, sampling at 12–28 d is indicated. When vitamin A status is unknown, sampling at 14 d is recommended, or a super-subject design can be used to obtain the group mean FaS at various times for RID prediction of TBS in individuals.

Evaluation of the “Olson Equation”, an Isotope Dilution Method for Estimating Vitamin A Stores

2014 ◽  
Vol 84 (Supplement 1) ◽  
pp. 9-15 ◽  
Author(s):  
Michael H. Green
Keyword(s):  
Vitamin A ◽  
Oral Dose ◽  
Isotope Dilution ◽  
Isotope Dilution Method ◽  
Dilution Method ◽  
Human Populations ◽  
Dilution Technique ◽  
Isotope Dilution Technique ◽  
Vitamin A Status ◽  
The Impact

Isotope dilution methods have been successfully used to estimate vitamin A status in human populations as well as to evaluate the impact of vitamin A interventions. The most commonly applied isotope dilution method is the retinol isotope dilution technique, which is based on the 1989 “Olson equation” for estimating total body vitamin A stores (sometimes equated to liver vitamin A) after an oral dose of labeled vitamin A. The equation relies on several factors related to absorption and retention of the dose, the equilibration of label in plasma vs. liver, and timing of a blood sample for measurement of labeled vitamin A. Here, the assumptions underlying these factors are discussed, and new results based on applying model-based compartmental analysis [specifically, the Simulation, Analysis and Modeling software (WinSAAM)] to data on retinol kinetics in humans are summarized. A simplification of the Olson equation, in which plasma tracer is measured 3 days after administration of the oral dose and several factors are eliminated, is presented. The potential usefulness of the retinol isotope dilution technique for setting vitamin A requirements and assessing vitamin A status in children, as well as the confounding effects of inflammation and likely variability in vitamin A absorption, are also discussed.

scholarly journals Retinol isotope dilution accurately predicts liver reserves in piglets but overestimates reserves in lactating sows

2019 ◽  
Vol 244 (7) ◽  
pp. 579-587 ◽  
Author(s):  
Jesse Sheftel ◽  
Rebecca L Surles ◽  
Sherry A Tanumihardjo
Keyword(s):  
Vitamin A ◽  
Isotope Dilution ◽  
Equilibration Time ◽  
Serum Retinol ◽  
Retinyl Acetate ◽  
Hypervitaminosis A ◽  
Post Dose ◽  
Human Infants ◽  
Lactating Women ◽  
Lactating Sows

Retinol isotope dilution (RID) is used to estimate total body vitamin A (VA) stores in groups to assess VA status. Metabolic differences during lactation may affect RID calculations as currently applied. We evaluated the time required for isotopic equilibration between serum and liver retinol in piglets, and the utility of milk retinol isotopic enrichment as a proxy for serum in lactating sows. Piglets ( n = 24) and sows ( n = 6) were fed 1.75 or 20 µmol 13 C2-retinyl acetate, respectively. Piglets ( n = 5 or 7) were killed on d 0, 4, 7, or 14. Blood and milk were collected at d 0, 0.5, 1, 2, 4, 7, 10, 14, and 21 before the sows were killed to collect liver. Retinol 13 C-enrichment was determined by gas chromatography-combustion-isotope ratio mass spectrometry. Equilibration time and RID-predicted liver VA reserves were calculated. In piglets, serum and liver retinol 13 C-enrichment differed significantly in individuals at d 4 and 7 ( P = 0.008, 0.03) but not d 14 ( P = 0.06); however, mean values were not different by d 4 ( P = 0.62). Current RID equations accurately predicted VA deficiency (means ≤0.027 µmol/g liver) in the piglets. In sows, milk and serum retinol 13 C-enrichment reached equilibrium between 2 and 7 d post-dose. After correcting for dose lost to milk, RID equations predicted higher liver stores than measured values even though the serum to liver atom % was 1.00 ± 0.01 at kill. In VA deficient infants, a shorter period may be accurate in population-level RID studies when using appropriate assumptions. In lactating women, the RID may have decreased accuracy due to variable losses of tracer in milk. Furthermore, assumptions about storage and loss of the dose in milk must be evaluated in lactating women considering the observed discrepancy between predicted and measured stores. Impact statement Vitamin A (VA) deficiency and hypervitaminosis A have been reported in groups of people worldwide. Conventional biomarkers of VA deficiency (e.g. serum retinol concentration, dose response tests) are not able to distinguish between sufficiency and hypervitaminosis A. Retinol isotope dilution (RID) predictions of VA status have been validated in humans and animal models from deficiency through toxicity; however, RID during life stages with unique issues related to isotopic tracing, such as infancy and lactation, requires further evaluation. This study investigated RID in piglets and lactating sows as models for human infants and women. In piglets, RID successfully determined VA deficiency (confirmed with liver analysis), and that the tracer mixes quickly. Conversely, in lactating sows, although serum and milk enrichments were similar, traditional RID equations overestimated VA stores, likely due to losses of tracer and higher extrahepatic VA storage than predictions. These data inform researchers about the challenges of using RID during lactation.

