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Wally
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 Posted: Sat Sep 20, 2003 4:36 pm Post subject: Information and Articles about Vitamin A |
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In my Genetics class, we have to do a project. I decided to do mine of Vitamin A because I thought it would be interesting and this would give me the excuse and force me to actually learn more about it. I found out a lot of stuff, but also came up with more questions..... I think Vitamin A is one of the most important vitamins in the body. It affects the skin, the immune system, and vision. I had written up a whole, detailed sort of report on it, but then I figured that would only confuse people more, so I started over and summarized it to make it way more compact/easier to understand. Ever since I’ve have acne, I’ve tried to learn more about Vitamin A. It is used in most topical applications and in Accutane, the last resort for many. Vitamin A is found in some foods, like liver, whole milk, and eggs. Beta-carotene and other carotinoids are precursors to Vitamin A, they are not Vitamin A itself. Because they have to be converted to a more active form, true vitamin A that can be used by the body gets lost. In fact, beta-carotene has a ration of 13:1 to retinol, a more active form of Vitamin A, so while carrots have some Vitamin A, they are definitely not the best source!
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Dietary vitamin A is present mainly as retinyl esters and this together with the carotinoids aggregate with other lipids in the stomach. Absorption occurs in the upper small intestine with the assistance of bile and pancreatic enzymes. The retinyl esters and most of the b-carotenes are hydrolysed to retinol as they are transported into the small intestinal cells. In cells the retinol is bound and transported by a specific transport protein, which incorporates the retinol into the newly synthesised chylomicron which enters the lymph. The chylomicrons, containing retinol, are hydrolysed by the adipose tissue, and the resulting chylomicron-remnant is transported back to the liver.
More than 90% of the total vitamin A is stored in the liver. Retinol released from the liver into the circulation is bound to retinal binding protein (RBP). Retinol enters the target cell and combines with cellular retinol-binding protein (CRABP) to protect cells from the effects of free retinol or retinoic acid, which can be extremely damaging to cell metabolism. The resultant complex is targeted towards either the synthesis of the storage form of vitamin A (retinyl esters) or the predominantly active form (retinoic acid). |
Above is a good, quick, thorough explanation of how Vitamin A is taken in and then transported throughout the body. Retinoic acid is the last thing to be converted, creating potential for problems along the way. Retinoic acid is only found in tiny amounts in the skin, but its the most important.
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| Retinoic acid act as hormones to affect gene expression and thereby influence numerous physiological processes. Through the stimulation and inhibition of transcription of specific genes, retinoic acid plays a major role in cellular differentiation, the specilization of cells for highy specific physiological roles. |
Basically, retinoic acid helps control the growth of cells. When we don't have enough Vitamin A, which determines how much RA we have, then our cells will grow/die unhealthily.
I also found some other interesting points:
-Fat malabsorbtion affects Vitamin A. Could this help explain B5?
-Zinc is needed to transport Vitamin A through out the body. When we have more zinc, the body can use Vitamin A more efficiently
- Retinoic acid controls the skin, but also the lining of the gasto-intestinal tract
-Vitamin A also plays a big part in immune function.
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| Immune function. By increasing the activity of immune-system cells and helping to maintain a healthy mucous-secreting epithelial lining of the intestinal tract, lungs and eyes, vitamin A increases resistance to infection (the mucous membranes are the first lines of defence against foreign organisms). Deficiency in vitamin A results in atrophy of mucosal membranes, and small, unformed cells that do not perform their function properly are produced. |
That is a really brief summary of what I've found. I'm going to post the articles I found below so people can read them and maybe make more connections!
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Wally
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| Posted: Sat Sep 20, 2003 4:38 pm Post subject: 1 |
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Good, thorough overview of Vitamin A:
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NUTRIENT SUMMARY:
VITAMIN A (RETINOL)
General Information
The term vitamin A covers a group of lipid-soluble compounds (the retinoids) which have similar physiological functions and metabolic activities: retinol, retinal (the aldehyde form), and retinoic acid.
retinyl esters ß ŕ retinol ß ŕ retinal ŕ retinoic acid
Retinol inter-converts between retinyl esters and retinal, and retinoic acid is an end stage product - this distinction is important since they serve different functions: retinoic acid helps maintain the proper growth and differentiation of epithelial cells, whereas retinyl ester, retinol and retinal can all maintain cellular differentiation, support reproduction and prevent blindness.
Another form of vitamin A is found in the carotinoids from plant products. Carotinoids are pigments synthesised for photosynthesis. Only 50 of the over 600 carotinoids occurring in nature can be converted to vitamin A. The major pigment in plants is b-carotene (sometimes called provitamin A), which can be split to yield two retinol molecules.
Importantly, all the carotinoids, including those that cannot be converted to vitamin A can also bind to oxygen radicals and serve as antioxidants under certain conditions.
Functions
Vitamin A is essential throughout life as it is required in reproduction, embryonic and foetal development, vision, growth, differentiation and tissue maintenance.
Vision. Circulating retinol-RBP complex is required in the formation of rhodopsin (cis-retinal bound to the vision protein opsin), which is the light-sensitive pigment in the rod cells of the retina. Rod cells are important in night vision. In response to light energy the cis-retinal is converted to trans-retinal, the altered shape triggering a nerve impulse which is perceived as light in black and white vision. (Cone cells are important for colour vision and vision under bright light.) The period after the activation of many rhodopsin molecules (i.e. following a bright flash) involves a period of active rhodopsin synthesis.
Cell differentiation/growth and development. Retinoic acid acts as a hormone in many cells acting to regulate gene expression, thus controlling cell differentiation (or maturation). The actions of retinoic acid as a gene regulator is most evident in the maintenance of epithelial tissue (e.g. cornea, respiratory lining, skin, lining of gastro-intestinal tract) and mucous membranes. Vitamin A also participates in bone remodelling, especially important for children and adolescents during their growing years.
