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Articles

Can Lack of Improvement in Vitamin A Status Indicators Be Explained by Little or No Overall Change in Vitamin A Status of Humans?¹

Department of Nutritional Sciences, University of Wisconsin at Madison, Madison, WI 53706

²To whom correspondence should be addressed. E-mail: sherry{at}nutrisci.wisc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION Application of the model SUMMARY LITERATURE CITED

 
Changes in vitamin A status using conventional indicators, i.e., serum and breast milk retinol concentrations and the modified relative dose response test, following a vitamin A intervention have not always been shown. A simplified model to predict calculated changes in vitamin A status after intervention is described. The model shows that changes in indicator values cannot be expected if the change in vitamin A status is only marginal. A critical review of several papers using vitamin A status assessment indicators was undertaken. Assumptions that included current knowledge concerning vitamin A absorption and metabolism were made and applied to the data. Based on current recommended daily allowances for women and children, one cannot necessarily expect a change in indicators if an overall change in vitamin A status was not achieved. Thus, when designing vitamin A intervention studies, the following parameters should be considered if applicable to the population to be enrolled in the study: average body weight, estimated liver weight, amount of vitamin A administered, estimated loss in breast milk and study duration.

KEY WORDS: • vitamin A • retinol • serum retinol • breast milk retinol • modified relative dose response.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Application of the model SUMMARY LITERATURE CITED

 
Vitamin A status assessment has become more than simply measuring changes in serum retinol concentrations (1 ). As indicators become more sensitive, looking at issues that affect the biological power of a vitamin A intervention are of utmost importance during study design. Using current assessment methods available, some studies have determined "no effect" after intervention with vitamin A, ß-carotene or vegetables. Key issues to consider when designing an intervention study include the following: average body weight (BW)³, estimated liver weight (LW), amount of vitamin A administered, estimated loss in breast milk (if applicable) and study duration.

The objectives of this article are to evaluate several vitamin A intervention trials and to describe a simplified model to predict changes in the average subject enrolled in a study. The authors of two recent studies (2 ,3 ) in women did extensive analyses to determine which vitamin A assessment method outperformed the other. These methods included serum retinol concentrations, breast milk concentrations and the modified relative dose response (MRDR) test. Are these types of analyses legitimate if the improvement in vitamin A status may be marginal because of the doses of vitamin A used in the intervention or the timing between assessments?

	Application of the model

TOP ABSTRACT INTRODUCTION Application of the model SUMMARY LITERATURE CITED

 
Using data from these studies in women (2 ,3 ), the model considers the following: average body weight (BW) of 50 kg, estimated liver weight (LW) of 2.4 g/100 g BW, i.e., 1200 g; total amount of vitamin A administered during the trial [1 retinol equivalent (RE) = 1 µg retinol = 12 µg ß-carotene (4 )]; mean daily breast milk output of 0.7 L containing on average 300–400 µg retinol/L (anticipated group means); and time interval between data collection (Fig. 1 ). Vitamin A absorption and utilization rates are based on current knowledge (5 ).

View larger version (21K): [in this window] [in a new window]   Figure 1. A schematic illustration outlining the factors that should be considered when predicting changes in vitamin A status in response to an intervention study.

• Total amount of vitamin A given = 3.5 mg ß-carotene/d x 84 d x 1 µg retinol/12 µg ß-carotene = 24,500 µg retinol
  
• Estimated loss in breast milk = 0.7 L/d x 300 µg/L x 84 d = 17,640 µg [300 µg retinol/L (1.05 µmol/L) was the approximate published mean in these women]
  
• Amount of vitamin A left for non–breast milk needs = 24,500 - 17,640 = 6860 µg
  
• Thus, if 50% of the "extra" vitamin A is stored, a net increase of 3430 µg is apparent giving 3430 µg/1200 g liver = +2.9 µg/g liver vitamin A (0.01 µmol/g liver).
  

