Serum retinol concentrations demonstrate high specificity after correcting
          for inflammation but questionable sensitivity compared with liver stores calculated from
          isotope dilution in determining vitamin A deficiency in Thai and Zambian
          children

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.

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Research Recommendations for Applying Vitamin A-Labelled Isotope Dilution Techniques to Improve Human Vitamin A Nutrition

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000185 ◽

2014 ◽

Vol 84 (Supplement 1) ◽

pp. 52-59 ◽

Cited By ~ 5

Author(s):

Sherry A. Tanumihardjo ◽

Anura V. Kurpad ◽

Janet R. Hunt

Keyword(s):

Public Health ◽

Vitamin A ◽

Vitamin A Deficiency ◽

Human Subjects ◽

The Body ◽

Pool Size ◽

Serum Retinol ◽

Vitamin A Status ◽

Status Assessment ◽

Total Body

The current use of serum retinol concentrations as a measurement of subclinical vitamin A deficiency is unsatisfactory for many reasons. The best technique available for vitamin A status assessment in humans is the measurement of total body pool size. Pool size is measured by the administration of retinol labelled with stable isotopes of carbon or hydrogen that are safe for human subjects, with subsequent measurement of the dilution of the labelled retinol within the body pool. However, the isotope techniques are time-consuming, technically challenging, and relatively expensive. There is also a need to assess different types of tracers and doses, and to establish clear guidelines for the use and interpretation of this method in different populations. Field-friendly improvements are desirable to encourage the application of this technique in developing countries where the need is greatest for monitoring the risk of vitamin A deficiency, the effectiveness of public health interventions, and the potential of hypervitaminosis due to combined supplement and fortification programs. These techniques should be applied to validate other less technical methods of assessing vitamin A deficiency. Another area of public health relevance for this technique is to understand the bioconversion of β-carotene to vitamin A, and its relation to existing vitamin A status, for future dietary diversification programs.

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Vitamin A Supplementation and Measles

Pediatrics in Review ◽

10.1542/pir.16.9.358 ◽

1995 ◽

Vol 16 (9) ◽

pp. 358-359

Author(s):

Glenn J. Fennelly

Keyword(s):

Vitamin A ◽

Acute Phase ◽

Vitamin A Deficiency ◽

Serum Levels ◽

Morbidity And Mortality ◽

Serum Retinol ◽

Vitamin A Supplementation

Vitamin A deficiency resulting from inadequate intake or induced by infection is associated with increased morbidity and mortality. Measles, the major single infectious cause of mortality in children worldwide, is more severe in children who have preexisting vitamin A deficiency. Several recent studies suggest that: 1) measles is associated with depressed serum levels of vitamin A; 2) hyporetinemia, defined as a serum retinol of less than 0.7 µmol/L, is associated with increased mortality from measles, especially in children younger than 2 years of age; and 3) vitamin A will decrease the risk of complications and death when administered during the acute phase of illness (within 5 days of the onset of rash).

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SEANUTS: the nutritional status and dietary intakes of 0.5–12-year-old Thai children

British Journal Of Nutrition ◽

10.1017/s0007114513002110 ◽

2013 ◽

Vol 110 (S3) ◽

pp. S36-S44 ◽

Cited By ~ 45

Author(s):

Nipa Rojroongwasinkul ◽

Kallaya Kijboonchoo ◽

Wanphen Wimonpeerapattana ◽

Sasiumphai Purttiponthanee ◽

Uruwan Yamborisut ◽

...

Keyword(s):

