Who is usually deficient in Vitamin A?

http://www.who.int/nut/vad.htm
Vitamin A deficiency (VAD) is the leading cause of preventable blindness in children and raises the risk of disease and death from severe infections. In pregnant women VAD causes night blindness and may increase the risk of maternal mortality.

http://www.yourhealth.com.au/index....tent.php?id=153
Vitamin A

What is it and What Does it Do?

Vitamin A is a fat-soluble vitamin that helps cells reproduce normally - a process called differentiation. Cells that have not properly differentiated are more likely to undergo precancerous changes. Vitamin A, by maintaining healthy cell membranes and supporting immune function, helps prevent infection. It is also needed for the formation of bone, protein, and growth hormone. Vitamin A may be produced in the body from the conversion of beta-carotene. People who limit their consumption of liver, dairy foods, and beta-carotene-containing vegetables can develop a vitamin A deficiency. Extremely low birth weight babies (2.2 pounds or less) are at high risk of being born with a deficiency, which increases the risk of lung disease. The earliest deficiency sign is poor night vision, however other symptoms include dry skin, increased frequency of infections, and metaplasia (a precancerous condition).

Deficiencies are likely to occur with a variety of conditions causing malabsorption. A high incidence of vitamin A deficiency in people infected with the HIV virus has also been reported. People with hypothyroidism have impaired ability to convert beta-carotene to vitamin A. Deficiency during pregnancy can cause birth defects.

Dietary Sources
Liver, dairy, and cod liver oil contain significant amounts of vitamin A.

Therapeutic Uses
Recurrent infections of the mucous membranes, including bronchitis, thrush, urinary tract infections, conjunctivitis
• Support for poor immune function, including HIV
• Night blindness, retinopathy
• Cystic fibrosis
• Digestive disorders including chronic gastritis, peptic ulcer, coeliac disease and Crohn’s disease
• Iron-deficiency anaemia
• Acne, poor wound healing
• Abnormal pap smear
• Hypothyroidism

Common and Optimal Dosage Range
• RDI for adults is approximately 2,500 IU. Greater amounts are needed in certain illness and during breastfeeding. Therapeutic doses range from 10,000 to 500,000 IU per day with careful monitoring.
• Taking vitamin A and iron together helps overcome iron deficiency more effectively than iron supplementation alone.
Cautions, Contraindications and Side Effects
• Up to 25,000 IU (7,500 mcg) of vitamin A per day is considered safe for most adults.
• Women who are or could become pregnant should take less than 10,000 IU (3,000 mcg) per day of vitamin A to avoid the risk of birth defects. All supplements containing vitamin A will carry the warning that more than 2,500 IU may cause birth defects. The Teratology Society in the United States recommends a daily intake of 8000 IU for pregnant women, or a supplement for pregnant women who receive less than 2,200 iu daily, because deficiencies are also associated with birth defects and poor pregnancy outcomes.
• In rare cases, intake above 25,000 iu (7,500 mcg) per day can cause headaches, dry skin, hair loss, fatigue, bone problems, and liver damage. At higher levels (for example 100,000 IU per day) these problems become more common.
• Certain medications may interact with vitamin A. Please discuss the use of vitamin A and your current medication(s) with your healthcare practitioner.

Now to address the concern re vitamin A toxicity in conjunction with vitamin A.

It seems in both cases it is the synthetic forms of the vitamins that are toxic in large doses, not the natural ones. Gee , I guess the body can tell the difference between natural and synthetic vitamins after all!!! So much for those who say the body is too stupid!!

http://cerhr.niehs.nih.gov/genpub/t...min_a-ccae.html
Overview

Vitamin A is a chemical that is essential to sustain human life and must be provided in adequate amounts through food or other dietary supplements. However, excessive consumption of vitamin A can cause birth defects. Recently, birth defects have been observed in children born to mothers taking synthetic vitamin A drugs used to treat acne. These observations raised concerns that high vitamin A intake during pregnancy could cause birth defects in unborn children. Initial studies comparing levels of vitamin A intake during pregnancy in women who had healthy infants to woman who gave birth to infants with birth defects were contradictory. However, birth defects were observed in the young of animals fed high concentrations of vitamin A during pregnancy. The California Environmental Protection Agency (CAL/EPA) has identified retinol or retinyl esters (types of pre-formed vitamin A) as developmental toxins when administered at doses greater than 10,000 International Units (IU). The Food and Drug Administration has established a daily recommended allowance (RDA) of 5,000 IU for vitamin A. Because vitamin A is required to ensure reproductive health, it has been recommended that pregnant woman maintain their intake around 8,000 IU and that vitamin A be taken in the form of beta-carotene, which is not considered toxic. Women can take vitamin A in many forms. Pre-formed vitamin A (retinol or retinyl esters) is found in liver, vitamin tablets, and fortified cereals. Beta-carotene is found in fruits and vegetables and is converted to vitamin A in the body.

Description of Vitamin A

Vitamin A occurs in several different forms. Pre-formed vitamin A is a family of substances called retinol or retinyl esters (Teratology Society; 1987). Retinyl palmitate and retinyl acetate are examples of retinyl esters that are commonly used in vitamins (FDA Talk Paper; October 6, 1995). Pre-formed vitamin A is also found in animal products like liver and in fortified cereals and vitamin tablets (FDA Talk Paper; October 6, 1995). Beta-carotene, found in fruits and vegetables, is a vitamin A precursor, which means that it is converted to vitamin A in the body.

Concentrations of vitamin A are expressed in terms of International Units (IU) or retinol equivalents (RE) (Teratology Society; 1987). An IU is equivalent to 0.3 milligrams (mg) of a vitamin A compound called all-trans-retinol. Units of RE are used to standardize different forms of dietary vitamin A and 1 RE is equal to 1 mg of all-trans-retinol.