The average woman in this study, based on this model, had a marginal improvement in vitamin A status during the intervention. This subtle change in vitamin A status, i.e., +2.9 µg/g liver vitamin A, is unlikely to be detected by most assay methods.

In the studies by Rice et al. (3 ,7 ), a 200,000 IU (60,000 µg) vitamin A capsule was given 2 wk postpartum to Bangladeshi women who were also assumed to weigh 50 kg. Vitamin A status was assessed at baseline and 2.5 mo later. The storage efficiency of this large dose is 40%. Haskell et al. (5 ) reported a storage efficiency of 30–42% for smaller isotopically labeled doses that was dependent upon initial vitamin A status. Thus:

• The total amount of vitamin A administered during the trial = 60,000 µg x 0.4 = 24,000 µg absorbed and stored
  
• Estimated losses in breast milk over 2.5 mo = 0.7 L x 400 µg/L x 77 d = 21,560 µg [400 µg retinol/L (1.4 µmol/L) was the approximate published mean in these women]
  
• Amount of vitamin A left in storage = 24,000 - 21,560 = 2440 µg
  
• Increased liver stores = 2440 µg/1200 g liver = +2 µg/g liver vitamin A (0.007 µmol/g liver)
  
• Thus, most of the dose administered postpartum was secreted into the breast milk by 2.5 mo.
  

Both the de Pee and Rice articles cite a study by Tanumihardjo et al. (8 ) in lactating Indonesian women in whom 8000 IU (2400 µg) of vitamin A was given for 35 d. Applying the same model to predict change in vitamin A status, the following is calculated:

• µg x 35 d = 84,000 µg administered
  
• If 50% of these small daily doses was stored in the liver, a net increase of 42,000 µg occurred during the intervention
  
• Estimated losses in breast milk during the intervention time = 0.7 L x 300 µg/L x 35 d = 7,350 µg [using the breast milk mean retinol of the de Pee et al. study in Indonesian women (2 ,6 )]
  
• Amount of vitamin A left in storage after deduction for breast milk loss = 42,000 - 7,350 = 34,650 µg
  
• Liver store increase = 34,650 µg/1200 g = +29 µg/g liver (0.1 µmol/g liver)
  
• Thus, using this simplified predictive model, the Tanumihardjo et al. study would have had an 10-fold higher liver storage amount than the other two interventions.
  

This model can also be applied to interventions in children (Fig. 1) . For example, using the study of Tanumihardjo et al. (9 ), who administered 200,000 IU (60,000 µg) of vitamin A to children weighing 12.5 kg with LW being 4 g/100 g BW, i.e., 500 g, the following is calculated:

• Total amount of vitamin A administered: 60,000 µg, administered by "snip and dispense capsule" of which 75% of the dose, i.e., 60,000 µg x 0.75 = 45,000 µg, is delivered
  
• Estimated 40% of large dose is stored: 45,000 µg x 0.40 = 18,000 µg stored. Thus, the immediate increase in liver reserve was 18,000 µg vitamin A/500 g = + 36 µg/g liver (0.13 µmol/g)
  
• The second MRDR test was performed 21–28 d after the large dose of vitamin A was given. Thus, using a daily recommended intake of 400 µg/d for children 4–8 y old (4 ), which overestimates average needs, the amount of retinol needed for adequate status during that time was 21–28 d x 400 µg = 8400–11,000 µg, leaving +14–20 µg/g liver (0.05–0.07 µmol/g).
  
• Therefore, an MRDR test performed 21–28 d after the dose would still detect appreciable liver reserves. Had the MRDR test been performed 2 mo later, however, without other supplementation or good dietary intake, the MRDR test may have been positive again, i.e., a dehydroretinol to retinol value of 0.060, in many of the children.
  

