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Article ; Online: Time Since Dose and Dietary Vitamin A Intake Affect Tracer Mixing in the 13C-Retinol Isotope Dilution Test in Male Rats.

Sheftel, Jesse / Smith, Jordan B / Tanumihardjo, Sherry A

2022 Volume 152, Issue 6, Page(s) 1582–1591

Abstract: Background: Retinol isotope dilution (RID) estimates total liver vitamin A reserves (TLRs), the gold-standard vitamin A (VA) biomarker. RID equation assumptions are based on limited data.: Objectives: We measured the impact of tracer choice, mixing ... ...

Abstract	Background: Retinol isotope dilution (RID) estimates total liver vitamin A reserves (TLRs), the gold-standard vitamin A (VA) biomarker. RID equation assumptions are based on limited data. Objectives: We measured the impact of tracer choice, mixing period, and VA intake on tracer mixing [ratio of tracer enrichment in serum to that in liver stores (S)] in VA-deficient, -adequate, and hypervitaminotic rats. Methods: Study 1 was a 3 × 2 × 3 design (18 groups, n = 5/group). Male Sprague-Dawley rats (21 d old) received 50, 100, or 3500 nmol VA/d for 21 d, were administered 52 nmol 13C2- or 13C10-retinyl acetate orally, and killed 5, 10, or 15 d later. Unlabeled VA (50 nmol/d) was given on days 11-14. Study 2 used 100 nmol VA/d for 21 d with 3 groups (n = 6-7): 52 nmol 13C2- or 13C10-retinyl acetate and 100 nmol VA/d throughout 14-d mixing, or 13C2-retinyl acetate without VA. Repeated-measures, 1-factor, and 3-factor ANOVAs were used for analysis. Results: Mean ± SD TLRs (μmol/g liver) reflected intake: 0.11 ± 0.04 (50 nmol VA/d), 0.16 ± 0.04 (100 nmol VA/d), and 5.07 ± 1.58 (3500 nmol VA/d) in Study 1 and 0.24 ± 0.08 (100 nmol VA/d) in Study 2. In Study 1, mean ± SD S was 1.65 ± 0.26 (5 d), 1.16 ± 0.09 (10 d), and 0.92 ± 0.08 (15 d). The interactions tracerVA intake and timeVA intake were significant between days 10 and 15 (P < 0.05). In Study 2, mean ± SD S was 1.07 ± 0.02 without VA during mixing, and 0.81 ± 0.04 (13C2) and 0.79 ± 0.03 (13C10) with VA intake throughout. Estimated:measured TLRs varied by VA intake and time in Study 1 but not between groups in Study 2. Conclusions: The 13C-content effect on RID through S is inconsistent. S is highly variable at 5 d, contraindicating early-time point RID. VA intake effects on S vary with timing and quantity. Assuming S = 0.8 at 14 d with consistent VA intake in human studies is likely appropriate.
MeSH term(s)	Animals ; Carbon Isotopes ; Liver ; Male ; Rats ; Rats, Sprague-Dawley ; Vitamin A ; Vitamin A Deficiency
Chemical Substances	Carbon Isotopes ; Vitamin A (11103-57-4) ; Carbon-13 (FDJ0A8596D)
Language	English
Publishing date	2022-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218373-0
ISSN	1541-6100 ; 0022-3166
ISSN (online)	1541-6100
ISSN	0022-3166
DOI	10.1093/jn/nxac051
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Article ; Online: Systematic Review and Meta-Analysis of the Relative Dose-Response Tests to Assess Vitamin A Status.

Sheftel, Jesse / Tanumihardjo, Sherry A

Advances in nutrition (Bethesda, Md.)

2020 Volume 12, Issue 3, Page(s) 904–941

Abstract: Vitamin A (VA) is an essential nutrient often lacking in the diets of people in developing countries. Accurate biomarkers of VA status are vital to inform public health policy and monitor interventions. The relative dose-response (RDR) and modified-RDR ( ... ...