Vitamin A Toxicity During Pregnancy

Some women who used the synthetic vitamin A drug Accutane® while pregnant gave birth to babies with birth defects, according to the March of Dimes (March of Dimes 1999). Examples of birth defects were "hydrocephaly (enlargement of the fluid-filled spaces in the brain); microcephaly (small head); mental retardation; ear and eye abnormalities, cleft lip and palate, and other facial abnormalities and heart defects." Women who took the drug also had a higher risk of miscarriage. The active ingredient in Accutane®, isotretinoin, is produced in the body in small amounts after eating vitamin A. Therefore, concerns were raised that a high intake of vitamin A by pregnant women could cause birth defects in infants.

Contradictory results have been obtained in studies that examined vitamin A intake during pregnancy and birth defects in humans. A study sponsored by the National Institute of Child Health and Human Development (NICHD) compared vitamin A intake during pregnancy in women who had given birth to infants who were healthy, who had a neural tube defect (defects in the brain and spinal cord), and who had a cranial-neural-crest defect (malformation of cleft palate, face, or heart) (NIH News Alert; July 22, 1997). It was concluded, "When compared to women in the control group, neither the women in the neural tube defect group nor those in the group pregnant with children having other major malformations were found to have been more likely to have consumed between 8,000 and 10,000 IU of vitamin A."

A similar study conducted at the Boston University School of Medicine compared vitamin A intake during pregnancy in women who had given birth to healthy infants or who had cranial-neural-crest defects (defects of the head, face, nervous system excluding the neural tubes, thymus, and heart), neural tube defects (defects in brain or spinal cord), or defects of the bones, muscles, or urinary tract (New England Journal of Medicine Journal Club; 333:1369-73; 11/23/95). The study found that women who took about 10,000 IU or more vitamin A during pregnancy were more likely to give birth to a child with a cranial-neural-crest defect. It was estimated that intakes of greater than 10,000 IU of vitamin A by pregnant women could result in a defect in one of every 57 infants.

According to the Teratology Society, there are several reports of malformations in humans following a vitamin A intake of 25,000 IU/day or more during pregnancy (Teratology Society; 1987). Some of the defects were similar to those caused by isotretinoin.

Animal studies have demonstrated birth defects similar to those produced by Accutane®. Cleft palates and defects of the head, face, and eye were seen in the young of pregnant rats fed 35,000 IU of vitamin A (Teratology Society; 1987). Similar defects were also observed following vitamin A administration to pregnant mice, guinea pigs, hamsters, and rabbits.

Vitamin A Regulations and Recommendations

Retinol/retinyl esters (pre-formed vitamin A) in doses greater than 10,000 IU, or 3,000 retinol equivalents are listed on the CAL/EPA Proposition 65 list of developmental toxins (Cal/EPA Proposition 65 List). This means that an expert group of scientists found sufficient evidence that the compounds can be harmful to unborn children. The following statement is included with the listing, "NOTE: Retinol/retinyl esters are required and essential for maintenance of normal reproductive function. The recommended daily level during pregnancy is 8,000 IU".

Several recommendations have been made for vitamin A intake by pregnant women. The FDA has recommended that pregnant women obtain vitamin A in the form of beta-carotene whenever possible (FDA Talk Paper; October 6, 1995). According to the FDA, "beta-carotene is a substance found naturally in plants, and it can be converted to vitamin A in the body. It is considerably less toxic than the pre-formed vitamin A. Therefore, women of child-bearing age are advised to choose fortified foods that contain vitamin A in the form of beta-carotene rather than pre-formed vitamin A, whenever possible. The vitamin A in fruits and vegetables is naturally in the form of beta-carotene, and high intakes of vitamin A from these sources are generally not of concern. Taking too little vitamin A can result in adverse effects just as can taking in too much. The key is in finding the 'right amount' through carefully reading product nutrition labeling."

The following list contains recommendations from the Teratology Society (Teratology Society; 1987):

Supplementation of 8,000 IU vitamin A (as retinol/retinyl esters) per day should be considered the recommended maximum prior to or during pregnancy until further evaluations can be performed in the human population. It is important to determine the type of vitamin A consumed, since beta-carotene has not been associated with vitamin A toxicity in animals or man.

Manufacturers of vitamin A (as retinol or retinyl esters) should lower the maximum amount of vitamin A per unit dosage to 5,000-8,000 IU (1,500-2,400 RE) and identify the source of the vitamin A. High dosages of vitamin A as retinol/retinyl esters (25,000 IU or more) are not recommended.

Labeling of products containing vitamin A supplements (as retinol/retinyl esters) should indicate (a) that consumption of excessive amounts of vitamin A may be hazardous to the embryo/fetus when taken during pregnancy; and (b) that women of childbearing potential should consult with their physicians before consuming these products.

Dr. Larry Gilstrap of the American College of Obstetricians and Gynecologists was quoted as saying (USA Today), "We want to reassure women that the amount (of vitamin A) in their prenatal vitamin is safe, and so is the amount they're likely getting from their diet.'' Gilstrap went on to say that vitamins given to pregnant women usually contain 4,000-5,000 IU. Dr. Gilstrap considered this amount of vitamin A to be sufficient because it leaves room for dietary sources of vitamin A such as meat and dairy products.

G. Oakley and J. Erickson from the Centers for Disease Control and Prevention (CDC) stated that pregnant women should take supplements containing less than 8,000 IU vitamin A and limit the amount of liver they eat (New England Journal of Medicine Journal Club; 333:1369-73; 11/23/95).

Another study
http://www.biotech-info.net/disorders.html

Vitamin A Deficiency Disorders: Origins of the Problem and Approaches to Its Control"

Alfred Sommer, MD, MHS
Dean
The Johns Hopkins University
Bloomberg School of Public Health
2001

The announcement that Swiss scientists had genetically modified a strain of rice to produce beta-carotene, a precursor of vitamin A, set off heated debate between those who believe this would solve the global problem of vitamin A deficiency and those who argue that such genetically engineered products might do more harm than good. Neither extreme is tenable. If — and it remains a big “if” — “golden rice” and its variants prove safe and effective, they will be a valuable new tool for controlling vitamin A deficiency. Under the most optimistic of circumstances, however, they will never solve the global problem by themselves. This review attempts to place this new tool in perspective.

