Vitamin A_term paper

Ashish Pokharel Discussion on Vitamin A

Vitamin A: Introduction, Role in Public Health, and High Dose

Supplementation as an Intervention Strategy

I. Introduction to Vitamin A

Forms and Functions

Vitamin A is a fat soluble vitamin required for various metabolic activities such as proper

functioning of visual system, cell reproduction and differentiation, proper immune function,

proper functioning of epithelial tissues, and normal growth and development of the body (FAO,

2001 and Sherwin et. al., 2012) .Vitamin A is considered an essential micronutrient which is

required for the aforementioned metabolic activities in the body. Vitamin A is not a single

compound, rather it is a group of similar compounds which can be processed into the active

retinol form within the body. This includes compounds such as retinal, retinoic acid, and retinyl

esters. Likewise, carotenoids which act as precursors of retinol are also classified as vitamin A.

Carotenoids such as Beta-carotene, lycopene, and Beta-cryptoxanthin are a few compounds

which act as a precursor to retinol. The bioavailability of retinoid form is much higher than

carotenoids form.

Vitamin A has a crucial role in visual system in the body. The necessity of vitamin A for the

proper functioning of the visual system was recognized by researchers from earlier studies. In the

rod cells of the retina in the eye, vitamin A is required for the functioning of rhodopsin which

helps us to see in the dark. Thus, deficiency of vitamin A leads to night blindness, the first form

of Xeropthalmia. With further depletion of vitamin A in the body, Xeropthalmia chronologically

proceeds to more progressive forms like Bitot’s spot, corneal xerosis, reversible keratomalacia,

non-reversible keratomalacia, and corneal scar. (Sherwin et. al., 2012) Xeropthalmia is often


associated with poor nutrition and diseases like diarrhea, measles, and respiratory infection.

(Sherwin et. al., 2012)

Another crucial role of vitamin A is in cellular differentiation and reproduction of the epithelial

tissues in the body. Various epithelial tissues in skin, gastrointestinal, respiratory and urogenital

tracts require vitamin A for differentiation and reproduction. Furthermore, vitamin A is thought

to be required in bone growth and reproductive processes. As a result, vitamin A is very

important for the growth and development of the body, especially among children. Finally, the

role of vitamin A in immune system function is also very important. Studies suggest the vitamin

A is involved in phagocytic activity, T-lymphocyte function, and antibody response to bacterial,

viral, and parasitic infections. (Ross A, 1992) Undoubtedly, these functions of vitamin A have

played major roles public health and nutrition policies as governments and stakeholders see

vitamin A interventions as a strategy to reduce blindness, infection, and mortality among

children under 5 years of age.

Food Sources of vitamin A

Normally vitamin A is obtained in the body through intake of foods which are either a source of

retinoid form or a carotenoid form of vitamin A. Retinoid form of vitamin A comes from animal

source food such as beef, liver, red meats, eggs, milk, butter, cheese, fish etc. (Sherwin et. al.,

2012) Similarly, carotenoid form comes from plant source food such as dark green leafy

vegetables ( e.g. spinach, kale) and deep orange/yellow/red foods ( e.g. mangoes, sweet potatoes,

squash, carrots, papayas, pumpkins). (Sherwin et. al., 2012)


Absorption and Storage in the body

Regardless of form of intake, the digestion, absorption, and transport of vitamin A requires

adequate amount of fat in the diet. In the stomach and the intestine, the vitamin A compounds

bound to proteins are released with the help of enzymes. These vitamin A compounds combine

with fats into globular form which is absorbed and transported through the intestinal wall as

micelle. The vitamin A is then transported to other cells using chylomicron, a lipoprotein

structure that also carries fat in the body. The extra vitamin A obtained thorough diet is stored as

retinoid form in the stellate cells of the liver for future uses. This helps to keep the blood retinol

level in the fairly constant. The liver can store a lot of extra vitamin A for future use and toxicity

occurs only in very high doses when the liver cells are vitamin A replenished to its full capacity.

These characteristics of vitamin A are important as it forms the basis for the high dose

supplementation strategy, which is discussed in the following sections of this paper.