Vitamin D ◽

Vitamin A ◽

Nutritional Status ◽

Rural Areas ◽

Urban Areas ◽

Vitamin A Deficiency ◽

Public Health Problem ◽

Rural Children ◽

Major Public Health Problem ◽

Serum Retinol

In the present study, we investigated nutritional status and health-related factors in a multistage cluster sample of 3119 Thai urban and rural children aged 0·5–12·9 years. In a subsample, blood samples were collected for the measurement of Hb, transferrin receptor, vitamin A and vitamin D concentrations. The prevalence of stunting and underweight was higher in rural children than in urban children, whereas the wasting rate was similar in both rural and urban areas. Among children aged 3·0–5·9 years, the prevalence of overweight was significantly higher in urban areas than in rural areas and so was the obesity rate in children aged 6·0–12·9 years. Protein intakes of all age groups were relatively high in both the areas. Intakes of Ca, Fe, Zn and vitamin C were significantly higher in urban areas than in rural areas. The prevalence of anaemia in rural areas was twice as high as that in urban areas, particularly in infants and young children. However, the prevalence of Fe-deficiency anaemia was similar in both urban and rural areas. While the prevalence of vitamin A deficiency (by serum retinol cut-off < 0·7 μmol/l) seemed to be very low, vitamin A insufficiency (by serum retinol cut-off < 1·05 μmol/l) was more prevalent (29·4–31·7 %) in both the areas. The prevalence of vitamin D insufficiency ranged between 27·7 and 45·6 % among the children. The present study indicates that the double burden of malnutrition is still a major public health problem in Thailand. Further studies need to explore the associated risk factors for these nutrient deficiencies. Effective strategies and actions are needed to tackle the nutritional problems in Thai children.

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Cassava with enhanced β-carotene maintains adequate vitamin A status in Mongolian gerbils (Meriones unguiculatus) despite substantial cis-isomer content

British Journal Of Nutrition ◽

10.1017/s0007114508184720 ◽

2009 ◽

Vol 102 (3) ◽

pp. 342-349 ◽

Cited By ~ 25

Author(s):

Julie A. Howe ◽

Bussie Maziya-Dixon ◽

Sherry A. Tanumihardjo

Keyword(s):

Vitamin A ◽

Vitamin A Deficiency ◽

Meriones Unguiculatus ◽

Provitamin A ◽

Carotenoid Content ◽

Mongolian Gerbils ◽

Serum Retinol ◽

Vitamin A Status ◽

Isomer Content ◽

Β Carotene

Efforts to increase β-carotene in cassava have been successful, but the ability of high-β-carotene cassava to prevent vitamin A deficiency has not been determined. Two studies investigated the bioefficacy of provitamin A in cassava and compared the effects of carotenoid content and variety on vitamin A status in vitamin A-depleted Mongolian gerbils (Meriones unguiculatus). Gerbils were fed a vitamin A-free diet 4 weeks prior to treatment. In Expt 1, treatments (ten gerbils per group) included 45 % high-β-carotene cassava, β-carotene and vitamin A supplements (intake matched to high-β-carotene cassava group), and oil control. In Expt 2, gerbils were fed cassava feeds with 1·8 or 4·3 nmol provitamin A/g prepared with two varieties. Gerbils were killed after 4 weeks. For Expt 1, liver vitamin A was higher (P < 0·05) in the vitamin A (1·45 (sd 0·23) μmol/liver), lower in the control (0·43 (sd 0·10) μmol/liver), but did not differ from the β-carotene group (0·77 (sd 0·12) μmol/liver) when compared with the high-β-carotene cassava group (0·69 (sd 0·20) μmol/liver). The bioconversion factor was 3·7 μg β-carotene to 1 μg retinol (2 mol:1 mol), despite 48 % cis-β-carotene [(Z)-β-carotene] composition in cassava. In Expt 2, cassava feed with 4·3 nmol provitamin A/g maintained vitamin A status. No effect of cassava variety was observed. Serum retinol concentrations did not differ. β-Carotene was detected in livers of gerbils receiving cassava and supplements, but the cis-to-trans ratio in liver differed from intake. Biofortified cassava adequately maintained vitamin A status and was as efficacious as β-carotene supplementation in the gerbil model.

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Vitamin A deficiency - experience from a tertiary referral UK hospital; not just a low- and middle-income country issue

Public Health Nutrition ◽

10.1017/s1368980021003347 ◽

2021 ◽

pp. 1-15

Author(s):

Alexandra Marley ◽

Samuel CL Smith ◽

Ruhina Ahmed ◽

Peter Nightingale ◽

Sheldon C Cooper

Keyword(s):

