1. Vitamin A Physiology
1.1. Vitamin A and provitamin A
The term vitamin A should be used as the generic descriptor for retinoids exhibiting the qualitative
biological activity of retinol. The main molecular structure contains a cyclic part and a non-cyclic chain
with 5 double bonds in the all transposition. A functional group is found at the end of the non-cyclic
part which can be an alcohol (retinol), an aldehyde (reninaldehyde), a palmitate (retinolpalmitate), etc.
The term provitamin A carotenoid should be used as the generic descriptor for all carotenoids exhibiting
qualitatively the biological activity of beta-carotene.
In order to have some indicator of activity we now speak of retinol equivalents.
1mcg retinol equivalent = 1 mcg retinol
= 6 mcg beta carotene
= 12 mcg other carotenoids
1 IU (international unit) = 0.3 mcg retinol
1mcg retinol = 3.3 IU
1.2. Metabolism
Vitamin A is, after ingestion, absorbed in the gut in the chylomicron fraction and then transported via
the lymphatics, to the liver. The availability of fats in the intestine will influence the fraction of the
available vitamin that will be absorbed.
Once stored in the liver as retinolpalmitate it will be transported to the target organs bound to a protein,
the retinol binding protein (RBP). Zinc and an adequate intake of protein are required for normal
production of RBP.
1.3. Vitamin A activities
1. Function as Rhodopsin for night vision.
2. Role in the differentiation process of epithelial tissues.
3. Necessary for the normal ciliary function.
4. Role in the synthesis of glycoprotein.
5. Stabiliser of lysosomal membranes.
6. Function in the cell mediated immunity.
7. Reproduction.
As a result of this wide spectrum of activities, a deficit of vitamin A will have a diversified effect.
1. It causes night blindness.
2. It causes Xerophthalmia.
3. Increases the over all mortality. Some authors believe by as much as 16% even.
4. Increases morbidity. A higher frequency of Diarrhoea, ARI (acute respiratory tract infection)
and Otitis Media’s have been noted.
5. Is an attributing factor in the causality of stunting.
Chapter 7, page 2
2. Importance of the problem
1. Vitamin A deficiency is the most important cause of blindness in children in the world today.
More important than gonorrhoea, trachoma cataract or glaucoma.
2. It is an important factor in the cause of stunting which is more prevalent than malnutrition.
3. It is an important contributing factor in mortality which is still very high in the majority of the
third world countries. This can for a large extend be explained by the role vitamin A has in
maintaining the immunological response and the differentiation and maintenance of epithelial
surfaces, like the skin, bronchi, gut and genito-urinal tract, which are more prone to invasion by
bacteria in a vitamin deficiency states. These effects are present well before there are overt
clinical signs at the level of the eye.
4. The prevalence: At risk 190 M
Deficient 40 M increased morbidity, mortality
Clinical signs: 13 M 1/4 – 1/3 become blind every year.
3. Diagnosis of vitamin A deficiency
3.1 Definitions
Before going into further details it is necessary to revise some important definitions:
Although it literally means (xeros= dry ; Ophthalmos = eye) dryness of the eye and is used as
such by the ophthalmologists, it is used in a broader sense in the public health context of
vitamin A def. Here it means all lesions, internal and external, attributable to the deficit of vit
A: dryness of conjunctiva and cornea, bitot spots, Keratomalacia and night blindness.
Is a liquefaction necrosis of the cornea varying from small ulcerations to softening and rupture
of the cornea, with resulting loss of anterior chamber fluid and collapse of the eye.
In young children Keratomalacia can occur without preceding stages such as dryness of the
conjunctiva or bitot spots.
Is a dryness. The clinical dryness of the conjunctiva in vitamin A deficiency is rather a
squamous metaplasia and keratinization.
Bitot spots
Greyish – whitish spot, foamy aspect to be found on the conjunctiva. It can have different
forms, round, oval, small spots dispersed. The triangular form is the most frequent. The basis is
against the rim of the cornea “the limbus cornea” and the top points to the outside of the eye.
Can be uni- or bilateral. This lesion does not hurt.
The diagnosis can be made:
3.1. Clinically
3.2. By measuring hepatic reserves.
3.3. By measuring plasma levels of retinol.
3.4. Impression cytology
3.5. Vital staining
Chapter 7, page 3
3.2. Clinical picture
The natural course of the disease progresses from night blindness to dryness of the cornea, sometimes
with bitot spots, to Keratomalacia. Night blindness is not always perceived because it is a subjective
sign on the one hand and because it’s perception is very much influenced by the availability of electricity
on the other hand.
Night blindness
Is the inability to see in poor lighting conditions like those which prevail at the end of the day
when the evening is setting, and a longer adaptation of vision to the dark, like when one is
getting from a light to a darker environment. People will complain of stumbling over objects in
the house in the evening or that their children can’t find the parents anymore in the house in the
Quantifiable: dark adaptation test, Dutch ophthalmologist.
Difficult to evaluate objectively in children.
Conjunctival xerosis
Dry appearance of the cornea, looses it lustre. Some undulation can be seen.