II. Vitamin A in Public Heath

Prevalence of Vitamin A deficiency (VAD)

Globally, VAD is a major nutrition and public health problem among vulnerable population

groups such as infants, children, and pregnant women because they have increased requirements

due to rapid growth and development in the body. Vitamin A is of significant public health

concern because VAD manifests into poor growth and symptoms of Xeropthalmia, and also due

to its role in preventing infection and mortality among children. Although adults and elders may

also suffer from VAD, children under 5, pregnant and lactating women are recognized as the

most at-risk population group for VAD. Lancet Series 2008 defines VAD as having symptoms of

Xeropthalmia or blood serum retinol of <0.7micromol/L. (Black et. al, 2008) Severe deficiency


is defined as having <0.35 micromol/L blood serum retinol. Lancet 2008 shows that the

prevalence of VAD among children under 5 is high mainly in countries of Africa, South Asia,

and sub national population in Brazil and China. Among pregnant women, the global prevalence

of night blindness among is 7.8%, which accounts to 9.7 million pregnant women. Similarly,

15.3% of pregnant women (i.e. 19.1 million) are estimated to have low serum retinol levels. Data

for children (aged 6-59 months) states that about 2-3% i.e. about 157,000 child deaths are

attributable to VAD. Similarly, the prevalence of VAD among preschool children is estimated to

be around 33% or 90 million children globally. (Black et. al., 2013)The prevalence of night

blindness among preschool children is estimated to be about 0.9% or 5.17 million children

globally.

Given the prevalence and the risk among vulnerable population, the prevention and treatment of

VAD deficiency has been a public health priority for many countries especially in the last few

decades. The increased focus is also because optimal levels of vitamin A has been shown to

reduce mortality among children (especially via reduction in measles and diarrhea related

mortality). Likewise, studies have found that poor health and infection are increased among

children with depleted vitamin A stores. This public health significance is backed by many

clinical studies that have established the critical role of vitamin A in proper functioning of

mucosal surfaces and immune function. In addition, vitamin A metabolites interact with the

genome to control the sequence of expression in various genes. In summary, it can be said that

these findings has led to vitamin A status among infants, children, and pregnant and lactating

women being top national public health and nutritional priorities for many governments

throughout the world.


Causes for Vitamin A deficiency

There are various dietary, socio-economic, environmental, and biological causes that leads to

vitamin A deficiency. Dietary causes include diets low in vitamin A rich foods such as meat,

liver, beef, eggs, dark leafy vegetables, and orange and red colored fruits. Similarly, poor diets of

pregnant and lactating women leads to depleted stores in women and consequently leads to

vitamin A deficiency in infants and neonates. Also, inadequate intake of fats may cause vitamin

A deficiency as it is a fat soluble vitamin. Other poor infant and young child feeding (IYCF)

practices such as sub-optimal breastfeeding and complementary feeding practices can also cause

vitamin A deficiency. Social causes like poverty, limited income, and marginalized groups are

also contributing cause for VAD as poor households. Lower socio-economic households have

limited access (financial and/or market access) to vitamin A rich foods like meat, liver, eggs,

green leafy vegetables, and orange or red fruits. Environmental factors such as repeated

infections due to unhygienic living environment may also lead to VAD by increasing

requirements, metabolism, and excretion. (Stephenson, 1994) Finally, there can be biological and

physiological causes for vitamin A deficiency such as decreased bioavailability due to liver or

pancreatic problems, fat malabsorption, and competition with vitamin D for absorption.

As a result of multi-faceted causes for vitamin A deficiency, various types of interventions can

be used for improving vitamin A status among vulnerable population. High dose vitamin A

supplementation, food fortification, improvement of IYCF practices, provision of

complementary foods, improvements of perinatal health services, and school feeding programs

are some examples of intervention for addressing VAD. Moreover, there are cross-sectoral

interventions which aim to tackle the underlying causes for poor nutrition and health.


Improvement in quality and quantity of agricultural products, social safety net programs,

improvement of market access are some interventions that aim to address a broader set of

underlying causes for poor health and nutrition. This paper focuses on high dose vitamin A

supplementation as an intervention strategy.