Abstract	Vitamin A (VA) is an essential nutrient often lacking in the diets of people in developing countries. Accurate biomarkers of VA status are vital to inform public health policy and monitor interventions. The relative dose-response (RDR) and modified-RDR (MRDR) tests are semi-quantitative screening tests for VA deficiency that have been used in Demographic and Health Surveys and VA intervention studies. A systematic review and meta-analysis of sensitivity and specificity were conducted to summarize the physiological evidence to support the RDR tests as methods to assess VA status and investigate the impact of different pathological and physiological states on the tests. A total of 190 studies were screened for inclusion, with 21 studies comparing the RDR tests with the gold-standard biomarker, liver VA concentration (68% and 80% sensitivity and 85% and 69% specificity for the RDR and MRDR, respectively). Nearly all studies with VA interventions in VA-deficient populations demonstrated a response of the tests to VA intake that would be expected to improve VA status. The impacts of chronic liver disease, protein malnutrition, age, pregnancy and lactation, infection and inflammation, and various other conditions were examined in 51 studies. The RDR and MRDR tests were reported to have been used in 39 observational studies, and the MRDR has been used in at least 6 national micronutrient surveys. The RDR and MRDR are sensitive tests for determining population VA status and assessing VA interventions. Although they are robust to most physiological and pathological states, caution may be warranted when using the tests in neonates, individuals with chronic liver disease, and those with protein or iron malnutrition. Research on further improvements to the tests to increase accessibility, such as sampling breast milk instead of blood or using intramuscular doses in subjects with malabsorption, will allow wider adoption. This review was registered with PROSPERO as CRD42019124180.
MeSH term(s)	Breast Feeding ; Dose-Response Relationship, Drug ; Female ; Humans ; Infant, Newborn ; Lactation ; Milk, Human/chemistry ; Nutritional Status ; Vitamin A/analysis ; Vitamin A Deficiency/diagnosis
Chemical Substances	Vitamin A (11103-57-4)
Language	English
Publishing date	2020-11-03
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	2583634-1
ISSN	2156-5376 ; 2156-5376
ISSN (online)	2156-5376
ISSN	2156-5376
DOI	10.1093/advances/nmaa136
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Article: Systematic Review and Meta-Analysis of the Relative Dose-Response Tests to Assess Vitamin A Status

Sheftel, Jesse / Tanumihardjo, Sherry A

Advances in nutrition. 2020 Oct. 31, v. 12, no. 3

2020

Abstract	Vitamin A (VA) is an essential nutrient often lacking in the diets of people in developing countries. Accurate biomarkers of VA status are vital to inform public health policy and monitor interventions. The relative dose-response (RDR) and modified-RDR (MRDR) tests are semi-quantitative screening tests for VA deficiency that have been used in Demographic and Health Surveys and VA intervention studies. A systematic review and meta-analysis of sensitivity and specificity were conducted to summarize the physiological evidence to support the RDR tests as methods to assess VA status and investigate the impact of different pathological and physiological states on the tests. A total of 190 studies were screened for inclusion, with 21 studies comparing the RDR tests with the gold-standard biomarker, liver VA concentration (68% and 80% sensitivity and 85% and 69% specificity for the RDR and MRDR, respectively). Nearly all studies with VA interventions in VA-deficient populations demonstrated a response of the tests to VA intake that would be expected to improve VA status. The impacts of chronic liver disease, protein malnutrition, age, pregnancy and lactation, infection and inflammation, and various other conditions were examined in 51 studies. The RDR and MRDR tests were reported to have been used in 39 observational studies, and the MRDR has been used in at least 6 national micronutrient surveys. The RDR and MRDR are sensitive tests for determining population VA status and assessing VA interventions. Although they are robust to most physiological and pathological states, caution may be warranted when using the tests in neonates, individuals with chronic liver disease, and those with protein or iron malnutrition. Research on further improvements to the tests to increase accessibility, such as sampling breast milk instead of blood or using intramuscular doses in subjects with malabsorption, will allow wider adoption. This review was registered with PROSPERO as CRD42019124180.
Keywords	biomarkers ; blood ; breast milk ; dose response ; health policy ; inflammation ; kwashiorkor ; lactation ; liver ; liver diseases ; malabsorption ; meta-analysis ; pregnancy ; systematic review ; vitamin A
Language	English
Dates of publication	2020-1031
Size	p. 904-941.
Publishing place	Oxford University Press
Document type	Article
ZDB-ID	2583634-1
ISSN	2156-5376
ISSN	2156-5376
DOI	10.1093/advances/nmaa136
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Article ; Online: Recommendations to adjust national vitamin A intervention policy must follow a consistent framework.