Immune function. By increasing the activity of immune-system cells and helping to maintain a healthy mucous-secreting epithelial lining of the intestinal tract, lungs and eyes, vitamin A increases resistance to infection (the mucous membranes are the first lines of defence against foreign organisms). Deficiency in vitamin A results in atrophy of mucosal membranes, and small, unformed cells that do not perform their function properly are produced.
Cancer and heart disease prevention. Studies have shown an inverse relationship between vitamin A intake and the prevalence of certain forms of cancer, although not all reports have provided consistent findings. Carotenoids may also play a role in cancer and heart disease prevention by acting as antioxidants and scavenging high energy free radicals. However, research to date has been inconclusive.
Physiology and Metabolism
Dietary vitamin A is present mainly as retinyl esters and this together with the carotinoids aggregate with other lipids in the stomach. Absorption occurs in the upper small intestine with the assistance of bile and pancreatic enzymes. The retinyl esters and most of the b-carotenes are hydrolysed to retinol as they are transported into the small intestinal cells. In cells the retinol is bound and transported by a specific transport protein, which incorporates the retinol into the newly synthesised chylomicron which enters the lymph. The chylomicrons, containing retinol, are hydrolysed by the adipose tissue, and the resulting chylomicron-remnant is transported back to the liver.
More than 90% of the total vitamin A is stored in the liver. Retinol released from the liver into the circulation is bound to retinal binding protein (RBP). Retinol enters the target cell and combines with cellular retinol-binding protein (CRABP) to protect cells from the effects of free retinol or retinoic acid, which can be extremely damaging to cell metabolism. The resultant complex is targeted towards either the synthesis of the storage form of vitamin A (retinyl esters) or the predominantly active form (retinoic acid).
Requirements and RDI
Retinol equivalent (RE) = Dietary retinol (µg) + b-carotene (µg) + other carotenoids (µg)
6 12
Why is this the case when b-carotene yields 2 retinol molecules? The formula is the best approximation - it takes inefficiency of conversion and inefficiency of absorption into account.
RDI: 750 µgRE/day.
Most margarines in Australia are fortifed with Vitamin A.
Some Dietary Sources
There are two major sources of vitamin A retinol, and b-carotene and some other carotenes. Of the carotenes that can be converted to vitamin A some yield only one retinol molecule and therefore have only half the provitamin A activity of b-carotene.
Food
Serving
Vitamin A (µg RE)
Mango
1 medium
800
Papaya
1 medium
610
Cantaloupe (chunks)
1 cup
520
Apricot (dried)
50 g
300
Carrot (raw)
1 medium
2000
Carrot (cooked)
1/2 cup
1900
Sweet potato (cooked)
1/2 cup
1200
Pumpkin (cooked)
1/2 cup
600
Spinach (cooked)
1/2 cup
500
Bok choy (cooked)
1/2 cup
220
Broccoli (cooked)
1/2 cup
110
Milk, skim
1/2 cup
75
Milk, whole
1/2 cup
38
Margarine (fortified)
1 tbsp
100 (approx)
Butter
1 tbsp
107
Cheese
50 g
120-200
Egg
1 large
119
Deficiency
Depending on the size of body stores it may take as long as two years for deficiency symptoms to become apparent. Vitamin A depends on proteins as carriers in the body so a lack of protein will also impact on vitamin A status. Deficiency is rare in the Western world but in the third world it is expected to affect 100 million children.
Infectious diseases. The severity of some childhood infections relates to vitamin A status. Measles, for example, is relatively benign in Western countries but is associated with high mortality in developing nations. The severity of infection often correlating with the degree of deficiency, with deaths usually due to related illnesses like pneumonia and severe diarrhoea. Vitamin A may greatly reduce infant susceptibility to infection, regardless of the child's state of other nutrients.
Night Blindness. One of the first detectable signs of vitamin A deficiency. With this condition the blood supplying rod cells contains insufficient cis-retinal to rapidly replace the trans-retinal formed on exposure to bright light (bleaching). The resulting condition is night blindness.
Blindness (Xeropthalmia). The next stage is total blindness. Xeropthalmia occurs when the soft, lubricated membrane of the eye transforms to a dry, keratinised epithelium which ultimately ulcerates and becomes susceptible to infection. The specific cause is a lack of mucous production by the eye.
Keratinisation. Deficiency of vitamin A also produces skin changes. Keratinisation is the accumulation of keratin, a water insoluble protein, in tissues. The skin becomes dry and rough and looks like millions of tiny red spots over the surface of the skin.
As the absorption of vitamin A is dependent on fat absorption, poor dietary intake and fat malabsorption syndromes contribute to deficiency. Diminished vitamin status may be seen in pre-school children who do not eat enough vegetables, alcoholics, the poor and the elderly.
Toxicity
Vitamin A, being fat soluble, can be stored and hence excessive intakes results in toxic effects. Care must be taken with the use of vitamin A supplements.
Hypercarotenosis - is usually seen with excessive intakes of carrot or tomato juice, which results in hypercarotaemia (increased blood carotene levels) and carotenodermia (yellow-orange skin colouration). This does not progress to hypervitaminosis A.
Hypervitaminosis A - occurs at recurrent intakes of 10 times RDI. Signs include alopecia, bone and muscle pain, headache and visual impairment. Liver damage is also possible.
Excess retinol may be particularly dangerous for the unborn child. It is for this reason that women who are pregnant, or who might become pregnant are advised not to take high-dose vitamin A supplements unless they are advised to do so by a health professional.
Consuming large amounts of carotenoids from foods does not readily result in toxicity. |
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Wally
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| Posted: Sat Sep 20, 2003 4:43 pm Post subject: 2 |
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General Info:
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Vitamin A (Retinol)
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Vitamin A and its metabolites play diverse roles in physiology, ranging from incorporation into vision pigments to controlling transcription of a host of important genes. Health depends on maintaining vitamin A levels within a normal range, as either too little or too much of this vitamin lead to serious disease.