III. Discussion on High Dose Vitamin A Supplementation

Evidence for Supplementation

It was already established from clinical trials that vitamin A plays a major role in correcting the

symptoms of Xeropthalmia such as night blindness, corneal damage, and blindness. From a

public health point of view, the interest in vitamin A supplementation as a major intervention

strategy for reducing mortality started with a large study among more than 25000 children from

450 villages in Sumatra. (Sommer et al, 1986). The study found that child mortality in children

without the vitamin A supplementation (control villages) was 49% higher than mortality in

children with vitamin A supplementation. In summary, the study predicted that vitamin A

supplementation can reduce mortality by 34%. The results of this large research prompted a

series of studies that aimed to examine the effects of high dose vitamin A supplementation on

mortality. There were vitamin A supplementation studies conducted in various developing

countries with high burden of vitamin A deficiency. The results of 10 such experimental studies

was analyzed in a UN policy brief in 1992 and it concluded that vitamin A supplementation can

reduce mortality among children by about 23% ( Relative risk ratio= 0.77, 95% CI 0.68 - 0.88

random effects model). These studies were from high burden countries like India, Nepal, Sudan,

Ghana, and Indonesia. (United Nations, 1992) The results of the analysis is shown in Appendix

A. The same policy brief also examined the role of vitamin A on morbidity. It concluded that


although effects of vitamin A supplementation on morbidity could not be teased out, there

seemed to be a clear benefit of good vitamin A status on fighting infection. Especially the

severity of morbidity and mortality due to measles and diarrhea was reduced by vitamin A.

Following these findings, the public health and nutrition policy realm started to recommend high

dose supplementation as an intervention strategy in treating vitamin A deficiency. This is evident

in the World Health Organization (WHO) report in 1996 which stated that the objective of

supplementation strategy is to achieve high coverage of vitamin A doses for children in high

VAD endemic areas by a system that is administratively feasible, culturally acceptable, and

economically practical. (WHO, 1996)

Supplementation as a Prominent Intervention Strategy

The results from these vitamin A supplementation studies on treating night blindness and

reducing mortality was picked up by many governments with high burden of vitamin A

deficiency among children in their country. Many governments pursued high dose vitamin A

supplementation as an intervention strategy starting the late 1990s. An advantage of the

supplementation strategy was that it was a straightforward intervention strategy that could be

carried out by governments with limited resources and capacities. Supplementation strategy

which commonly included giving one high dose vitamin A capsule (200 000) IU to children (6-

59) months twice a year was manageable by most governments.

The popularity in supplementation strategy is evident in UNICEF vitamin A supplementation

2007 report which points out that out of 60 high impact supplementation countries most have an

under 5 vitamin A supplementation program and many countries also pursue a post-partum

supplementation program. (UNICEF, 2007) In comparison, other intervention strategies such as

food fortification is only carried out in a smaller number of the countries.


Usually, the dosage of vitamin A supplementation capsule is many times higher (about 400 times

higher) than the recommended daily requirement for children. However, the scientific rationale

behind this strategy is that since vitamin A is fat soluble and is stored in liver, the high dose

replenishes the vitamin A stores in children which can be later mobilized in the body during

deficits due to poor intake. (WHO, 2011) When the stores of vitamin A are replete in the body, it

usually takes months of deprivation of vitamin A rich diet to result in vitamin A deficiency in the

body. Hence, high dose vitamin A supplementation every 4-6 months helps to keep adequate

stores of vitamin A in the body. Despite the potential use of supplementation and the justification

by scientific knowledge, it is important to note that high dose vitamin A supplementation was

recommended as a temporary treatment and prevention measure for VAD in endemic areas and it

was not recommended as a long term solution or replacement of other food based vitamin A

interventions. (WHO, 1996)

Argument against Supplementation

In subsequent years, many researchers point out that despite of the limited evidence on the

effectiveness of high dose supplementation, many governments and stakeholders are using

supplementation as the major intervention strategy against VAD. One of the most influential

study for backing this argument is the DEVTA study in the Uttar Pradesh region of India. This 5

year study used a cluster-randomized study to measure the effects of vitamin A supplementation

and deworming in 1 million pre-school children in Uttar Pradesh. The final analyses by Awasthi

et. al. showed no statistically significant difference in the final mortality rate ratio of children (1-

6 years) between the vitamin A supplemented group and the control group. The mortality results

were not statistically significant even when disaggregated by gender, diseases, time period, and

presence or absence of deworming. For diarrheal mortality (responsible for 28% of all deaths)


the risk ratio was 0·94 (95% CI 0·83–1·06) and for measles mortality (6% of all deaths). Overall,

the study concluded moderate effect of vitamin A supplementation which is significantly less

than previous estimation. (Awasthi et.al., 2013) The results of the DEVTA study is shown in

Appendix B.