	SUMMARY

TOP ABSTRACT INTRODUCTION Application of the model SUMMARY LITERATURE CITED

 
In designing an intervention study, looking at the predicted change in vitamin A status based on the above arguments will help to estimate whether the intervention will be successful in actually improving vitamin A status as measured by vitamin A liver reserves. If the vitamin A status of the group does not appreciably increase, changing the method of vitamin A assessment will not make a difference. Clearly the model has limitations because it does not, for example, include losses due to infection (10 ). Nevertheless, it can be used as a tool to help design a study, to estimate if vitamin A status will be improved and to predict if indicators of vitamin A status will be effective in assessing a change in overall status.

	ACKNOWLEDGMENTS

	FOOTNOTES

 
¹ Funded in part by Hatch-Wisconsin Agricultural Experiment Station (grant no. WIS0438). Presented in part as a poster at the XX International Vitamin A Consultative Group meeting, Hanoi, Vietnam.

³ Abbreviations used: BW, body weight; LW, liver weight; MRDR, modified relative dose response; RE, retinol equivalents.

Manuscript received July 18, 2001.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION Application of the model SUMMARY LITERATURE CITED

 

1. Tanumihardjo, S.A. (2002) Assessing vitamin A status: past, present and future. J. Nutr. in press.

2. de Pee, S., Yuniar, Y. & West, C. E., Muhilal (1997) Evaluation of biochemical indicators of vitamin A status in breast-feeding and non-breast-feeding Indonesian women. Am. J. Clin. Nutr. 66:160-167.[Abstract/Free Full Text]

3. Rice, A. L., Stoltzfus, R. J., de Francisco, A. & Kjolhede, C. L. (2000) Evaluation of serum retinol, the modified-relative-dose-response-ratio, and breast-milk vitamin A as indicators of response to postpartum maternal vitamin A supplementation. Am. J. Clin. Nutr. 71:799-806.[Abstract/Free Full Text]

4. Vitamin, A (2001) Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 2001:65-126 National Academy Press Washington, DC. .

5. Haskell, M. J., Handelman, G. J., Peerson, J. M., Jones, A. D., Rabbi, M. A., Awal, M. A., Wahed, M. A., Mahalanabis, D. & Brown, K. H. (1997) Assessment of vitamin A status by the deuterated-retinol-dilution technique and comparison with hepatic vitamin A concentration in Bangladeshi surgical patients. Am. J. Clin. Nutr. 66:67-74.[Abstract/Free Full Text]

6. de Pee, S., West, C. E., Muhilal, , Karyadi, D. & Hautvast, J. G. (1995) Lack of improvement in vitamin A status with increased consumption of dark-green leafy vegetables. Lancet 346:75-81.[Medline]

7. Rice, A. L., Stoltzfus, R. J., de Francisco, A., Chakraborty, J., Kjolhede, C. L. & Wahed, M. A. (1999) Maternal vitamin A or beta-carotene supplementation in lactating Banglasdeshi women benefits mothers and infants but does not prevent subclinical deficiency. J. Nutr. 129:356-365.[Abstract/Free Full Text]

8. Tanumihardjo, S. A., Muherdiyantiningsih, , Permaesih, D., Komala, , Muhilal, , Karyadi, D. & Olson, J. A. (1996) Daily supplements of vitamin A (8.4 µmol, 8000 IU) improve the vitamin A status of lactating Indonesian women. Am. J. Clin. Nutr. 63:32-35.[Abstract/Free Full Text]

9. Tanumihardjo, S. A., Permaesih, D., Muherdiyantiningsih, , Rustan, E., Rusmil, K., Fatah, A. C., Wilbur, S., Muhilal, , Karyadi, D. & Olson, J. A. (1996) Vitamin A status of Indonesian children infected with Ascaris lumbricoides after dosing with vitamin A supplements and albendazole. J. Nutr. 126:451-457.

10. Stephensen, C. B., Alvarez, J. O., Kohatsu, J., Hardmeier, R., Kennedy, J. I., Jr & and Gammon, R. B., Jr (1994) Vitamin A is excreted in the urine during acute infection. Am. J. Clin. Nutr. 60:388-392.[Abstract/Free Full Text]

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