Vitamin A deficiency disorders encompass the full spectrum of clinical consequences associated with suboptimal vitamin A status.(1) These disorders are now known to include reduced immune competence resulting in increased morbidity and mortality (largely from increased severity of infectious diseases); night blindness, corneal ulcers, keratomalacia and related ocular signs and symptoms of xerophthalmia; exacerbation of anemia through suboptimal absorption and utilization of iron; and other conditions not yet fully identified or clarified (e.g., retardation of growth and development).(2)

Magnitude and Distribution

Clinical and sero-epidemiologic studies and surveys indicate that vitamin A deficiency is widespread throughout the developing world. Vitamin A deficiency has long been recognized in much of South and Southeast Asia (India, Bangladesh, Indonesia, Vietnam, Thailand, the Philippines) by the common presentation of clinical cases of xerophthalmia (night blindness to permanently blinding keratomalacia). Subsequent studies in Africa, where it had been less well recognized, indicated that a large proportion of pediatric blindness was due to acute deterioration in vitamin A status during measles and similar childhood infections.(3, 4)

Vitamin A deficiency was found to increase childhood morbidity and mortality(2, 5-10) in populations in which xerophthalmia was not readily recognized(11) and in greater numbers than would be expected solely from the increase in mortality associated with xerophthalmia.(2, 12) This discovery led to the recognition that seemingly mild biochemical deficiency, insufficient to cause xerophthalmia, accounts for large numbers of preventable childhood deaths.

The extent and distribution of vitamin A deficiency and its consequences are remarkably well established. Numerous local and national surveys have been conducted. In countries where they have not been conducted, data from nearby countries with similar characteristics (under-5-year mortality, poverty, diet) allow for judicious extrapolation. The few intensive national surveys linked to longitudinal studies(13) and extrapolations from sero-surveys and community-based randomized intervention trials show that vitamin A deficiency poses a significant problem in more than 70 countries.(14) Recent calculations suggest that roughly 150 million children are deficient: every year 10 million children develop xerophthalmia, 500,000 children are permanently blinded from xerophthalmia and 1 to 2 million children die unnecessarily.(15)

Vitamin A deficiency disorders have not been quantified in women of childbearing age. Older anecdotal reports(16, 17) and recent surveys(18, 19) indicate that night blindness from vitamin A deficiency is common among pregnant women in India, Indonesia, Bangladesh, Nepal and elsewhere, particularly during the latter half of pregnancy. Most surveys reveal rates of night blindness of 10% or more during pregnancy in populations in which the children are commonly deficient.(1) A recent large-scale randomized placebo-controlled trial of vitamin A or beta-carotene supplementation in Nepali women reduced maternal mortality by approximately 40%,(20, 21) an effect that persisted for at least one year postpartum.(22)

Vitamin A deficiency disorder affects large numbers of young children and women of childbearing age throughout the developing world. Current estimates do not include China, where recent visits with nutritionists and pediatricians in the southwestern regions identified cases of xerophthalmia and where a recent UNICEF survey revealed depressed serum retinol values and night blindness during pregnancy in large, impoverished regions.(23-25) The size of the global problem is therefore likely to grow as additional data are gathered.

Origins of Deficiency

Children begin life with an urgent need for vitamin A. Full-term infants — even those of well-nourished mothers in wealthy countries — are born with barely enough vitamin A to sustain them during the first few days of life. During the first six months of life they need at least 125 mg of retinol equivalents daily to prevent xerophthalmia and about 300 mg to thrive (and accumulate adequate liver stores of 20 mg per gram of liver).(1, 26, 27)

The only significant source of vitamin A for young infants is breast milk (or equivalent formulas). Except when mothers suffer from severe protein-energy malnutrition, the quantity of breast milk is roughly similar around the globe, but the concentration of vitamin A in that milk varies dramatically with the vitamin A status of the mother.(26, 28) When mothers are vitamin A deficient, breast milk concentrations will be low. Without supplemental vitamin A, their infants will become deficient.

Children in developing countries are at risk of consuming a vitamin A~deficient diet throughout life, not just during early infancy. Although Western populations receive abundant preformed vitamin A from animal products (eggs, butter, cheese, liver, processed foods fortified with vitamin A), poor rural populations in developing countries rely on beta-carotene, a precursor of vitamin A found in dark-green leafy vegetables, carrots and colored fruits (mango and papaya). Even when abundant, these are poor substitutes for animal sources of the preformed vitamin: many children do not like dark-green leafy vegetables; fruits are often costly, sold as a cash crop or highly seasonal (e.g., mangos); and many vegetables bind beta-carotene tightly to their cellular matrices, yielding little during digestion. Recent data indicate that the bioavailability (and bioconversion) of dark-green leafy vegetable sources of beta-carotene is much lower than previously supposed,(29, 30) with perhaps no more than 2% to 4% being absorbed, converted to vitamin A, and made available to meet metabolic needs.

Children in the developing world probably need more vitamin A than do their better nourished Western counterparts. Diarrhea, childhood exanthematous diseases and respiratory infections are more common in poor rural populations, further reducing vitamin A absorption (diarrhea) while increasing utilization (measles) and excretion (respiratory infection).

Why young children in developing countries are deficient in vitamin A is clear. Their greatest risk of becoming vitamin A deficient is during the first few years of life, when their diets are the least diverse, growth (hence need) is greatest and they are at highest risk of life-threatening infections. As they enter their school-age years these factors begin to moderate even though deficiency persists and mild manifestations (e.g., night blindness and Bitot’s spots) remain common.

Why women are so frequently deficient is less clear. They also have a similarly unvaried diet that is largely deficient in good sources of preformed vitamin A. Pregnancy and lactation place additional burdens on their meager vitamin A stores. Other consequences of pregnancy probably explain why deficiency is most severe — and night blindness most common — during the latter half of pregnancy. Even though pregnancy-related night blindness spontaneously disappears during the early postpartum period, the underlying deficiency does not. As a consequence these women suffer an increase in mortality for at least one year postpartum.(20-22)

Combating Vitamin A Deficiency

There is global agreement on the need to combat vitamin A deficiency.(2, 14) More than 70 countries have formal intervention programs, although only a few (Nepal, Indonesia, Tanzania, Bangladesh, Vietnam) have made significant, discernible progress. Three basic strategies exist for increasing vitamin A intake: increasing the consumption of foods rich in vitamin A and provitamin A; fortifying commonly consumed dietary items with vitamin A (or beta-carotene); and providing large, periodic, vitamin A supplements to high-risk populations.