The results from DEVTA and other studies were used by academics to show the flaws in vitamin

A supplementation strategy. For instance, Mason et.al. point out that many of the studies used for

the establishing the initial 23% reduction of mortality finding was based on trials in late 1980s

and early 1990s with varied results and inconclusive findings. (Mason et. al., 2014) Furthermore,

Mason points out that only one vitamin A study after 1994 has shown significant effect on

mortality. Mason states that newer meta-analyses adding nine newer studies (which includes

DEVTA) with the original studies have estimated the effect of vitamin A supplementation at 11

% rather than the initial 23%. He adds that the patterns of disease have changed over the years

and many developing countries have reduced the prevalence of diseases like measles and

diarrhea. This might be the reason for seeing newer studies showing significantly lesser effect (or

no effect) of vitamin A supplementation on mortality. When the results of the newer studies are

combined with the older studies, the estimated effect of vitamin A is reduced from 23% to 11%.

Mason criticizes the policymakers for using high dose vitamin A supplementation strategy as a

cheap fix for VAD rather than focusing on diet based approaches. He points out that the rate of

decrease of VAD prevalence from 1990-2005 is just 0.3 percentage points per year clearly

outlining the ineffectiveness of the current supplementation strategy and the need for pursuing

other strategies.


IV. Recommendations

Need for change

Over the years the criticism against high dose vitamin A supplementation has grown. The recent

studies have failed to show substantive benefits of vitamin A supplementation on mortality and

health. The evidence for recommending high dose vitamin A supplementation was based on

studies that were conducted about 25-30 years ago. Critics point out that the nature of diseases

have changed over the years and fewer children die from diseases like measles and diarrhea.

Hence, the policy and programming response for correcting VAD has to change. More

worryingly, critics point out that the extensive use of this strategy is diverting resource from

other long term interventions such as improved dietary diversity and fortification of foods.

The risk of toxicity and side effects from mega dosing is another argument against high dose

supplementation. This is the reason why WHO strongly recommends no supplementation for

pregnant women, postpartum women, neonates, and infants from 1-5 months. Supplementation is

only strongly recommended for children aged 6-59 months. (Sherwin et al., 2012)

Alternative Interventions

Currently, single intervention or a combination of interventions such as food fortification,

consumption of vitamin A rich foods via diverse diets, improved breastfeeding, better

complementary feeding practices, and improved WASH practices are proposed as the

alternatives to high dose supplementation. Many agree that the primary focus for treatment of

VAD should be improved production and consumption of vitamin A rich foods like dark green

leafy vegetables and red/yellow fruits.(Kapil, 2009) Furthermore, increased production and

consumption of animal source foods such as eggs, liver, meat, and milk should also be the focus


for countering VAD. In his chapter “Vitamin A” Solomons provides evidence that consumption

of indigenous fish in Bangladesh and addition of milk or meat to school snacks in Kenya have

improved vitamin A intake. Similarly, in South Africa and Thailand home gardening

interventions promoting consumption of plant sources have also shown improvements in vitamin

A. (Solomons, 2012)

Fortification of commonly consumed food with low doses of vitamin A is another intervention

strategy that is widely used to treat VAD. Usually, large scale fortification involves selecting an

appropriate vehicle food that is consumed universally by the population group (regardless of

social status and income). (Solomons, 2012) Sugar and oil are the common vehicle for

fortification as they are widely consumed by all groups of people in most population. Bio

fortification is another type of fortification includes modifying the food source so that it has

more nutritional values. Golden rice and orange flesh sweet potatoes are some popular examples

of bio fortification. (Solomons, 2012)

Finally other cross cutting interventions aimed at improvement of health and nutrition are

recommended for reduction in VAD. Since pregnant and lactating women, neonates, infants and

children under 5 years are the most vulnerable group for vitamin A deficiency, cross cutting

interventions such as IYCF practices, better complementary foods, improvement in prenatal

health services, improved WASH practices, and behavior change are effective in improvement of

vitamin A status.