Structure
Vitamin A or retinol has a structure depicted to the right. Retinol is the immediate precursor to two important active metabolites: retinal, which plays a critical role in vision, and retinoic acid, which serves as an intracellular messenger that affects transcription of a number of genes. Vitamin A does not occur in plants, but many plates contain carotenoids such as beta-carotene that can be converted to vitamin A within the intestine and other tissues.
Physiologic Effects of Vitamin A
Vitamin A and its metabolites retinal and retinoic acid appear to serve a number of critical roles in physiology, as evidenced by the myriad of disorders that accompany deficiency or excess states. In many cases, precise mechanisms are poorly understood. Some of the well-characterized effects of vitamin A include:
Vision: Retinal is a necessary structural component of rhodopsin or visual purple , the light sensitive pigment within rod and cone cells of the retina. If inadequate quantities of vitamin A are present, vision is impaired.
Resistance to infectious disease: In almost every infectious disease studied, vitamin A deficiency has been shown to increase the frequency and severity of disease. Several large trials with malnourished children have demonstrated dramatic reductions in mortality from diseases such as measles by the simple and inexpensive procedure of providing vitamin A supplementation. This "anti-infective" effect is undoubtedly complex, but is due, in part, to the necessity for vitamin A in normal immune responses. Additionally, many infections are associated with inflammatory reactions that lead to reduced synthesis of retinol-binding protein and thus, reduced circulating levels of retinol.
Epithelial cell "integrity": Many epithelial cells appear to require vitamin A for proper differentiation and maintenance. Lack of vitamin A leads to dysfunction of many epithelia - the skin becomes keratinized and scaly, and mucus secretion is suppressed. It seems likely that many of these effects are due to impaired transcriptional regulation due to deficits in retinoic acid signalling.
Bone remodeling: Normal functioning of osteoblasts and osteoclasts is dependent upon vitamin A.
Reproduction: Normal levels of vitamin A are required for sperm production, reflecting a requirement for vitamin A by spermatogenic epithelial (Sertoli) cells. Similarly, normal reproductive cycles in females require adequate availability of vitamin A.
Sources of Vitamin A
Vitamin A is present in many animal tissues, and is readily absorbed from such dietary sources in the terminal small intestine. Liver is clearly the richest dietary source of vitamin A.
Plants do not contain vitamin A, but many dark-green or dark-yellow plants (including the famous carrot) contain carotenoids such as beta-carotene that serve as provitamins because they are converted within the intestinal mucosa to retinol during absorption.
Vitamin A is stored in the liver as retinyl esters and, when needed, exported into blood, where it is carried by retinol binding protein for delivery to other tissues.
Vitamin A Deficiency and Excess States
Both too much and too little vitamin A are well known causes of disease in man and animals.
Vitamin A deficiency usually results from malnutrition, but can also be due to abnormalities in intestinal absorption of retinol or carotenoids. Deficiency is prevalent in humans, especially children, in certain underdeveloped countries. In herbivores such as cattle, vitamin A deficiency is usually due to lack of green feed, such as in animals coming off of dry summer pastures or those fed poor quality hay. Because the liver stores rather large amounts of retinol, deficiency states typically take several months to develop. Some of the more serious manifestations of vitamin A deficiency include:
Blindness due to inability to synthesize adequate quantities of rhodopsin. Moderate deficiency leads to deficits in vision under conditions of low light ("night blindness"), while severe deficiency can result in severe dryness and opacity of the cornea (xeropthalmia).
Increased risk of mortality from infectious disease has been best studied in malnourished children, but also is seen in animals. In such cases, supplementation with vitamin A has been shown to substantially reduce mortality from diseases such as measles and gastrointestinal infections.
Abnormal function of many epithelial cells, manifest by such diverse conditions as dry, scaly skin, inadequate secretion from mucosal surfaces, infertility, decreased synthesis of thyroid hormones and elevated cerebrospinal fluid pressure due to inadequate absorption in meninges.
Abnormal bone growth in vitamin A-deficient animals can result in malformations and, when the skull is affected, disorders of the central nervous system and optic nerve.
Vitamin A excess states, while not as common as deficiency, also lead to disease. Vitamin A and most retinoids are highly toxic when taken in large amounts, and the most common cause of this disorder in both man and animals is excessive supplementation. In contrast, excessive intake of carotinoids are not reported to cause disease - you cannot use the excuse of potential vitamin A toxicity to avoid eating carrots or green vegetables!
Teratogenic effects: Both hypovitaminosis A and hypervitaminosis A are known to cause congenital defects in animals and likely to have deleterious effects in humans. Pregnant women are advised not to take excessive vitamin A supplements, and some medical authorities also recommend that they consume liver only in moderation, which is usually not a hard sell to make.
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Back to the index of Vitamins
References and Reviews
Bates CJ: Vitamin A. Lancet 345:31, 1995.
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Last updated on July 4, 1999
Author: R. Bowen
Send comments via form or email to rbowen@lamar.colostate.edu |
http://arbl.cvmbs.colostate.edu/hbooks/pathphys/misc_topics/vitamina.html
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Wally
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| Posted: Sat Sep 20, 2003 4:48 pm Post subject: > |
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GREAT DETAILED article!!!!!!!
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Information Center Home LPI Home Nutrient Index Disease Index
Function
Deficiency
The RDA
Disease Prevention
Disease Treatment
Sources
Safety
The LPI Recommendation
References
Glossary
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VITAMIN A
Vitamin A is a generic term for a large number of related compounds. Retinol (an alcohol) and retinal (an aldehyde) are often referred to as preformed vitamin A. Retinal can be converted by the body to retinoic acid, the form of vitamin A known to affect gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. Beta-carotene and other carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids. Hundreds of different carotenoids are synthesized by plants, but only about 10 % of them are provitamin A carotenoids (1). The following discussion will focus mainly on preformed vitamin A and retinoic acid.