Bitot spots
A triangular whitish, pearly coloured spot, which is usually found on the lateral side of the
conjunctiva. Has a foamy appearance. Note that the progression of the clinical picture does not
always pass through this stage.
Corneal dryness
The light reflex of the cornea looses its well-defined appearance and becomes mottled and hazy.
The cornea becomes less translucent and more opaque.
Small lesions like ulcerations can develop. The cornea looses its spherical appearance, softens
and bulges. Eventually it ruptures and the anterior chamber liquid runs out and the eye
Fundus examination
Small white spots can be found on the retina.
Moderate forms (loss of night vision, conjunctival dryness) will disappear after 2-4 days of treatment
without leaving any lesions or sequels.
3.3. Biochemical diagnosis
Hepatic reserves
Are only measured on an experimental and research basis. Are measured as a rapid dose
response (RDR). After administration of a small dose of retinol (1.800 IU) the plasma retinol
levels are measured again and compared with the retinol concentrations before the
Chapter 7, page 4
administration. If the concentration increases with more than 20 % we say that the reserves are
Plasma levels
The problem with measuring plasma retinol levels is that they only change after a prolonged
period of vitamin deficit, due to the buffering action of the liver. Their use is limited to research
evaluations of vitamin A deficiency and of very little practical use in real life situations.
Plasma retinol
>= 30 mcg/100 ml
30-20 mcg/100 ml
20- 10 mcg/100 ml
< 10 mcg/100 ml
mild deficiency
associated with night blindness, bitot spots
moderate deficiency
definitely low, severe deficiency
3.4 Impression cytology
A technique to detect the degree of metaplasia of the conjunctiva. The lack of differentiation
and the decrease or absence of goblet cells is looked for. Not a routine diagnostic test.
3.5. Vital staining
Detecting the degree of conjunctival metaplasia by putting dye (Lissamon green or Bengal rose)
on the conjunctiva. This method lacks specificity.
4. Vitamin A deficiency as a Public Health problem
Since vitamin A deficiency gives a multitude of signs and symptoms reflecting different degrees of
progress a classification has been proposed by the WHO. Minimum prevalence rates for the clinical
stages of Xerophthalmia and low plasma retinol levels have been published by the WHO to assist in
defining the public health significance of vitamin A in the community. (table 1)
Chapter 7, page 5
Table 1
Criteria for assessing the Public Health Significance of
Xerophthalmia and vitamin A deficiency, based on the prevalence
among children aged 6 months – 6 years.
Criterion Classification Minimum prevalence
Night blindness
Conjunctival dryness
Bitot spots
Corneal xerosis
Corneal ulceration/Keratomalacia < 1/3
Corneal ulceration/Keratomalacia >= 1/3
Serum retinol less than 10 mcg/100 ml
0.5 %
0.01 %
0.5 %
5.0 %
5. Causes of vitamin A deficiency
Both an insufficient input and an increased need can result in the deficiency.
5.1. Insufficient intake :
– animal sources of vit A: milk – butter – fish oils – liver – meat – egg yolk
– vegetables: green leaf vegetables – carrots
– fruits: mango – papaya
– oils : palm oil
Infections of the gut, malabsorption, worm infestations and particularly giardiasis decrease vitamin A
5.2. Increased needs
Infections can increase vitamin A demands dramatically. Some investigators even calculated the
increase during infections in the order of 3000 IU per day. Particularly children with measles are very
likely to develop a very fast progressing Keratomalacia.
3. PEM
There is a very strong association of vitamin A deficiency with malnutrition. Both are diseases of the
poorer layers of the population and of the deprived.
They will have an over all lower food intake but particularly of meats and milk products, sources rich in
vitamin A, and of oils and fats, which are necessary for the vitamin A absorption.
Chapter 7, page 6
These children will also have more frequent infections, increasing their demands and interfering with the
absorption at the level of the gut.
Once their serum protein levels decrease like in severe malnutrition the necessary enzymes for
absorption and transportation to the target organs will diminish, aggravating further the deficiency.
6. Recommended daily intakes
adult: 750 mcg
pregnancy: 750 mcg
Breastfeeding: 1200 mcg
< 1 yr: 300 mcg
1-4 yr: 250 mcg
4-6 yr: 300 mcg
7-9 yr: 400 mcg
10-12 yr: 575 mcg
13-15 yr: 725 mcg
7. Treatment
The presence of clinical signs of vitamin a deficiency should be considered and emergency. Large and
repeated doses are therefore given. Associated illnesses should always be treated.
Who should be treated?
– All children with signs of Xerophthalmia. The most urgent are those infants with corneal signs.
– All suspected cases
– In an endemic zone, all children with PEM and measles.
Children < 1 yr Children 1 yr and above and adults except pregnant women
100.000 IU immediately
100.000 IU after 24 hrs
100.000 IU after 14 days *
200.000 IU immediately
200.000 IU after 24 hrs
200.000 IU after 14 days
* the last dose is mainly to replenish liver stores
Below one year of below 8 kg the dose is half of what is found in the vitamin a high dosage capsules.
These contain 6 drops. Throw away tree drops and give the remainder.