Sheftel, Jesse / Suri, Devika J / Tanumihardjo, Sherry A

The American journal of clinical nutrition

2021 Volume 113, Issue 6, Page(s) 1707–1708

MeSH term(s)	Child ; Dietary Supplements ; Humans ; India ; Nutrition Policy ; Vitamin A ; Vitamin A Deficiency/epidemiology ; Vitamin A Deficiency/prevention & control
Chemical Substances	Vitamin A (11103-57-4)
Language	English
Publishing date	2021-06-01
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.1093/ajcn/nqab104
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Article ; Online: Retinol isotope dilution accurately predicts liver reserves in piglets but overestimates reserves in lactating sows.

Sheftel, Jesse / Surles, Rebecca L / Tanumihardjo, Sherry A

Experimental biology and medicine (Maywood, N.J.)

2019 Volume 244, Issue 7, Page(s) 579–587

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Carbon Isotopes ; Female ; Lactation/metabolism ; Liver/growth & development ; Liver/metabolism ; Male ; Milk/metabolism ; Radioisotope Dilution Technique/standards ; Radioisotope Dilution Technique/veterinary ; Swine ; Vitamin A/blood ; Vitamin A/metabolism ; Vitamin A Deficiency/diagnosis ; Vitamin A Deficiency/veterinary
Chemical Substances	Carbon Isotopes ; Vitamin A (11103-57-4)
Language	English
Publishing date	2019-03-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	4015-0
ISSN	1535-3699 ; 1525-1373 ; 0037-9727
ISSN (online)	1535-3699 ; 1525-1373
ISSN	0037-9727
DOI	10.1177/1535370219838785
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Article: Retinol isotope dilution accurately predicts liver reserves in piglets but overestimates reserves in lactating sows

Sheftel, Jesse / Surles, Rebecca L. / Tanumihardjo, Sherry A.

Experimental Biology and Medicine. 2019 May, v. 244, no. 7

2019

Abstract: 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 ... ...

Abstract	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.
Keywords	animal models ; biomarkers ; blood serum ; ewe milk ; hypervitaminosis A ; isotope dilution technique ; isotope labeling ; lactating females ; lactation ; liver ; piglets ; sow milk ; sows ; vitamin A ; vitamin A deficiency ; vitamin status
Language	English
Dates of publication	2019-05
Size	p. 579-587.
Publishing place	SAGE Publications
Document type	Article
ISSN	1535-3702
DOI	10.1177/1535370219838785
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Article ; Online: Modified relative dose response values differ between lactating women in the United States and Indonesia.

Sheftel, Jesse / Bresnahan, Kara A / Fadjarwati, Tetra / Tanumihardjo, Sherry A

Experimental biology and medicine (Maywood, N.J.)

2020 Volume 245, Issue 9, Page(s) 797–804

Abstract: Impact statement: Vitamin A (VA) deficiency is a major health issue globally, and lactating women are particularly vulnerable due to increased needs for milk production. Accurate detection of VA deficiency is important; however, most population surveys ... ...

Abstract	Impact statement: Vitamin A (VA) deficiency is a major health issue globally, and lactating women are particularly vulnerable due to increased needs for milk production. Accurate detection of VA deficiency is important; however, most population surveys measure VA status using serum retinol, which is affected by inflammation and lacks sensitivity. The modified relative dose response (MRDR) test qualitatively distinguishes between VA deficiency and sufficiency and could improve population surveys if completed in a randomly selected subsample of individuals in surveys. The original relative dose response test required two blood samples, while MRDR requires only one, a significant improvement in accessibility of the technique by decreasing burden on subjects and investigators. This work demonstrates significant deficiency in Indonesian women compared with US women. In combination with previous research using lactating sows, these human data support milk as a surrogate for blood in the MRDR, which may be less invasive, but requires further validation.
MeSH term(s)	Adult ; Female ; Humans ; Indonesia ; Lactation ; Milk, Human/chemistry ; United States ; Vitamin A/administration & dosage ; Vitamin A/analogs & derivatives ; Vitamin A/analysis ; Vitamin A Deficiency/blood ; Vitamin A Deficiency/diagnosis
Chemical Substances	3,4-didehydroretinyl acetate ; Vitamin A (11103-57-4)
Language	English
Publishing date	2020-04-23
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	4015-0
ISSN	1535-3699 ; 1525-1373 ; 0037-9727
ISSN (online)	1535-3699 ; 1525-1373
ISSN	0037-9727
DOI	10.1177/1535370220921550
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Article ; Online: Chronic and acute hypervitaminosis A are associated with suboptimal anthropometric measurements in a cohort of South African preschool children.