FUNCTION
Vision
The retina is located at the back of the eye. When light passes through the lens, it is sensed by the retina and converted to a nerve impulse for interpretation by the brain. Retinol is transported to the retina via the circulation, where it moves into retinal pigment epithelial cells (diagram). There, retinol is esterified to form a retinyl ester, which can be stored. When needed, retinyl esters are broken apart (hydrolyzed) and isomerized to form 11-cis retinol, which can be oxidized to form 11-cis retinal. 11-cis Retinal can be shuttled across the interphotoreceptor matrix to the rod cell, where it binds to a protein called opsin to form the visual pigment, rhodopsin (visual purple). Rod cells with rhodopsin can detect very small amounts of light, making them important for night vision. Absorption of a photon of light catalyzes the isomerization of 11-cis retinal to all-trans retinal and results in its release. This isomerization triggers a cascade of events, leading to the generation of an electrical signal to the optic nerve. The nerve impulse generated by the optic nerve is conveyed to the brain where it can be interpreted as vision. Once released all-trans retinal is converted to all-trans retinol, which can be transported across the interphotoreceptor matrix to the retinal epithelial cell to complete the visual cycle (2). Inadequate retinol available to the retina results in impaired dark adaptation, known as "night blindness."
Regulation of gene expression
Retinoic acid (RA) and its isomers act as hormones to affect gene expression and thereby influence numerous physiological processes. All-trans RA and 9-cis RA are transported to the nucleus of the cell bound to cytoplasmic retinoic acid-binding proteins (CRABP). Within the nucleus, RA binds to retinoic acid receptor proteins (diagram). All-trans RA binds to retinoic acid receptors (RAR) and 9-cis RA binds to retinoid receptors (RXR). RAR and RXR form RAR/RXR heterodimers, which bind to regulatory regions of the chromosome called retinoic acid response elements (RARE). A dimer is a complex of two protein molecules. Heterodimers are complexes of two different proteins, while homodimers are complexes of two of the same protein. Binding of all-trans RA and 9-cis RA to RAR and RXR respectively allows the complex to regulate the rate of gene transcription, thereby influencing the synthesis of certain proteins used throughout the body. RXR may also form heterodimers with thyroid hormone receptors (THR) or vitamin D receptors (VDR). In this way, vitamin A, thyroid hormone, and vitamin D may interact to influence gene transcription (3). Through the stimulation and inhibition of transcription of specific genes, retinoic acid plays a major role in cellular differentiation, the specialization of cells for highly specific physiological roles. Most of the physiological effects attributed to vitamin A appear to result from its role in cellular differentiation.
Immunity
Vitamin A is commonly known as the anti-infective vitamin, because it is required for normal functioning of the immune system (4). The skin and mucosal cells (cells that line the airways, digestive tract, and urinary tract) function as a barrier and form the body's first line of defense against infection. Retinol and its metabolites are required to maintain the integrity and function of these cells (5). Vitamin A and retinoic acid (RA) play a central role in the development and differentiation of white blood cells, such as lymphocytes that play critical roles in the immune response. Activation of T-lymphocytes, the major regulatory cells of the immune system, appears to require all-trans RA binding of RAR (3).
Growth and Development
Both vitamin A excess and deficiency are known to cause birth defects. Retinol and retinoic acid (RA) are essential for embryonic development (4). During fetal development, RA functions in limb development and formation of the heart, eyes, and ears (6). Additionally, RA has been found to regulate expression of the gene for growth hormone.
Red blood cell production
Red blood cells, like all blood cells, are derived from precursor cells called stem cells. These stem cells are dependent on retinoids for normal differentiation into red blood cells. Additionally, vitamin A appears to facilitate the mobilization of iron from storage sites to the developing red blood cell for incorporation into hemoglobin, the oxygen carrier in red blood cells (2, 7).
Nutrient Interactions
Zinc and vitamin A: Zinc deficiency is thought to interfere with vitamin A metabolism in several ways: 1) Zinc deficiency results in decreased synthesis of retinol binding protein (RBP), which transports retinol through the circulation to tissues (e.g., the retina). 2) Zinc deficiency results in decreased activity of the enzyme that releases retinol from its storage form, retinyl palmitate, in the liver. 3) Zinc is required for the enzyme that converts retinol into retinal (8, 9). At present, the health consequences of zinc deficiency on vitamin A nutritional status in humans are unclear (10).
Iron and vitamin A: Vitamin A deficiency may exacerbate iron deficiency anemia. Vitamin A supplementation has been shown to have beneficial effects on iron deficiency anemia and improve iron nutritional status among children and pregnant women. The combination of vitamin A and iron seems to reduce anemia more effectively than either iron or vitamin A alone (11).
DEFICIENCY
Vitamin A deficiency and vision
Vitamin A deficiency among children in developing nations is the leading preventable cause of blindness (12). The earliest evidence of vitamin A deficiency is impaired dark adaptation or night blindness. Mild vitamin A deficiency may result in changes in the conjunctiva (corner of the eye) called Bitot's spots. Severe or prolonged vitamin A deficiency causes a condition called xeropthalmia (dry eye), characterized by changes in the cells of the cornea (clear covering of the eye) that ultimately result in corneal ulcers, scarring, and blindness (4,  .
Vitamin A deficiency and infectious disease
Vitamin A deficiency can be considered a nutritionally acquired immunodeficiency disease (13). Even children who are only mildly deficient in vitamin A have a higher incidence of respiratory disease and diarrhea, as well as a higher rate of mortality from infectious disease, than children who consume sufficient vitamin A (14). Supplementation of vitamin A has been found to decrease the severity of and deaths from diarrhea and measles in developing countries, where vitamin A deficiency is common (15). HIV-infected women who were vitamin A deficient were three to four times more likely to transmit HIV to their infants (16). The onset of infection reduces blood retinol levels very rapidly. This phenomenon is generally believed to be related to decreased synthesis of retinol binding protein (RBP) by the liver. In this manner, infection stimulates a vicious cycle, because inadequate vitamin A nutritional status is related to increased severity and likelihood of death from infectious disease (17).