Dietary Diversification

Many nutritionists consider increasing the consumption of natural dietary sources of vitamin A to be the logical long-range solution to deficiency. Despite occasional demonstration projects and correlational analyses,(31) little definitive evidence exists that vitamin A sufficiency can be achieved — let alone sustained — through traditional food sources, particularly those available to poor, rural, high-risk populations. As noted, vegetables are poor sources of provitamin A beta-carotene. Although they contain considerable quantities of beta-carotene, these are not readily bioavailable. It needs to be shown that vulnerable children can consume quantities of dark-green leafy vegetables sufficient to normalize their vitamin A status.

Adults may be able to obtain sufficient vitamin A by consuming far larger amounts of vegetables and fruits than children consume or through the greater diversity of their diet, but this too needs documentation. In at least two studies, women provided daily with large helpings of dark-green leafy vegetables failed to significantly improve their vitamin A status(29, 32) in contrast to those fed cookies containing pure synthetic (therefore readily absorbed) beta-carotene.(29) Introducing animal sources of preformed vitamin A (e.g., eggs) into the diet might make a significant difference but remains beyond the resources (and cultural patterns) of many of the populations at highest risk.

Fortification by Conventional Means

Fortifying dietary items with preformed vitamin A or beta-carotene is a proven strategy for preventing deficiency.(33) In the early 1900s Denmark legislated vitamin A fortification of margarine because its growing dairy exports deprived the poorer classes of once-abundant butter, for which they initially substituted vegetable oil~based margarine, which is naturally devoid of vitamin A. In the United States, Western Europe and most wealthy countries, a wide variety of dietary items is fortified with vitamin A (milk, margarine, cereal products). Developing countries have experimented with fortifying a range of products with vitamin A (monosodium glutamate, wheat, noodles, sugar). To date, only sugar fortification, primarily in Latin America, has taken hold.(34)

Traditional fortification techniques require a dietary item that is consumed in suitable quantities by the groups at highest risk; is processed at a limited number of sites where the fortificant can be conveniently added; stabilizes vitamin A during its normal shelf life in the marketplace (vitamin A is unstable in salt, making salt unsuitable for vitamin A but fine for delivering iodine); results in little increase in cost to the consumer; and has acceptable organoleptic qualities (color, smell, taste). These requirements have been difficult to achieve for high-risk poor populations that generally consume a monotonous diet devoid of expensive, centrally processed items.

Fortification by Genetic Modification

In an attempt to overcome some of the obstacles facing conventional fortification, scientists have begun to genetically modify traditional dietary items to produce beta-carotene. Monsanto produced rape seed and mustard rich in beta-carotene and, more recently, scientists funded by the Rockefeller Foundation produced a strain of rice — golden rice — genetically modified to produce beta-carotene.(35) This may well herald an important strategy for controlling vitamin A deficiency, particularly because rice is the dietary staple of many of the most-deficient populations.

Some hurdles need to be surmounted before golden rice or its variants can have an effect. The strains must be able to grow under the varied conditions in countries with vitamin A~deficient populations. The yield and the cost must be attractive to the farmer (or benefit from public sector subsidization). The organoleptic qualities of the rice must be acceptable to the target population (women and children). The beta-carotene needs to be bioavailable, the degree dependent on its concentration in the rice, the matrices to which it is bound, the effect of traditional cooking methods and the amount consumed.

Although genetically modified rice could go a long way toward controlling vitamin A deficiency, it will never completely solve the problem. Many deficient populations do not consume rice, and even within traditional rice-consuming countries, some high-risk groups will not be able to afford it.

Supplementation

Vitamin A (retinol) supplements — naturally occurring (as in cod liver oil) or synthetically derived (multivitamin preparations) — have long been used to prevent vitamin A deficiency and its associated disorders.(2, 36) Vitamin A is a component of prenatal and infant multivitamins routinely consumed by Western populations. Periodic administration of large doses of vitamin A to children was pioneered in India(37) and advanced globally after the first major international meeting on the control of vitamin A deficiency in 1974.(32)

Periodic supplementation is the most widely implemented intervention for controlling vitamin A deficiency in the developing world. Countries have found these programs to be relatively easy and quick to initiate at relatively modest marginal cost.(2, 38) Supplements are extremely inexpensive, at 2 to 4 cents per dose of 200,000 international units (IU). Most of the cost is for the gelatin capsule; the cost for the vitamin A is less than 1 cent.

The major cost for (and impediment to) population-wide supplementation is the delivery system. Recommendations called for the administration of 200,000 IU every 4 to 6 months to all children 12 to 60 months of age. Unfortunately, that often requires a delivery mechanism such as that presently used successfully in a number of countries (e.g., Nepal and Bangladesh). In Nepal, 37,000 village women volunteers reach more than 2 million children during special “Vitamin A Days” held twice every year.(39)

To better use existing delivery channels, many countries have piggybacked vitamin A distribution onto regular immunization efforts. In particular, 25,000 or 50,000 IU of vitamin A is given to young children at ages 6, 10, and 14 weeks when they receive their diptheria, pertussis and tetanus immunizations. A fourth dose (100,000 IU) is administered at age 9 months with measles immunization.(40) The rationale for this schedule is that an existing distribution mechanism is available, minimizing the marginal cost of delivery; a high risk of deficiency exists during the first year of life (200,000 IU is given to mothers 6 to 8 weeks postpartum to boost breast milk vitamin A concentration); and infants are at greatest risk for the consequences of deficiency, particularly mortality. Coverage achieved by supplement distribution programs has dramatically risen in the past two years, largely because vitamin A administration was included in national immunization days, which were designed to deliver polio vaccine. More than 40 countries reported covering more than 80% of their target children with vitamin A supplements during 1998.(1, 41)

Although randomized controlled clinical trials have demonstrated the value of periodic supplementation,(2) in practice it has proved difficult to reach children after the first year of life; indeed, with immunization rates falling below expected targets, these too have not met their goals. To compound the problem, national immunization days will soon be phased out.