Pregnant women
Should not receive large doses of vitamin A due to the possible teratogenic effect. Smaller
doses up to 10.000 IU per day are safe. A total dose of 200.000 IU should be aimed at.
Chapter 7, page 7
Lactating women
Should receive 200.000 IU in the first month postpartum. One month after delivery again
smaller doses up to 10.000 IU per day are preferred. This because one month after delivery
there is the possibility of renewed pregnancy.
8. Prophylaxis
“Appropriateness” is a basic premise for vitamin A intervention. Two conditions dictate whether a
program, designed to prevent vitamin A deficiency, is appropriate:
1. A substantial segment of the population is “at risk” of developing clinical or biochemical vitamin A
deficiency of sufficient severity to be considered of Public Health importance; and
2. The problem is serious enough to warrant the diversion of scarce resources toward a program to
control vitamin A deficiency versus other preventable diseases or community projects within the
Currently vitamin A prophylaxis is approached through one of the three major intervention strategies:
1. A change in diet directed toward achieving a continuous intake of vitamin A rich foods,
2. Fortification of an appropriate dietary vehicle with vitamin A,
3. Or administration of a single, large dose of vitamin A administered on a periodic basis.
8.1. Change in dietary intake
Different strategies have been applied to increase dietary intake:
* Promotion of breastfeeding. Children entirely breastfed, provided the mother has adequate
daily intakes of vitamin A, do not develop vitamin A deficiency in the first six months of life
and have a lower prevalence of mild and severe Xerophthalmia during early childhood.
* Nutritional education.
* Income generating programs
* Kitchen gardening programs.
* Larger scale agricultural programs.
8.2. Vitamin A fortification
Fortification of Mono-sodium Glutamate in the Philippines and of sugar in Guatemala have been highly
successful. The success of this type of program depends on the identification of a suitable vehicle, which
has to be consumed by all and particularly the population at risk, and in a continuous and constant
fashion. Fluctuations between people and in time should be as small as possible. The cost of the
program on a national scale is usually high enough to raise the question as to who is going to bear it ; the
government, the industry or the consumer. Disagreement over this last point have led to the
discontinuation of the fortification programs.
8.3. Distribution of large dose vitamin A capsules
Large doses of 200.000 IU are distributed at regular intervals, most frequently every six months. The
seasonal distributions, to protect children in the higher prevalence seasons, reduces cost while
maintaining the same impact.
Three delivery strategies are possible:
Chapter 7, page 8
a. The ‘medical’ or ‘therapeutic’ approach, which offers treatment to children who present to a health
facility with an illness episode. They will be given a dose of vitamin A according to a set of pre-set
criteria of high risk of developing vitamin A deficiency.
b. The ‘targeted’ distribution which covers groups within the larger general target population; e.g.,
residents of a high prevalence neighbourhood, those attending mother and child health clinics, etc.
c. The ‘universal’ distribution in which all pre-school children and not pregnant lactating mothers in a
prescribed region are dosed at prescribed intervals by single or multipurpose workers in the
The logistics, supervision, personnel demand and cost of this type of program are usually very high
compared with the money available for general health care in the country. This type of programme
costs 4 BF in India and 8 BF in Indonesia per administered dose. Although effective, large dose
distribution has been discontinued in a number of countries for these reasons.
9. Vitamin A toxicity
9.1. Acute hypervitaminosis
Ingestion of large dose can give rise to transient signs and symptoms of toxicity, which are self limiting
and completely reversible. No deaths have been reported after the ingestion of the doses used in
treatment and prevention.
Common complaints include headaches and bulging fontanel in young children. Nausea, vomiting,
dizziness, headaches have been described in adults. Desquamation of the skin, bone pains and hair loss
can occur in the following days.
9.2. Chronic hypervitaminosis
Is due to ingestion of large doses on a daily basis. This can lead to hepatitis, cirrhosis, hair loss, dry
scaling skin, hyperpigmentation, hyperostosis and bone pains, hepato-splenomegaly and anaemia. It is
therefore recommended not to exceed a daily intake of 3000 mcg in children and 7500 mcg in adults.
9.3. Teratogenicity
Although teratogenic in animals, a clear correlation between ingestion of large doses of vitamin
A and congenital malformations has not been established. However it is recommended during
pregnancy not to give large doses of vitamin A and not to exceed 10.000 IU per day as
treatment dose.
10. References
1. Vit A. deficiency and Xerophthalmia. WHO technical report series. 590. 1976.
2. Control of vitamin A deficiency and xerophthalmia. WHO technical report series. 672. 1982.
3. Prevention and control of vitamin A deficiency, xerophthalmia, and nutritional blindness. WHO.
Nut. 85.6. May 1985.
4. Periodic, large oral doses of vitamin A for the prevention of vitamin A deficiency and xerophthalmia:
a summary of experiences. A report of the international vitamin A consultative group.
Chapter 7, page 9
5. Beaton GH, Martorelli R, Aronson KJ et al. Effectiveness of vitamin a supplementation in the
control of young child morbidity and mortality in developing countries. Paper 13, ACC/SCN,
Toronto, 1993.


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