The Recommended Dietary Allowance (RDA)
The RDA for vitamin A was revised by the Food and Nutrition Board (FNB) of the Institute of Medicine in 2001. The latest RDA is based on the amount needed to ensure adequate stores of vitamin A in the body to support normal reproductive function, immune function, gene expression, and vision (1.
Recommended Dietary Allowance (RDA) for Vitamin A as Preformed Vitamin A (Retinol)
Life Stage Age Males: mcg/day (IU/day) Females: mcg/day (IU/day)
Infants 0-6 months 400 (1333 IU) 400 (1333 IU)
Infants 7-12 months 500 (1667 IU) 500 (1667 IU)
Children 1-3 years 300 (1000 IU) 300 (1000 IU)
Children 4-8 years 400 (1333 IU) 400 (1333 IU)
Children 9-13 years 600 (2000 IU) 600 (2000 IU)
Adolescents 14-18 years 900 (3000 IU) 700 (2333 IU)
Adults 19 years and older 900 (3000 IU) 700 (2333 IU)
Pregnancy 18 years and younger - 750 (2500 IU)
Pregnancy 19-years and older - 770 (2567 IU)
Breastfeeding 18 years and younger - 1,200 (4000 IU)
Breastfeeding 19-years and older - 1,300 (4333 IU)
DISEASE PREVENTION
Cancer
Studies in cell culture and animal models have documented the capacity for natural and synthetic retinoids to reduce carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites (2). However, the results of human studies examining the relationship between the consumption of preformed vitamin A and cancer are less clear.
Lung cancer: At least ten prospective studies have compared blood retinol levels at baseline among people who subsequently developed lung cancer and those who did not. Only one of those studies found a statistically significant inverse association between serum retinol and lung cancer risk (19). The results of the Beta-Carotene And Retinol Efficacy Trial (CARET) suggest that high-dose supplementation of vitamin A and b-carotene should be avoided in people at high risk of lung cancer (20). About 9,000 people (smokers and people with asbestos exposure) were assigned a daily regimen of 25,000 IU of retinol and 30 milligrams of b-carotene, while a similar number of people were assigned a placebo. After four years of follow up the incidence of lung cancer was 28% higher in the supplemented group. Presently, it seems unlikely that increased retinol intake decreases the risk of lung cancer, although the effects of retinol may be different for nonsmokers compared to smokers (19).
Breast cancer: Retinol and its metabolites have been found to reduce the growth of breast cancer cells in the test tube, but observational studies of dietary retinol intake in humans have been less optimistic (21). The majority of epidemiologic studies have failed to find significant associations between retinol intake and breast cancer risk in women (22-25), although one large prospective study found total vitamin A intake to be inversely associated with the risk of breast cancer in premenopausal women with a family history of breast cancer (26). Blood levels of retinol reflect the intake of both preformed vitamin A and provitamin A carotenoids like b-carotene. Although a recent case-control study found serum retinol levels and serum antioxidant levels to be inversely related to the risk of breast cancer (27), two recent prospective studies did not observe significant associations between blood retinol levels and the subsequent risk of developing breast cancer (28, 29). Presently, there is little evidence in humans that increased intake of preformed vitamin A or retinol reduces breast cancer risk.
DISEASE TREATMENT
Pharmacologic doses of retinoids
It is important to note that treatment with high doses of natural or synthetic retinoids overrides the body's own control mechanisms, and therefore carries with it risks of side effects and toxicity. Additionally, all of these compounds have been found to cause birth defects. Women who have a chance of becoming pregnant should avoid treatment with these medications. Retinoids tend to be very long acting; side effects and birth defects have been reported to occur months after discontinuing retinoid therapy (2). The retinoids discussed below are prescription drugs, and should not be used without medical supervision.
Retinitis pigmentosa
Retinitis pigmentosa describes a broad spectrum of genetic disorders that result in the progressive loss of photoreceptor cells (rods and cones) in the eye's retina (30). Early symptoms of retinitis pigmentosa include impaired dark adaptation and night blindness, followed by the progressive loss of peripheral and central vision over time. The results of a randomized controlled trial in more than 600 patients with common forms of retinitis pigmentosa indicated that supplementation with 4,500 mcg (15,000 IU)/day of preformed vitamin A (retinol) significantly slowed the loss of retinal function over a period of 4-6 years (31). In contrast, supplementation with 400 IU/day of vitamin E increased the loss of retinal function by a small but significant amount, suggesting that patients with common forms of retinitis pigmentosa may benefit from long term vitamin A supplementation but should avoid vitamin E supplementation at levels higher than those found in a typical multivitamin. Up to 12 years of follow-up in these patients did not reveal any signs of liver toxicity as a result of excess vitamin A intake (32). High dose vitamin A supplementation to slow the course of retinitis pigmentosa requires medical supervision and must be discontinued if there is a possibility of pregnancy (see Safety).
Acute promyelotic leukemia
Normal differentiation of myeloid stem cells in the bone marrow gives rise to platelets, red blood cells, and white blood cells, which are important for the immune response. Altered differentiation of those stem cells results in the proliferation of immature leukemic cells, giving rise to leukemia. A mutation of the retinoic acid receptor RAR has been discovered in patients with a specific type of leukemia called acute promyelotic leukemia (APL). Treatment with all-trans retinoic acid or high doses of all-trans retinyl palmitate restores normal differentiation, and leads to improvement in some APL patients (2,17).
Diseases of the skin
Both natural and synthetic retinoids have been used as pharmacologic agents to treat disorders of the skin. Etretinate and acitretin are retinoids that have been useful in the treatment of psoriasis, while tretinoin (Retin-A) and isotretinoin (Accutane) have been used successfully to treat severe acne. Retinoids most likely affect the transcription of skin growth factors and their receptors (2).