A recent multinational trial sponsored by the World Health Organization (WHO) suggests that the present regimen of dosing mothers with 200,000 IU postpartum and their children three times in the first 14 weeks of life with 25,000 IU does not improve vitamin A status much beyond age 6 months.(42) In response, a recent informal consultation organized by WHO recommended that doses to infants and mothers be increased: 400,000 IU to postpartum women (in two doses during the preconceptual period) and 50,000 IU to infants at least three times before age 6 months. Although the effect of these increases is yet to be ascertained, evidence suggests they will be safe and effective.(27)

Safety Considerations

Undue concern over vitamin A toxicity, a rare and transient condition,(43) has complicated the design of intervention strategies and unnecessarily diverted attention and commitment from effective control strategies. Because safety relates to the prevention of deficiency, only two issues arise: teratogenicity and acute toxicity.

Very large doses of vitamin A during the first trimester of pregnancy can be teratogenic, so high-dose supplementation of women of childbearing age is only recommended during the infertile postpartum period.(40) Acute toxicity, although harmless and transient, can result in nausea and vomiting. If mothers notice and are concerned, it might result in lower compliance rates, so supplement size is adjusted for the child’s age. Even so, young children who might inadvertently receive multiples of the recommended dose (in addition to increased amounts in breast milk) will not suffer significant, permanent sequelae.(1) The implications for intervention strategies are minimal.

Diet

Traditional foods cannot produce teratogenic or toxic effects. For deficient populations the primary source of vitamin A is vegetables, which lack the preformed vitamin. Ingesting large quantities of carrots and other carotenoid-rich vegetables may produce high carotene levels, but these are harmless. Because the body regulates conversion of beta-carotene to vitamin A, serum retinol does not rise to toxic levels.

Fortification

Programs that add retinyl palmitate (preformed vitamin A) to dietary items carefully adjust the level of fortification to benefit consumers whose diets are most deficient without exposing wealthier segments of society, whose diets might be richer in preformed vitamin A, from consuming excessive amounts. These programs take pains to achieve a balance that best serves both groups. The choice of vehicle can optimize this relationship.

Fortifying a product or a specific package of that product (e.g., the smallest packets of monosodium glutamate) uniquely ingested by those who are most deficient increases the amount of vitamin A that can be safely added. Nonetheless, ongoing surveillance is valuable in identifying isolated groups or individuals who purposely purchase and consume large doses of supplements on a sustained basis.

Fortification through genetic modification poses no risks of vitamin A toxicity. Genetically modified crops (e.g., golden rice, enriched canola oil) produce beta-carotene, not preformed vitamin A.

Supplementation

This intervention is potentially the most problematic because it is theoretically possible to overdose the recipient through frequent, inadvertent dosing. From a practical standpoint, however, serious or sustained side effects require very high, frequent and persistent dosing (50,000 to 100,000 IU daily for 3 to 6 months).(1, 27, 40, 43) An often expressed concern is that a child might receive three or even four high-dose supplements within a month (a regular distribution, a dose during measles, plus a third or fourth from an overly zealous local health worker). The worst result, however, would be a day or two of nausea and vomiting. This risk pales in comparison with the millions of children who would otherwise die or be blinded.

Conclusions

A decade ago the public health and nutrition communities recognized the need to improve the vitamin A status of young children throughout the developing world.(44) The World Bank has estimated that vitamin A supplementation (the only approach they modeled) was among the most cost-effective health interventions available, at less than US$1 per disability-adjusted life year.(45) Although more than 70 countries have embraced the global goal of eliminating vitamin A deficiency as a public health problem, progress has been slow, largely because of the costs and logistical challenges to changing behavior (diets), delivering large-dose supplements regularly, and fortifying traditional dietary items. A number of bilateral and international agencies recently recommitted themselves to these efforts, even as continuing research expands the implications of deficiency. New tools, such as genetically modified staple crops, could provide important strategies and stimulate these global efforts.

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And...

http://members.iinet.net.au/~warpf/vitamina.html

What are the results of the vitamin A treatment study?

A six-year study of 600 patients with typical Retinitis Pigmentosa (RP) concluded that, on average, the course of retinal degeneration was slowed among patients receiving a specified daily vitamin A palmitate supplement. There was almost a 20% slower annual decline of remaining retinal function in the study patients who took 15,000 IU vitamin A palmitate compared to those who took only trace amounts, as monitored by electroretinographic (ERG) amplitudes (8.3% compared to 10.0%). The results also suggested that the course of disease might be faster on average among patients receiving a daily high dose supplement of vitamin E (400 IU) than among those receiving a trace dose of vitamin E. Based on the results of this study, it is recommended that most adult patients with the common forms of RP take a daily 15,000 IU supplement of vitamin A palmitate under the supervision of an ophthalmologist, and avoid the use of high dose supplements of vitamin E, such as 400 IU. TOP

Is this a cure?

Unfortunately, no. But it may be a help for many. This treatment may decrease the yearly loss of retinal function, but will not stop it. Adults who use this treatment may have on average slower annual decline of remaining retinal function than those not using this treatment. While this does not represent a cure, it does represent a first step in managing typical RP. The patient must not expect improved vision from one year to the next, nor expect that vision loss would be completely arrested. Research aimed toward the development of additional treatments, cure and prevention actively continues. TOP

What types of RP may be helped by this treatment?