Sheftel, Jesse / van Stuijvenberg, Martha E / Dhansay, Muhammad A / Suri, Devika J / Grahn, Michael / Keuler, Nicholas S / Binkley, Neil C / Tanumihardjo, Sherry A

The American journal of clinical nutrition

2022 Volume 115, Issue 4, Page(s) 1059–1068

Abstract: Background: Excessive vitamin A (VA) can cause bone resorption and impair growth. Government-mandated VA supplementation (VAS) and adequate intake through dietary fortification and liver consumption led to excessive VA in South African children.: ... ...

Abstract	Background: Excessive vitamin A (VA) can cause bone resorption and impair growth. Government-mandated VA supplementation (VAS) and adequate intake through dietary fortification and liver consumption led to excessive VA in South African children. Objectives: We evaluated the relation between VAS and underlying hypervitaminosis A assessed by retinol isotope dilution (RID) with measures of growth and bone turnover in this cohort. Methods: Primary outcomes in these children (n = 94, 36-60 mo) were anthropometric measurements [height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ) z scores], serum bone turnover markers [C-terminal telopeptide of type I collagen (CTX) and N-terminal propeptide of type I procollagen (P1NP)], and inflammation defined as C-reactive protein (CRP; ≥5 mg/L) and/or α1-acid glycoprotein (AGP; ≥1 g/L). VA status was previously measured by RID-estimated total body VA stores (TBSs) and total liver VA reserves (TLRs), and serum retinol and carotenoid concentrations, before and 4 wk after children were administered 200,000 IU VAS. Serum 25-hydroxyvitamin D3 was measured by ultra-performance LC. Results: In this largely hypervitaminotic A cohort, HAZ, WAZ, and WHZ were negatively associated with increasing TLRs, where TLRs predicted 6-10% of the variation before VAS (P < 0.05), increasing to 14-19% 4 wk after VAS (P < 0.01). Bone resorption decreased after VAS (P < 0.0001), whereas formation was unaffected. Neither CTX nor P1NP were correlated with TLRs at either time. Serum carotenoids were low. One child at each time point was vitamin D deficient (<50 nmol/L). CRP and AGP were not associated with growth measurements. Conclusions: Excessive TLRs due to dietary VA intake and VAS are associated with lower anthropometric measures and bone resorption decreased after supplementation. VA supplementation programs should monitor VA status with biomarkers sensitive to TLRs to avoid causing negative consequences in children with hypervitaminosis A. This trial is registered at clinicaltrials.gov as NCT02915731.
MeSH term(s)	Child, Preschool ; Diet ; Humans ; Hypervitaminosis A ; South Africa ; Vitamin A ; Vitamin A Deficiency
Chemical Substances	Vitamin A (11103-57-4)
Language	English
Publishing date	2022-01-12
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.1093/ajcn/nqab422
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Article: Modified relative dose response values differ between lactating women in the United States and Indonesia

Sheftel, Jesse / Bresnahan, Kara A. / Fadjarwati, Tetra / Tanumihardjo, Sherry A.

Experimental Biology and Medicine. 2020 May, v. 245, no. 9

2020

Abstract: Vitamin A (VA) deficiency is a major health issue globally, and lactating women are particularly vulnerable due to increased needs for milk production. Accurate detection of VA deficiency is important; however, most population surveys measure VA status ... ...