SOURCES
Retinol activity equivalency (RAE)
Different dietary sources of vitamin A have different potencies. For example, beta-carotene is less easily absorbed than retinol and must be converted to retinal and retinol by the body. The most recent international standard of measure for vitamin A is retinol activity equivalency (RAE), which represents vitamin A activity as retinol. Two micrograms (mcg) of beta-carotene in oil provided as a supplement can be converted by the body to 1 mcg of retinol giving it an RAE ratio of 2:1. However, 12 mcg of beta-carotene from foods are required to provide the body with 1 mcg of retinol, giving dietary beta-carotene an RAE ratio of 12:1. Other provitamin A carotenoids in foods are less easily absorbed than beta-carotene, resulting in RAE ratios of 24:1. The RAE ratios for beta-carotene and other provitamin A carotenoids are shown in the table below (1. An older international standard, still commonly used, is the international unit (IU). One IU is equivalent to 0.3 mcg of retinol.
Retinol activity equivalency (RAE) ratios for beta-carotene and other provitamin A carotenoids
Quantity Consumed Quantity Bioconverted to Retinol RAE ratio
1 mcg of dietary or supplemental vitamin A 1 mcg of retinol 1:1
2 mcg of supplemental beta-carotene 1 mcg of retinol 2:1
12 mcg of dietary beta-carotene 1 mcg of retinol 12:1
24 mcg of dietary alpha-carotene 1 mcg of retinol 24:1
24 mcg of dietary beta-cryptoxanthin 1 mcg of retinol 24:1
Food sources
Free retinol is not generally found in foods. Retinyl palmitate, a precursor and storage form of retinol, is found in foods from animals. Plants contain carotenoids, some of which are precursors for vitamin A (e.g., alpha-carotene and beta-carotene). Yellow and orange vegetables contain significant quantities of carotenoids. Green vegetables also contain carotenoids, though the pigment is masked by the green pigment of chlorophyll (1). A number of good food sources of vitamin A are listed in the table below along with their vitamin A content in retinol activity equivalents (mcg RAE). In those foods where retinol activity comes mainly from provitamin A carotenoids, the carotenoid content and the retinol activity equivalents are presented. You may use the USDA-NCC carotenoid database to check foods for their content of several different carotenoids, including lutein and xeaxanthin. For more information on the nutrient content of foods you eat frequently, search the USDA food composition database.
Food Serving Vitamin A
(mcg RAE) Alpha-Carotene
(mcg) Alpha-Carotene
(mcg RAE) Beta-Carotene (mcg) Beta-Carotene
(mcg RAE)
Cod liver oil 1 tablespoon 4,080 0 0 0 0
Fortified cereal 1 cup 140-280 0 0 0 0
Egg 1 large 119 0 0 0 0
Butter 1 tablespoon 107 0 0 0 0
Whole milk 1 cup (8 ounces) 76 0 0 0 0
Sweet potato 1/2 cup, mashed 1,136 0 0 13,635 1,136
Carrot (raw) 1/2 cup, chopped 595 2,975 124 5,655 471
Cantaloupe 1/2 medium melon 370 75 3 4,402 367
Spinach 1/2 cup, cooked 393 0 0 4,717 393
Apricot 1 piece of fruit 74 0 0 893 74
Squash, butternut 1/2 cup, cooked 42 0 0 505 42
Zucchini, summer 1/2 cup, cooked 31 0 0 369 31
Supplements
The principal forms of preformed vitamin A (retinol) in supplements are retinyl palmitate and retinyl acetate. Beta-carotene is also a common source of vitamin A in supplements, and many supplements provide a combination of retinol and beta-carotene (33). If a percentage of the total vitamin A content of a supplement comes from beta-carotene, this information is included in the Supplement Facts label under vitamin A (see example supplement label). Most multivitamin supplements available in the U.S. provide 1,500 mcg (5,000 IU) of vitamin A, substantially more than the current RDA for vitamin A. This is due to the fact that the Daily Values (DV) used by the FDA for supplement labeling are based on the RDAs established in 1968 rather than the most recent RDAs, and multivitamin supplements typically provide 100% of the DV for most nutrients. Because retinol intakes of 5,000 IU/day have recently been associated with an increased risk of osteoporosis in older adults (see Safety), some companies have reduced the retinol content in their multivitamin supplements to 750 mcg (2,500 IU).
SAFETY
Toxicity
The condition caused by vitamin A toxicity is called hypervitaminosis A. It is caused by overconsumption of preformed vitamin A, not carotenoids. Preformed vitamin A is rapidly absorbed and slowly cleared from the body, so toxicity may result acutely from high-dose exposure over a short period of time, or chronically from much lower intake (2). Vitamin A toxicity is relatively rare. Symptoms include nausea, headache, fatigue, loss of appetite, dizziness, and dry skin. Signs of chronic toxicity include, dry itchy skin, loss of appetite, headache, and bone and joint pain. Severe cases of hypervitaminosis A may result in liver damage, hemorrhage, and coma. Generally, signs of toxicity are associated with long-term consumption of vitamin A in excess of 10 times the RDA (8,000 to 10,000 mcg/day or 25,000 to 33,000 IU/day). However, there is evidence that some populations may be more susceptible to toxicity at lower doses, including the elderly, chronic alcohol users, and some people with a genetic predisposition to high cholesterol (9). In January 2001, the Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper level (UL) of vitamin A intake for adults at 3,000 mcg (10,000 IU)/day of preformed vitamin A (1.
Tolerable Upper Level of Intake (UL) for Preformed Vitamin A (Retinol)
Age Group UL in mcg/day (IU/day)
Infants 0-12 months 600 (2,000 IU)
Children 1-3 years 600 (2,000 IU)
Children 4-8 years 900 (3,000 IU)
Children 9-13 years 1,700 (5,667 IU)
Adolescents 14-18 years 2,800 (9,333 IU)
Adults 19 years and older 3,000 (10,000 IU)
Safety in pregnancy
Because excess preformed vitamin A consumed during pregnancy is known to cause birth defects, pregnant women are cautioned not to consume more than 800 mcg/day (2,600 IU/day) of retinol from supplements (34). Additionally, etretinate and isotretinoin (Accutane), synthetic derivatives of retinol, are known to cause birth defects and should not be taken during pregnancy or if there is a possibility of becoming pregnant. Tretinoin (Retin-A), another retinol derivative, is prescribed as a topical preparation that is applied to the skin. Because of the potential for systemic absorption of topical tretinoin, its use during pregnancy is not recommended.