Vitamin A ◽

Vitamin A Deficiency ◽

Binary Logistic Regression ◽

Signs And Symptoms ◽

University Teaching ◽

Serum Retinol ◽

Middle Income ◽

Reactive Protein ◽

Active Inflammation ◽

Low And Middle Income

Abstract Objective: Vitamin A (VA) deficiency, more common in low- and middle-income countries (LMIC) secondary to malnutrition, is associated with increased morbidity and mortality. The prevalence and impact of VA deficiency in high-income countries (HIC) where chronic conditions may predispose is less well understood. Setting: We examined the scale of low and deficient VA status in our tertiary University Teaching Hospital (HIC). Participants: Patients undergoing serum retinol concentrations 2012-2016 were identified from laboratory records, and records examined. Design: Interpretation of serum retinol may be affected by inflammation, so C-reactive protein (CRP) levels were sought. Binary logistic regression and generalised estimating equations were performed to review the relationship between CRP and VA. Results: 628 assays were requested, with 82 patients VA low (0.7-0.99umol/L) or deficient (<0.7umol/L). 16 patients were symptomatic (15 deficient), predominantly visual. Only one symptomatic patient’s VA deficiency was secondary to poor intake. Other symptomatic patients had chronic illnesses resulting in malabsorption. The incidence of a low VA level increases significantly with a raised CRP. Conclusion: The majority of patients tested either were replete or likely to have abnormal VA levels due to concomitant inflammation. A minority of patients had signs and symptoms of VA deficiency and was a cause of significant morbidity, but aetiology differs from LMIC, overwhelmingly malabsorption, most commonly secondary to surgery or hepatobiliary disease. A correlation between inflammation and low VA levels exists, which raises the possibility that requesting a VA level in an asymptomatic patient with active inflammation may be of questionable benefit.

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A new approach to the assessment of marginal vitamin A deficiency in children in suburban Guwahati, India: hydrolysis of retinoyl glucuronide to retinoic acid

British Journal Of Nutrition ◽

10.1017/s0007114508047739 ◽

2008 ◽

Vol 101 (6) ◽

pp. 794-797 ◽

Cited By ~ 3

Author(s):

Pulin C. Sarma ◽

Bhabesh C. Goswami ◽

Krishna Gogoi ◽

Harsha Bhattacharjee ◽

Arun B. Barua

Keyword(s):

Retinoic Acid ◽

Vitamin A ◽

Vitamin A Deficiency ◽

Serum Retinol ◽

Serum Samples ◽

Group I ◽

High Prevalence ◽

Hydrolysis Of ◽

Β Carotene

The objective of the present study was to determine marginal vitamin A deficiency (VAD) by testing the hydrolysis of retinoyl glucuronide (RAG) to retinoic acid (RA) in children. Previous studies in rats showed that hydrolysis occurred when rats were vitamin A deficient. Children (n 61) aged 3–18 years, were divided into two groups, I and II. Blood was collected from the children in Group I (n 19) who were not dosed with RAG. Children in Group II (n 42) were administered all-trans retinoyl glucuronide (RAG) orally, and blood was collected 4 h after the dose. All serum samples were analysed for retinoids and carotenoids. RA was detected in serum only when serum retinol was < 0·85 μmol/l. Thus, hydrolysis of RAG to RA occurred in children with VAD or marginal VAD. Serum retinol was < 0·35 μmol/l in twenty-one children, 0·35–0·7 μmol/l in twenty-three children, 0·7–0·9 μmol/l in eleven children and >1 μmol/l in six children. Mean serum retinol in sixty-one children was 0·522 (sd 0·315) μmol/l. Mean β-carotene (0·016 (sd 0·015) μmol/l) was far below normal compared to the level of lutein (0·176 (sd 0·10) μmol/l) in sixty-one children. A low β-carotene level might be due to a low intake of carotene but high demand for vitamin A. The RAG hydrolysis test may prove to be a useful approach for the determination of marginal VAD with no clinical or subclinical signs of VAD. High prevalence of VAD amongst certain communities in Assam cannot be ruled out.

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Use of the retinol-binding protein : transthyretin ratio for assessment of vitamin A status during the acute-phase response

British Journal Of Nutrition ◽

10.1017/s0007114500000659 ◽

2000 ◽

Vol 83 (5) ◽

pp. 513-520 ◽

Cited By ~ 21

Author(s):

Suzanne M. Filteau ◽

Juana F. Willumsen ◽

Keith Sullivan ◽

Karin Simmank ◽

Mary Gamble

Keyword(s):