Does the Amount of Stable Isotope Dose Influence Retinol Kinetic Responses and Predictions of Vitamin A Total Body Stores by the Retinol Isotope Dilution Method in Theoretical Children and Adults?

2021 ◽  
Author(s):  
Michael H Green ◽  
Veronica Lopez-Teros ◽  
Joanne Balmer Green
Keyword(s):  
Stable Isotope ◽  
Vitamin A ◽  
Isotope Dilution ◽  
Specific Activity ◽  
Simulated Data ◽  
Compartmental Analysis ◽  
Isotope Dilution Method ◽  
Dilution Method ◽  
Plasma Retinol ◽  
Total Body

Abstract Background To minimize both cost and perturbations to the vitamin A system, investigators limit the amount of stable isotope administered when estimating vitamin A total body stores (TBS) by retinol isotope dilution (RID). Objectives We hypothesized that reasonable increases in the mass of stable isotope administered to theoretical subjects would have only transient impacts on vitamin A kinetics and minimal effects on RID-predicted TBS. Methods We adapted previously-used theoretical subjects (3 children, 3 adults) with low, moderate, or high assigned TBS and applied compartmental analysis to solve a steady state model for tracer and tracee using assigned values for retinol kinetic parameters and plasma retinol. To follow retinol trafficking when increasing amounts of stable isotope were administered [1.39-7 (children) and 2.8-14 µmol retinol (adults)], we added assumptions to an established compartmental model so that plasma retinol homeostasis was maintained. Using model-simulated data, we plotted retinol kinetics versus time and applied the RID equation TBS = FaS/SAp [Fa, fraction of dose in stores; S, retinol specific activity (SA) in plasma/SA in stores; SAp, SA in plasma] to calculate vitamin A stores. Results The model predicted that increasing the stable isotope dose caused transient early increases in hepatocyte total retinol; increases in plasma tracer were accompanied by decreases in tracee to maintain plasma retinol homeostasis. Despite changes in kinetic responses, RID accurately predicted assigned TBS (98-105%) at all loads for all theoretical subjects from 1-28 d postdosing. Conclusions Results indicate that, compared with doses of 1.4–3.5 µmol used in recent RID field studies, doubling the stable isotope dose should not affect accuracy of TBS predictions, thus allowing for experiments of longer duration when including a super-subject design (Ford et al., J Nutr 2020;150:411–8) and/or studying retinol kinetics.

scholarly journals Better Predictions of Vitamin A Total Body Stores by the Retinol Isotope Dilution Method Are Possible with Deeper Understanding of the Mathematics and by Applying Compartmental Modeling

2019 ◽  
Vol 150 (5) ◽  
pp. 989-993 ◽  
Author(s):  
Michael H Green ◽  
Joanne Balmer Green ◽  
Jennifer Lynn Ford
Keyword(s):  
Vitamin A ◽  
Isotope Dilution ◽  
Theoretical Data ◽  
Compartmental Analysis ◽  
Whole Body ◽  
Optimal Time ◽  
Isotope Dilution Method ◽  
Dilution Method ◽  
Model Based ◽  
Total Body