Abstract	Vitamin A (VA) deficiency is a major health issue globally, and lactating women are particularly vulnerable due to increased needs for milk production. Accurate detection of VA deficiency is important; however, most population surveys measure VA status using serum retinol, which is affected by inflammation and lacks sensitivity. The modified relative dose response (MRDR) test qualitatively distinguishes between VA deficiency and sufficiency and could improve population surveys if completed in a randomly selected subsample of individuals in surveys. The original relative dose response test required two blood samples, while MRDR requires only one, a significant improvement in accessibility of the technique by decreasing burden on subjects and investigators. This work demonstrates significant deficiency in Indonesian women compared with US women. In combination with previous research using lactating sows, these human data support milk as a surrogate for blood in the MRDR, which may be less invasive, but requires further validation.
Keywords	breast milk ; dose response ; lactating women ; lactation ; vitamin A deficiency ; vitamin status ; Indonesia ; United States
Language	English
Dates of publication	2020-05
Size	p. 797-804.
Publishing place	SAGE Publications
Document type	Article
ISSN	1535-3702
DOI	10.1177/1535370220921550
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Use of Stable Isotopes to Evaluate Bioefficacy of Provitamin A Carotenoids, Vitamin A Status, and Bioavailability of Iron and Zinc.

Sheftel, Jesse / Loechl, Cornelia / Mokhtar, Najat / Tanumihardjo, Sherry A

Advances in nutrition (Bethesda, Md.)

2018 Volume 9, Issue 5, Page(s) 625–636

Abstract: The ability of nutrition scientists to measure the status, bioavailability, and bioefficacy of micronutrients is affected by lack of access to the parts of the body through which a nutrient may travel before appearing in accessible body compartments ( ... ...

Abstract	The ability of nutrition scientists to measure the status, bioavailability, and bioefficacy of micronutrients is affected by lack of access to the parts of the body through which a nutrient may travel before appearing in accessible body compartments (typically blood or urine). Stable isotope-labeled tracers function as safe, nonradioactive tools to follow micronutrients in a quantitative manner because the absorption, distribution, metabolism, and excretion of the tracer are assumed to be similar to the unlabeled vitamin or mineral. The International Atomic Energy Agency (IAEA) supports research on the safe use of stable isotopes in global health and nutrition. This review focuses on IAEA's contributions to vitamin A, iron, and zinc research. These micronutrients are specifically targeted by the WHO because of their importance in health and worldwide prevalence of deficiency. These 3 micronutrients are included in food fortification and biofortification efforts in low- and middle-income regions of the world. Vitamin A isotopic techniques can be used to evaluate the efficacy and effectiveness of interventions. For example, total body retinol stores were estimated by using 13C2-retinol isotope dilution before and after feeding Zambian children maize biofortified with β-carotene to determine if vitamin A reserves were improved by the intervention. Stable isotopes of iron and zinc have been used to determine mineral bioavailability. In Thailand, ferrous sulfate was better absorbed from fish sauce than was ferrous lactate or ferric ammonium citrate, determined with the use of different iron isotopes in each compound. Comparisons of one zinc isotope injected intravenously with another isotope taken orally from a micronutrient powder proved that the powder increased total absorbed zinc from a meal in Pakistani infants. Capacity building by the IAEA with appropriate collaborations in low- and middle-income countries to use stable isotopes has resulted in many advancements in human nutrition.
MeSH term(s)	Adult ; Biological Availability ; Carotenoids/pharmacokinetics ; Child ; Female ; Humans ; Iron/pharmacokinetics ; Isotope Labeling/methods ; Isotopes/pharmacokinetics ; Male ; Micronutrients/pharmacokinetics ; Nutrition Assessment ; Nutritional Sciences/methods ; Nutritional Status ; Vitamin A/pharmacokinetics ; Zinc/pharmacokinetics
Chemical Substances	Isotopes ; Micronutrients ; Vitamin A (11103-57-4) ; Carotenoids (36-88-4) ; Iron (E1UOL152H7) ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2018-09-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2583634-1
ISSN	2156-5376 ; 2156-5376
ISSN (online)	2156-5376
ISSN	2156-5376
DOI	10.1093/advances/nmy036
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