Vitamin A ◽

Sensitivity And Specificity ◽

Assessment Tool ◽

Binding Protein ◽

Vitamin A Deficiency ◽

Retinol Binding Protein ◽

Serum Retinol ◽

Vitamin A Status ◽

Plasma Retinol

The ratio plasma retinol-binding protein (RBP) : transthyretin (TTR) has been proposed as a means to improve the assessment of vitamin A status of individuals with concurrent infection or inflammation. We have measured RBP and TTR in stored sera from South African children who had accidentally ingested kerosene. Samples were collected from these children in hospital when suffering acute inflammation and respiratory distress, and from them and neighbourhood control children 3 months later. Vitamin A status was defined by modified relative dose response (MRDR) tests of liver retinol stores at 3 months and by serum retinol concentration both when children were ill and when they were well. Illness was defined as either being in hospital or, at follow-up, as having a raised plasma α1-acid glycoprotein (AGP) level. The RBP : TTR value was significantly decreased by both illness and low liver retinol stores. When the effects on RBP : TTR of illness and vitamin A stores were considered together for the 3-month follow-up samples, only vitamin A status significantly decreased the value. We calculated sensitivity and specificity of the RBP : TTR ratio against established measures of vitamin A status using a cut-off value of 0·3 for RBP : TTR and standard cut-off values for MRDR (0·06) and plasma retinol (0·7 μmol/l). Compared with MRDR, RBP : TTR had sensitivities of 76 % and 43 % and specificities of 22 % and 81 % to detect vitamin A deficiency in hospitalized and well children respectively. Compared with plasma retinol, sensitivities were 88 % and 44 % and specificities were 55 % and 64 % in hospitalized and well children respectively. Only for the case of clinically well children with biochemical evidence of subclinical inflammation did sensitivity (62 % and 100 % against MRDR and plasma retinol respectively) and specificity (100 % and 60 % against MRDR and retinol) approach useful levels for an assessment tool. Overall, although a trend supporting the theory behind the use of the RBP : TTR for assessment of vitamin A status in infection was observed in the current study, the ratio did not provide adequate sensitivity and specificity to be a useful assessment tool.

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Vitamin A deficiency among children younger than 5 y in India: an analysis of national data sets to reflect on the need for vitamin A supplementation

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa314 ◽

2020 ◽

Author(s):

G Bhanuprakash Reddy ◽

Raghu Pullakhandam ◽

Santu Ghosh ◽

Naveen K Boiroju ◽

Shalini Tattari ◽

...

Keyword(s):

Vitamin A ◽

Vitamin A Deficiency ◽

Public Health Problem ◽

Sample Survey ◽

Dietary Vitamin ◽

High Dose ◽

Serum Retinol ◽

Indian Children ◽

Vitamin A Supplementation ◽

National Prevalence

ABSTRACT Background Biochemical vitamin A deficiency (VAD) is believed to be a serious public health problem (low serum retinol prevalence >20%) in Indian children, justifying universal high-dose vitamin A supplementation (VAS). Objective To evaluate in Indian children younger than 5 y the risk of biochemical VAD from the Comprehensive National Nutrition Survey, as well as dietary vitamin A inadequacy and excess over the tolerable upper limit of intake (TUL) from national and subnational surveys, factoring in fortification and VAS. Methods Child serum retinol data, corrected for inflammation, were examined to evaluate national- and state-level prevalence of VAD. Simultaneously, dietary intakes from the National Sample Survey Office and the National Nutrition Monitoring Bureau were examined for risk of dietary vitamin A deficiency against its average requirement (AR) derived for Indian children. Theoretical estimates of risk reduction with oil and milk vitamin A fortification were evaluated along with the risk of exceeding the TUL, as well as when combined with intake from VAS. Results The national prevalence of biochemical VAD measured in 9563 children was 15.7% (95% CI: 15.2%, 16.3%), and only 3 states had prevalence significantly >20%. The AR of vitamin A was 198 and 191 µg/d for boys and girls; the risk of dietary inadequacy was ∼70%, which reduced to 25% with oil and milk fortification. Then, the risk of exceeding the TUL was 2% and 1% in 1- to 3-y-old and 4- to 5-y-old children, respectively, but when the VAS dose was added to this intake in a cumulative 6-mo framework, the risk of exceeding the TUL rose to 30% and 8%, respectively. Conclusion The national prevalence of VAD risk is below 20% in Indian children. Because there is risk of excess intake with food fortification and VAS, serious consideration should be given to a targeted approach in place of the universal VAS program in India.

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

Experimental Biology and Medicine ◽

10.1177/1535370219838785 ◽

2019 ◽

Vol 244 (7) ◽

pp. 579-587 ◽

Cited By ~ 3

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.

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