ABSTRACT Retinol isotope dilution (RID) is a well-accepted technique for assessing vitamin A status [i.e., total body stores (TBS)]. Here, in an effort to increase understanding of the method, we briefly review RID equations and discuss their included variables and their coefficients (i.e., assumptions that account for the efficiency of absorption of an orally administered tracer dose of vitamin A, mixing of the dose with endogenous vitamin A, and loss due to utilization). Then, we focus on contributions of another technique, model-based compartmental analysis and especially the “super-person” approach, that advance the RID method. Specifically, we explain how adding this modeling component, which involves taking 1 additional blood sample from each subject, provides population-specific estimates for the RID coefficients that can be used in the equation instead of values derived from the literature; using model-derived RID coefficients results in improved confidence in predictions of TBS for both a group and its individuals. We note that work is still needed to identify the optimal time for applying RID in different groups and to quantify vitamin A absorption efficiency. Finally, we mention other contributions of modeling, including the use of theoretical data to verify the accuracy of RID predictions and the additional knowledge that model-based compartmental analysis provides about whole-body vitamin A kinetics.

scholarly journals Comparisons among Equations Used for Retinol Isotope Dilution in the Assessment of Total Body Stores and Total Liver Reserves

2015 ◽  
Vol 145 (5) ◽  
pp. 847-854 ◽  
Author(s):  
Bryan M Gannon ◽  
Sherry A Tanumihardjo
Keyword(s):  
Vitamin A ◽  
Isotope Dilution ◽  
Vitamin A Deficiency ◽  
Storage Site ◽  
Serum Retinol ◽  
Negative Effects ◽  
Hypervitaminosis A ◽  
Major Drawback ◽  
Vitamin A Status ◽  
Wide Range

Abstract Vitamin A plays an essential role in animal biology and has negative effects associated with both hypo- and hypervitaminosis A. Many notable interventions are being done globally to eliminate vitamin A deficiency, including supplementation, fortification, and biofortification. At the same time, it is important to monitor vitamin A status in nations where preformed vitamin A intake is high because of consumption of animal source foods (e.g., liver, dairy, eggs), fortified foods (e.g., milk, cereals, oil, sugar, margarine), or vitamin supplements (e.g., one-a-day multivitamins) to ensure the population does not reach hypervitaminosis A. To accurately assess population status and evaluate interventions aimed at improving vitamin A status, accurate assessment methods are needed. The primary storage site of vitamin A is the liver; however, routinely obtaining liver samples from humans is impractical and unethical. Isotope dilution using deuterium- or 13C-labeled retinol is currently the most sensitive indirect biomarker of vitamin A status across a wide range of liver reserves. The major drawback to its application is the increased technicality in sample analysis and data calculations when compared to less sensitive methodology, such as serum retinol concentrations and dose response tests. Two main equations have emerged for calculating vitamin A body pool size or liver concentrations from isotope dilution data: the “Olson equation” and the “mass balance equation.” Different applications of these equations can lead to confusion and lack of consistency if the underlying principles and assumptions used are not clarified. The purpose of this focused review is to describe the evolution of the equations used in retinol stable-isotope work and the assumptions appropriate to different applications of the test. Ultimately, the 2 main equations are shown to be fundamentally the same and differ only in assumptions made for each specific research application.

Usefulness of Vitamin A Isotope Methods for Status Assessment: From Deficiency through Excess

2014 ◽  
Vol 84 (Supplement 1) ◽  
pp. 16-24 ◽  
Author(s):  
Sherry A. Tanumihardjo
Keyword(s):  
Vitamin A ◽  
Isotope Dilution ◽  
Clinical Signs ◽  
Provitamin A ◽  
Serum Retinol ◽  
Vitamin A Status ◽  
Status Assessment ◽  
Indirect Indicator ◽  
Staple Foods ◽  
Retinol Concentration