Conclusion

The academic literature suggests that the evidence against high dose vitamin A supplementation

is mounting. However, policymakers and stakeholders are sticking to high dose supplementation

strategy in many countries. It is important to gradually phase out vitamin A supplementation

programs with more sustainable and long term interventions. All parties agree that improvement

of diet via production and consumption of vitamin A rich foods is the best option. The next best

option suggested by the academic literature is the adequate intake of vitamin A via low dose

fortification of most commonly used foods. Along with these two interventions, constant focus

and development of cross cutting sectors such as health, education, and agriculture also provide

dividends in future.

In defense of high dose supplementation, many countries still have areas with high burden of

vitamin A deficiency. Mainly people with low SES status, limited market access, and education

have high prevalence of VAD. Currently, high dose supplementation might be the only feasible

and economic way to help these groups. Then, there is the question of capacity and

implementation. Governments from many high burden countries have programmatic structures,

resources, and personnel to carry out high dose supplementation twice a year. Many countries

have claimed this intervention to be highly successful. It will be difficult to abruptly eliminate

these programs and push for other interventions. Hence, high dose supplementation must be

phased out gradually by working with the stakeholders.


References

Awasthi, S., Peto, R., Read, S., Clark, S., Pande, V., Bundy, D., & DEVTA team, (2013). Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet Series, 381, 1469-1477.

Black, R. E., Allen, L. H., Bhutta, Z. A., Laura E Caulfield, deOnis, M., Ezzati, M., . . . Rivera, J.

(2008). Maternal and child undernutrition: global and regional exposures and health consequences. Lancet Series, 371, 243-260. doi:10.1016/S0140-6736(07)61690-0

Black, R. E., Victora, C. G., Walker, S. P., Bhutta, Z. A., Christian, P., deOnis, M. (2013). Maternal and child undernutrition and overweight in low-income and middle-income

countries. Lancet Series, 382, 427-451. FAO. Chapter 7. Vitamin A. Human Vitamin and Mineral requirements, 2001.

Kapil U. Invited commentary: Time to stop giving indiscriminate massive doses of synthetic vitamin A to Indian children. Public Health Nutrition 2009;12:285-86.

Mason J, Greiner T, Shrimpton R, Sanders D, Yukich J. Vitamin A policies need rethinking. International Journal of Epidemiology 2014:1-10.

Ross A. Vitamin A and protective immunity, Nutr Today. 1992;27: 18-26

Sherwin JC, Reacher MH, Dean WH, Ngondi J. Epidemiology of vitamin A deficiency and xerophthalmia in at-riskpopulations. Royal Society for Tropical Medicine and Hygiene 2012; 106:205-14.

Solomons NW. Vitamin A. In: John W. Erdman Jr IAMaSHZ, editor. Present Knowledge in

Nutrition: International Life Sciences Institute; 2012.

Sommer, A., Tarwotjo, I, Djunaedi, E., West, Jr., K. P., Loeden, A. A., Tilden, R., Mele, L., and the Aceh Study Group (1986). Impact of vitamin A supplementation on childhood mortality: a

randomised controlled community trial. Lancet 327: 1169−73. Stephensen CB, Alvarez JO, Kohatsu J, Hardmeier R, Kennedy Jr JI, Gammon Jr RB. Vitamin A

is excreted in the urine during acute infection. Am J Clin Nutr 1994;60:388–92.

UNICEF. Vitamin A Supplementation: A Decade of Progress. 2007.

United Nations. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries − Nutrition policy discussion paper No.

13 1992.

WHO. Guideline: Vitamin A supplementation in infants and children 6–59 months of age 2011.


WHO. Indicators for Assessing Vitamin A Deficiency And their Application in Monitoring and Evaluating Intervention Programmes. 1996.


Appendix A

Source: United Nations. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries − Nutrition policy discussion paper No. 13 1992.


Appendix B

Source: Awasthi, S., Peto, R., Read, S., Clark, S., Pande, V., Bundy, D., & DEVTA team, (2013).

Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India:

DEVTA, a cluster-randomised trial. Lancet Series, 381, 1469-1477

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Vitamin A_term paper