The clinical treatment trial of vitamin supplementation included patients with typical forms of RP, including the common inheritance types of X-linked, autosomal dominant, and autosomal recessive, as well as isolated RP and Usher syndrome type 11. Several other less common forms of RP were not included because too few patients were available for the study. Also, there was no preliminary evidence to suggest that vitamins could modify the course of these forms. Usher syndrome type 1, atypical RP (for example, cone-rod dystrophy and unilateral RP), Bardet-Biedl syndrome, Lebers congenital amaurosis, Refsum disease and other less common syndromes that involve RP were not included. Also, patients were not evaluated in this study if they had very advanced RP; if they were below the fifth percentile of normal for body weight for their age, sex and height, if they had impaired liver function; or if they were under age 18. Therefore, based on this study, formal recommendation of vitamin A supplementation cannot be made for these groups of patients. They should be assessed individually by their doctors. TOP

Was any type of macular degeneration included in this study?

No. This study was limited only to typical RP. Macular degeneration, whether the juvenile onset or late onset, age-related form, was not included in this trial. In fact, because macular degeneration has different symptoms, it also might be caused by different disease processes than RP. Recommendations regarding vitamin supplementation for patients with macular degeneration will have to await completion of other studies now being conducted through projects supported by the US government. TOP

Can children who have RP be given supplements of vitamin A?

This is a very difficult question to answer. Because patients under the age of 18 were not evaluated in this study, no formal recommendation can be made. However, it seems reasonable for children with RP to be assessed individually by their ophthalmologist and paediatrician for possible vitamin A treatment with a dose that takes into account the age, weight, general health status, and published guidelines for the safe use of vitamin A. Your child’s doctor might consider use of a standard children’s multiple vitamin capsule containing 5,000 IU vitamin A and 30 IU vitamin E, among other components. The 15,000 IU daily supplement of vitamin A recommended for adults is well above a child’s recommended daily allowance. Refer below to questions 6 and 7 for a discussion of the potential adverse side effects from high intake of vitamin A. TOP

What are the possible side effects of taking too much vitamin A?

For normal healthy adults the US Recommended Daily Allowance (US RDA) of vitamin A is 5,000 IU. The RDA for children depends on age and weight, and ranges from 1400 IU for an infant to 3300 for a ten year old weighing 60 pounds. The designation "IU" stands for International Unit. It is based on a standardised level of activity and defines the amount of activity of the specific substance present in the capsule. Based on the study results, the daily dose recommended for most adult patients with RP is 15,000 IU from capsule supplements of vitamin A palmitate, in addition to a regular balanced diet, which typically provides 3,000-4,000 IU per day. This totals approximately 18,000 IU per day of vitamin A. Regular long-term intake of 25,000 IU or more daily as a supplement has been associated with liver damage and with birth defects if taken during pregnancy. Other side effects sometimes caused by very high doses include throbbing headache, appetite loss, weight loss, nausea, vomiting, dry skin, hair loss, fatigue and ankle swelling, among others. TOP

Is it safe to take 15,000 IU of vitamin A for many years?

There is not much information available now about the possible adverse effects of taking supplemental vitamin A for many years, even decades. However, no evidence of systemic illness or toxicity attributable to the daily intake of vitamin A palmitate capsules (15,000 IU) could be established during the six-year study based on blood tests, urinalyses, patient responses to a symptom questionnaire, and, in some cases, examination by a consulting internist. Nevertheless, it is extremely important that your own condition be monitored by a physician on a regular basis while you are taking vitamin A for extended time periods that will probably exceed the six-year term of this study. Development of side effects, including liver disease, cannot be excluded. Therefore, patients should have a yearly evaluation by their doctor while taking vitamin A supplements. TOP

Tell me more about this study on vitamin A. Why was it done?

This study was a prospective, double-masked clinical trial. Neither patient nor clinician knew to which treatment group the patient had been assigned. It was designed to assess the effectiveness of vitamin A and E supplements in halting or slowing the progression of RP. An independent Data Safety and Monitoring Committee provided advice to the investigators and monitored the accumulating data on a regular basis for evidence of harm or benefit to study participants. A total of 600 patients affected with typical RP from across the United States and Canada were enrolled in the study. All were in good general health, between the ages of 18 and 49, and entered the study with different initial levels of retinal function. TOP

Following an examination, participants were assigned randomly to one of four treatment groups:

15,000 IU vitamin A plus 3 IU vitamin E

75 IU vitamin A plus 3 IU vitamin E

15,000 IU vitamin A plus 400 IU vitamin E

75 IU vitamin A plus 400 IU vitamin E

Where can I get a copy of the full report on this study?

The report from this clinical treatment trial was published in the June 1993 issue of the scientific journal Archives of Ophthalmology, pages 761-772. You and your doctor should refer to this article and the accompanying editorial for a complete presentation and discussion of the results. This journal is available through medical school and university libraries. Your local library may be able to obtain a copy of the article for you. The RP Foundation is not able to provide copies of this report. TOP

Do the results of this study imply that vitamin A deficiency or an excess of vitamin E was the cause of my RP?

There is no clue now that isolated cases have been caused by vitamin imbalance. In fact, vitamin A and E levels present in the blood of unaffected and affected individuals do not differ significantly. Scientists have discovered that the actual cause of most typical RP is a mutation in one of several important genes, which then produces a defective protein. This explanation of the cause is borne out by the inheritance of RP as a genetic disease and by the discovery of the actual disease gene mutations in a large percentage of RP cases. It is possible that non-genetic causes for isolated cases of RP may be discovered in the future. TOP

What is vitamin A?

Vitamins are relatively complex organic substances that are not made by the human body. They are required in small amounts from a balanced diet in order to sustain normal metabolism and good health. Diseases caused by extreme vitamin deficiency can usually be cured when the lacking vitamin is supplied.

The vitamin A family includes all naturally occurring compounds with the biological activity of retinol. It occurs in precursor form (for example, beta-carotene) or preformed principally in animal fats including dairy products, fish liver oils and some yellow and dark-green vegetables. Vitamin A is essential for normal growth and development. Extremely severe nutritional deficiency of vitamin A can cause disease, including degeneration of mucous membranes (especially of the eye) and some other eye disorders. There are several members of the vitamin a family that have different functions in the body and therefore cannot be used interchangeably as a therapy. The preformed palmitate form of vitamin A is one member of this family, and is the recommended form for this treatment. In well-nourished individuals without a specific need for increased vitamin A, sufficient amounts are obtained from a regular balanced diet. Most of the body’s reserve of vitamin A is stored in the liver and abnormally high stored amounts can be toxic. TOP

How does supplemental vitamin A palmitate preserve retinal function for RP patients?