Do high intakes of vitamin A increase the risk of osteoporosis?
The results of several recent prospective studies suggest that long term intakes of preformed vitamin A in excess of 1,500 mcg/day (5,000 IU/day) are associated with increased risk of osteoporotic fracture and decreased bone mineral density (BMD) in older men and women.(35-37) Although this level of intake is greater than the RDA of 700-900 mcg/day (2,300-3,000 IU/day), it is substantially lower than the UL of 3,000 mcg/day (10,000 IU/day). Only excess intakes of preformed vitamin A (retinol), not beta-carotene, were associated with adverse effects on bone health. Although these observational studies cannot provide the reason for the association between excess retinol intake and osteoporosis, limited experimental data suggest that excess retinol may stimulate bone resorption (3 or interfere with the ability of vitamin D to maintain calcium balance (39). In the U.S., retinol intakes in excess of 5,000 IU/day can be easily attained by those who regularly consume multivitamin supplements and/or fortified foods, including some breakfast cereals. At the other end of the spectrum, a significant number of elderly people have insufficient vitamin A intakes, which have also been associated with decreased BMD. One study of elderly men and women found that BMD was optimal at vitamin A intakes close to the RDA (36). Until supplements and fortified foods are reformulated to reflect the current RDA for vitamin A, it makes sense to look for multivitamin supplements that contain 2,500 IU of vitamin A or multivitamin supplements that contain 5,000 IU of vitamin A, of which at least 50% comes from beta-carotene (see example supplement label).
Drug Interactions
Chronic alcohol consumption results in depletion of liver stores of vitamin A, and may contribute to alcohol-induced liver damage (40). However, the liver toxicity of preformed vitamin A (retinol) is enhanced by chronic alcohol consumption, thus narrowing the therapeutic window for vitamin A supplementation in alcoholics (41). Oral contraceptives that contain estrogen and progestin increase retinol binding protein (RBP) synthesis by the liver, increasing the export of RBP-retinol complex in the blood. Whether this increases the dietary requirement of vitamin A is not known. Retinoids or retinoid analogs, including acitretin, all-trans-retinoic acid, bexarotene, etretinate and isotretinoin (Accutane), should not be used in combination with vitamin A supplements, because they may increase the risk of vitamin A toxicity (33).
THE LINUS PAULING INSTITUTE RECOMMENDATION
The RDA for vitamin A (2,300 IU/day for women and 3,000 IU/day for men) is sufficient to support normal gene expression, immune function, and vision. However, following the Linus Pauling Institute’s recommendation to take a multivitamin/multimineral supplement daily could supply as much as 5,000 IU/day of vitamin A as retinol, the amount that has been associated with adverse effects on bone health in older adults. For this reason, we recommend taking a multivitamin/multimineral supplement that provides no more than 2,500 IU of vitamin A or a supplement that provides 5,000 IU of vitamin A, of which at least 50% comes from beta-carotene (see example supplement label). High potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.
Older adults (65 years and older)
Presently there is little evidence that the requirement for vitamin A in older adults differs from that of younger adults. Additionally, vitamin A toxicity may occur at lower doses in older adults than in younger adults. Following the Linus Pauling Institute’s recommendation to take a multivitamin/multimineral supplement daily could supply as much as 5,000 IU/day of retinol, the amount that has been associated with adverse effects on bone health in older adults. For this reason, we recommend taking a multivitamin/multimineral supplement that provides no more than 2,500 IU of vitamin A or a supplement that provides 5,000 IU of vitamin A, of which at least 50% comes from beta-carotene (see example supplement label). High potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.
REFERENCES
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Reviewed by:
Norman I. Krinsky, Ph.D., Professor, Emeritus
Department of Biochemistry
Tufts University School of Medicine
USDA Human Nutrition Research Center on Aging
Do high intakes of vitamin A increase the risk of osteoporosis?
Reviewed by
Diane Feskanich, Sc.D.
Instructor in Medicine, Harvard Medical School
Associate Epidemiologist, Brigham and Women's Hospital
Last updated 08/14/2003 Copyright 2000-2003 The Linus Pauling Institute
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If you have questions or comments regarding information in the Micronutrient Information Center, send them to Jane Higdon, Ph.D. at jane.higdon@oregonstate.edu.
Top Information Center Home LPI Home Nutrient Index Disease Index |
http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/
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Wally
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| Posted: Sat Sep 20, 2003 4:54 pm Post subject: 4 |
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Quick, easy to read facts: (this one also tells about % in topical retinoids)
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The VIT A Fact File
Fact: Vitamin A is the dominant vitamin of the skin because it has a fundamental role in the control of normal activities of skin cells.
Fact: Vitamin A is of great importance in controlling normal activities of the DNA of the nucleus of the cell as well as the mitochondria. DNA maintains the normal activities of skin cells.
Fact: One must remember that vitamin A is also necessary for the formation of healthy blood cells in the bone marrow.
Fact: Names of Vit A are:
Retinyl palmitate,
Retinyl aldehyde,
Retinal aldehyde,
Retinol,
Retinoic acid,
Retinyl linoleate,
Retinyl propionate,
Retinyl acetate,
Beta-carotene.
Is it any wonder we get confused?
Fact: Vitamin A is normally found in the skin predominantly as retinyl palmitate, which is an ester of vitamin A.
Fact: An ester is the name applied to a chemical group of organic compounds, which consist of a combination of carbon and hydrogen atoms in a chain without any double bonds.
Fact: Esters as a cosmetic ingredient, they can be natural or synthetic and liquid or solid depending on properties of the reacting substances. Being insoluble in water, they replace oils and fats to provide uniform composition and preservation. They have good skin tolerance and a lubricating and emollient action.
Fact: There are numerous esters of vitamin A and the most commonly used are retinyl palmitate and retinyl acetate.