A variety of methods exist to assess vitamin A status of groups and populations. Vitamin A status is usually defined by the liver retinol concentration. Most indicators of status do not measure or estimate liver stores of retinol. Clinical signs only have utility when liver reserves are almost exhausted, and serum retinol concentrations have utility in the zone of overt deficiency. Dose response tests offer more coverage, but cannot distinguish among liver vitamin A stores in the adequate through toxic range. Different countries continue, or are beginning, to add preformed vitamin A to a variety of staple foods through fortification, and vitamin A supplements are still being distributed in many countries, especially to preschool children. Further, provitamin A biofortified crops are currently being released in several countries. Assessing population vitamin A status in response to these interventions needs to move beyond serum retinol concentrations. Indicators that work in the excessive to toxic range of liver reserves are needed. To date, the only indirect indicator that has been validated in this range of liver reserves in animals and humans is the retinol isotope dilution test using deuterium or 13C, which spans the entire liver reserve continuum from deficiency through excess.

scholarly journals Vitamin A status of neonatal foals assessed by serum retinol concentration and a relative dose response test

1996 ◽  
Vol 12 (3) ◽  
pp. 181-183 ◽  
Author(s):  
K M Greiwe-Crandell ◽  
D S Kronfeld ◽  
L S Gay ◽  
D Sklan ◽  
P A Harris
Keyword(s):  
Vitamin A ◽  
Dose Response ◽  
Serum Retinol ◽  
Response Test ◽  
Vitamin A Status ◽  
Serum Retinol Concentration ◽  
Retinol Concentration

scholarly journals Breast Milk–Derived Retinol Is a Potential Surrogate for Serum in the 13C-Retinol Isotope Dilution Test in Zambian Lactating Women with Vitamin A Deficient and Adequate Status

2020 ◽  
Vol 151 (1) ◽  
pp. 255-263
Author(s):  
Chisela Kaliwile ◽  
Charles Michelo ◽  
Jesse Sheftel ◽  
Christopher R Davis ◽  
Michael Grahn ◽  
...  
Keyword(s):  
Breast Milk ◽  
Vitamin A ◽  
Isotope Dilution ◽  
Policy Development ◽  
Demographic Data ◽  
Reproductive Age ◽  
Serum Retinol ◽  
Women Of Reproductive Age ◽  
Retinyl Acetate ◽  
Lactating Women

ABSTRACT Background Vitamin A (VA) deficiency (VAD) affects ∼19 million pregnant women worldwide. The extent of VAD in Zambian women of reproductive age is unknown owing to lack of survey inclusion or the use of static serum retinol concentrations, a low-sensitivity biomarker. Objectives This cross-sectional study employed isotopic techniques to determine VA status with serum and milk among women aged 18–49 y (n = 197) either lactating with infants aged 0–24 mo or nonlactating with or without infants. Methods Assistants were trained and piloted data collection. Demographic data, anthropometry, and relevant histories were obtained including malaria and anemia. For retinol isotope dilution (RID), baseline fasting blood and casual breast milk samples were collected before administration of 2.0 μmol 13C2-retinyl acetate and 24-h dietary recalls. On day 14, blood (n = 144) and milk (n = 66) were collected. Prevalence of total liver VA reserves (TLR) ≤0.10 μmol/g was defined as VAD with comparison to the DRI assumption of 0.07 μmol/g as minimally acceptable for North Americans. Results When a 20% adjustment for dose lost to milk was made in the RID equation for lactation, mean total body VA stores (TBS) for lactating women were 25% lower than for nonlactating women (P < 0.01), which was not the case without adjustment (P = 0.3). Mean ± SD TLR for all women were 0.15 ± 0.11 μmol/g liver. Using retinol purified from breast milk instead of serum for RID analysis yielded similar TBS and TLR, which were highly correlated between methods (P < 0.0001). Serum retinol ≤0.70 μmol/L had 0% sensitivity using either VAD liver cutoff and milk retinol ≤1.0 μmol/L had 42% sensitivity for VAD at 0.10 μmol/g. Conclusions Determining accurate VA status among women of reproductive age, especially lactating women, forms a basis for extrapolation to the general population and informing policy development and program implementation.

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