We don’t know. One well-defined function of vitamin A is in vision. It is intimately involved in the cascade of events triggered by light reaching the retina. A second major role of vitamin A is to keep cells healthy. A characteristic of RP is death of the specific, light-sensing cells in the retina, the photoreceptor cells called rods and cones. It is reasonable to hypothesise that high levels of vitamin A preserve these dying cells in some way. It is also possible that RP reduces the capacity of the retina to retain vitamin A. Likewise, RP cells may have an abnormal carrier protein causing vitamin A to be transported from the blood to the retina with lower efficiency. Whatever the explanation, it appears that vitamin A supplements may provide partial protection against loss of retinal call function as monitored by the ERG. TOP

Why should I avoid taking high dose supplements of vitamin E?

On average, study patients who took a daily supplement of 400 IU vitamin E with very low intake of vitamin A appeared to experience almost a 20% faster annual rate of decline of remaining retinal function than those who received only a trace amount of vitamin E (11.8% compared to 10.0%). Said another way, on average, a patient taking 400 IU of vitamin E might lose retinal function several years sooner. According to the study, if vitamin E supplements without vitamin A were started by the average patient at age 32, legal blindness could be accelerated by as much as five years. However, the study showed no evidence that normal dietary or small supplemental amounts of vitamin E have any adverse effect on RP. TOP

How could vitamin E cause an adverse effect on RP?

It is possible that taking frequent high doses of vitamin E might affect the course of RP at least in part by inhibiting the absorption or transport of vitamin A in the retina. In the study, it was observed that patients receiving 400 IU vitamin E had slight but significant decreases in vitamin A levels in their blood compared with those not receiving that dose of vitamin E. TOP

What if my doctor has advised me to take vitamin E for other reasons?

There is some early information from nutritional studies suggesting that supplemental vitamin E could be helpful in preventing heart disease. If your doctor has advised you to take vitamin E for any reason, you should ask to discuss the relative benefits and risks of taking vitamin E, or taking vitamin E along with vitamin A, given your general health and your eye disease. It is important to note that in the study vitamin A and E taken together did not appear to be as effective as vitamin A alone. TOP

To what extent might my vision be helped?

We can’t give you an answer that will predict your specific outcome. There are considerable differences in the severity of the disease among individuals at the same age, even within the same family. This study pooled the information from 600 patients and conclusions were based on "group averages". Actually, there are probably very few patients who exactly fit the "average" description. Some will have better vision and some will have worse vision than an average study patient. It isn’t possible to tell you the exact extent of benefit you will receive from this treatment. Some patients may not be helped at all, some may be helped more than others. Assurance cannot be given that a specific patient will benefit from this treatment. TOP

OK....what is the benefit of vitamin A for the "average" individual who has RP or Usher syndrome type 11?

In this clinical treatment trial, patients were examined annually for four to six years. Their retinal function was assessed by an ERG (electroretinogram). Those who took daily vitamin A palmitate supplements of 15,000 IU had almost a 20% slower loss of remaining retinal function each year than others in the study. Said another way, the average patient taking vitamin a could expect to keep retinal function for several years longer. If vitamin A supplements were started by the average patient at age 32, legal blindness could be delayed by as much as seven years. However, researchers cannot provide assurance that every patient will benefit from vitamin A treatment. TOP

But what does that say about me?

The best we can answer is that you may benefit from vitamin A treatment. It will be hard to tell by actual measurement, because this treatment slows the rate of degenerative process, but does not stop it. Complete blindness might be prevented in some people. Others might not be helped at all. TOP

Will I notice any change in my vision when I take vitamin A?

It is very unlikely that you will notice an improvement in your vision compared to any time in the past. The degenerative process will continue, although at a slower rate. Based on the results of this study, it is predicted that patients taking vitamin A over the long-term would have a higher probability of retaining the capacity to perform certain daily activities at a given age than patients not taking the vitamin A treatment. TOP

If I take vitamin A long enough, or start taking vitamin A as a young adult, will I be cured?

Vitamin a supplementation is not a cure for RP. "Cure" implies that health has been restored to normal, an a cure for RP would imply restoration of lost vision. Vitamin A supplementation has the potential to slow the disease course, therefore it is expected that supplementation begun in early adulthood may be more beneficial in the long-term than if begun later. For some patients, that might result in some amount of retained central vision for life. Since this study followed patients for four to six years, the benefits of longer term vitamin A supplementation will only be learned by following patients on this treatment throughout their lifetimes. TOP

Should I take vitamin A if I am already legally blind?

More than 50% of patients in the study were legally blind (defined as best corrected visual acuity of 20/200 or less or a central visual field diameter of 20 degrees or less in both eyes). However, as stated above, this study did not evaluate patients who were legally blind if they had very advanced RP because ongoing measurements of change in retinal function would have been difficult to assess. If you now have very advanced RP, you should consult with your ophthalmologist to get advice about the possible benefit of vitamin A for you. Other approaches being studied now may be helpful in the future for this group of patients. TOP

What should I do if I become pregnant or plan to become pregnant?

During your regular visits to your doctor, you should discuss the impact of vitamin A treatment on childbearing. You might be advised to stop taking vitamin A during periods leading up to planned pregnancies because of the potential for birth defects. Women who become pregnant should be advised to discontinue this dose of vitamin A during the entire pregnancy and during the period of breast feeding. However, you should continue to take prenatal vitamins as prescribed by your obstetrician. TOP

What should I do to begin vitamin A treatment?

This is a serious undertaking. First consult with an ophthalmologist, a medical doctor who specialises in eye care. Do no start taking vitamin A supplements on your own. Your ophthalmologist will want to do initial and subsequent annual evaluations, including tests to measure your blood level of vitamin A and to assess liver function. If these tests show that you have a pre-existing liver disease or abnormally high blood levels of vitamin A, your doctor may need to decrease your vitamin A intake accordingly. If you are not going to an ophthalmologist now, we suggest that you seek one out who is willing to advise you regarding your eye care. TOP

How can I find a doctor who is familiar with RP?

The WARP Foundation can give you a choice of ophthalmologists who specialise in retinal degenerative diseases. Please be aware that the Foundation is not an accrediting agency and has not screened those listed to judge their training, experience or standing in the medical community and cannot recommend one ophthalmologist in preference to another. Also, the Foundation cannot be held responsible for any services given by referral specialists or for the fees which they may charge. In conjunction with this list, you may wish to consult with your general practitioner or optometrist for their recommendation. TOP

How often will I need to be examined while taking vitamin A?

It would be a good practice to visit your ophthalmologist annually. Because liver disease is a potential side effect from long-term high dose vitamin A supplementation, blood tests to reassess liver function could be done at that time. Some ophthalmologists may want to measure annually the vision of their patients with RP, using tests to follow visual acuity, visual field and retinal function, like the ERG. TOP

Will my health insurance pay for annual appointments and tests?

You will need to check with your individual heath insurance carrier. Coverage of costs will depend on the individual insurance plan being used. You will need to look into this yourself. TOP

What do I need to know in order to buy the right capsules of vitamin A?

When you look for such a supplement, labels should be read very carefully to be sure the capsules contain vitamin A in the palmitate form, and not another component, especially beta-carotene. Beta-carotene is a natural precursor of the active form of vitamin A and in this instance is not a suitable substitute. Very high levels of beta-carotene are needed to achieve activity equivalent to 15,000 IU of vitamin A palmitate. The final activity could vary from person to person because people metabolise beta-carotene with different efficiencies. Therefore it is not a predictable source of the vitamin. Vitamin A in the palmitate form was used in this clinical treatment trial and the recommendations derived from the study apply specifically to this form. TOP

Where can I obtain capsules of 15,000 IU vitamin A palmitate?

At present, and to the best of our knowledge, vitamin A palmitate is available from most chemists and health food shops under the brand name "Nature’s Own" product number 203 but only in 5,000 IU capsules for approximately $6.00 for 100 capsules. To make up the correct dosage of 15,000 IU three capsules of 5,000 IU should be taken at one time. TOP

Do I need a prescription to get vitamin A supplements?

No. Vitamin A is classified as a food supplement and can be sold without a prescription. However, even though it is not a drug and a prescription is not required, vitamin A supplements potentially can cause side effects and should not be used for long periods without regular follow-up examinations by your ophthalmologist and/or physician. You should be sure to inform each doctor you see that you are taking supplements of vitamin A on a regular long-term basis because there may be instances where vitamin A sue could be contraindicated. TOP

When should I take the capsules and how should I store them

You might find it useful to develop a routine of taking the capsules each day right after breakfast. These vitamin A capsules have more than a one-year shelf life. You could purchase a full year supply (eleven bottles of 100 each) and store them at room temperature. TOP

Can I adjust my daily dose so that I can make use of lower or higher dosages that are sold at my local store?

In the study, optimal benefit occurred among patients with a total daily intake of 15,000 IU of vitamin A palmitate in capsule form and 3,000 IU vitamin A from diet. Lower intake gave less benefit and higher intake up to 25,000 IU provided no greater benefit. Toxic side effects have been associated with long-term intake of 25,000 IU and therefore, intake of below 15,000 IU and over should be avoided. Remember, more vitamin A than the dose recommended by this study is not better. Moreover, daily vitamin A intake exceeding 25,000 IU over the long-term may be toxic in adults and may cause side effects such as liver disease. TOP

Why can’t I simply take three "one-a-day" multiple vitamin capsules each day? Wouldn’t I get the right dosage of vitamin A by doing that?

In addition to 5,000 IU vitamin A, one-a-day multiple vitamin capsules contain other vitamins and components at 100% of the RDA (recommended daily allowance). Three such capsules daily would provide an excess of these components. In addition, most of these preparations include the RDA of vitamin E, which according to the study results appears to interfere with the beneficial action of vitamin A for RP when taken in high doses. TOP

Should I be concerned about getting the right amounts of vitamin A and vitamin E in my diet?

The average diet provides approximately 3,000-4,000 IU of vitamin A per day. In the clinical treatment trial, the actual average intake for the patients was 3,600 IU per day. This daily dietary amount was taken into account for the final recommendation of a supplement of 15,000 IU vitamin A palmitate per day as a treatment for RP. You should maintain a regular balanced diet, you should NOT try to specifically select foods that are high in vitamin A content. Also, you should NOT try to eliminate foods that are high in vitamin E content. TOP

Is there anything else I can do besides maintaining a balanced diet and taking vitamin A to preserve my vision?

At this time, there are no other approaches for preserving vision affected by RP that have been proved useful through a carefully controlled clinical treatment trial. Some doctors advise their patients to protect their eyes from bright light. As a precaution, individuals with RP are encouraged to protect their eyes from long-term exposure to bright sunlight until more is learned. Good quality sunglasses are useful for bright days outdoors. TOP

Should I be encouraged by the discovery of this treatment?

Yes, indeed! This breakthrough is a concrete reward for the many years of research that preceded it. Daily vitamin A supplementation is the first discovered means to partially control RP that is proved useful and safe for most patients. This clinical treatment trial has demonstrated that further ways to slow vision loss can now be proposed with the knowledge that it can be done. The trial is an extraordinary example of the value of carefully designed work. It was done under close monitoring for appropriate benefit and avoidance of risk to patients, and will serve as a model for future studies. TOP

Will other research on RP stop now that this treatment has been found?

No, just the opposite! The search for addition and improved treatments and the means to cure or prevent RP will continue. Studies on nutritional supplements represent only one aspect of the RP scientific research strategy. This disease must be understood at the most basic cellular level in order to understand how it is caused and how it can be stopped. Research in biochemistry and cell biology, as well as molecular genetics and clinical studies, will lead to the design and testing of other treatments that may stop the progression of the disease and ultimately prevent it from ever occurring.