Fact: The esters of vitamin A are less irritant and kinder to the skin and will eventually result as using the more aggressive versions of vitamin A.
Fact: The reason for this is that in the skin we have enzymes that convert the retinyl esters into retinol and from that the retinol is converted in retinal, that is retinyl aldehyde.
It is from there it is converted into retinoic acid and retinoic acid is the actual chemical that makes the changes in the DNA and cellular structures. However, only a tiny amount of retinoic acid is normally found in the skin. It also seems as though the natural ability to store vitamin A in the skin determines the level of retinoic acid that is found in the cells. In that way one can increase the amount of retinoic acid in the cells by increasing the amount of retinyl palmitate and other esters in the skin.
Fact: There are also Retinyl propionate and Retinyl linoleate.The theoretical advantage of the linoleate is that it is a combination of vitamin A with Vitamin F.
Fact: Vitamin A is extremely sensitive to sunlight and particularly to UVA.
Fact: With the development of modern sunscreens, we are not able to give sufficient protection of the skin from UVA.
Fact: Vitamin A is still damaged by exposure to light, even when a person is wearing a sun protection factor of 30 or 40.
Fact: By 1955, it was discovered that the application of vitamin A as retinyl palmitate to aged skin rejuvenates the skin to a small degree. The test period at that time was a mere six weeks. Sigmund Berg showed that people who suffered severe sunburn could be improved by oral administration of vitamin A in high dosage.
Fact: Today it is well recognized that the rejuvenation of skin can be achieved by applying Vitamin A to the skin.
Fact: When one reads about the various types of Vitamin A one may be confused as to which type of Vitamin A to use on the skin.
Fact: There are a number of related Molecules with Vitamin A activity and these are classed under the family name of retinoids.
Fact: The most common form of vitamin A is Retinyl palmitate, which is the form of Vitamin A that’s normal found in livers. Retinyl palmitate is also found in the liver of fish like halibut, cod and sharks.
Fact: Retinyl palmitate accounts for about 80% of the Vitamin A found in the skin.
Fact: Retinyl palmitate is an ester of Vitamin A.
Fact: Retinal or retinyl aldehyde. This is the form of vitamin, which is essential for normal vision, and a deficiency of this vitamin will lead to night blindness in the beginning.
Fact: Retinol is the alcohol form of vitamin A. This is the form of vitamin A that is used normally to transport vitamin A from the liver to the tissues. It is bound to certain proteins in the bloodstream, then taken up by the various organs, especially the skin.
Fact: Retinoic acid is the acid form of vitamin A and has gained great popularity and notoriety.
Fact: Retinoic acid: This is the most irritant form of Vitamin A and this is usually only available on prescription from a doctor. It is also known as tretinoin.
Fact: Only a tiny amount of Retinoic acid is normally found in the skin.
Fact: It also seems as though the natural ability to store vitamin A in the skin determines the level of Retinoic acid that is found in the cells.
Fact: In that way one can increase the amount of Retinoic acid in the cells by increasing the amount of Retinyl palmitate and other esters in the skin.
Fact: Another version of vitamin A is Beta-carotene, which is the plant version of Vitamin A. Under normal circumstance’s beta-carotene is maintained as beta-carotene and is normally found in skin in fairly high concentrations. In the oriental people the beta-carotene levels are higher than in the westerners. Beta-carotene has the ability to be cleaved into two molecules of retinal.
Fact: This is the reason why Vit A deficiency never occurs amongst vegetarians. It is important to remember that vitamin A deficiency is probably the most common deficiency in the world today. It is likely that the clinical deficiency of vitamin A in skin is also the greatest vitamin deficiency of the skin.
Fact: Vitamin A should be used daily, if used during daylight hours it should be accompanied with anti oxidant vitamins like vitamin C, E and beta carotene, so that it is relatively protected from ultra violet light.
Fact: A reliable UVA sunscreen should be used at the same time in preference to a high SPF ratio cream.
Fact: Vitamin A should also be replaced every evening as a topical application to the skin to try to address the daily loss of Vitamin A.
Fact: Because we cannot prevent the damage to the Vitamin A in the skin, it is essential to replace the vitamin A each day. So that we do not gradually develop the signs of Photoageing which are really also the signs of vitamin A deficiency of the skin?
Fact: Vit A is measured in international units (i.u.) per gram. The recommended effective doses are between 500 i.u. and 10,000i.u.
Fact: International units per gram expressed in percentages: 10 000 i.u./g = 1% pg 7000 i.u./g = 0.7%pg, 2 500 i.u./g = 0.25%pg, 1 250 i.u./g = 0.125%pg
Fact: Vit A metabolism is strongly tied to Vit C, and Vit C is essential for the proper function of Vit E.
Fact: Skin absorption is not efficient,, at most the most effective penetration of any cream is only in the region of 7% and 2% is considered average.
Fact: If you rub on a gram of Vit A cream containing 5000 i.u. g% on the face, then you will apply 5000 i.u. on to the facial skin, and of that 100 i.u. to a maximum of 350 i.u. will reach the Keratinocyte layer or the upper papillary dermis over about 260 square centimeters. This is 1.2 i.u. per square centimeter and this probably translates into a concentration of Vit A in the tissues that is close to the serum concentration. |
http://www.beautymagonline.com/pages/vitaminAfact_file.htm
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Wally
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| Posted: Sat Sep 20, 2003 5:14 pm Post subject: 5 |
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This article talks about Vitamin A and more specific diseases. It is focused a lot on the Gulf War Syndrome, put it mentions some other good information too.
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The Role of Vitamin A Deficiency in Autoimmune Diseases Including Gulf War Syndrome, Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, and Fibromyalgia ImmuneSupport.com
11-25-2002
By Frederick W. Plapp, Jr. Ph.D.
Professor Emeritus of Insecticide Toxicology, Texas A&M University,
SUMMARY
Immune system dysfunction may be a cause of multiple human autoimmune diseases, ranging from rheumatoid arthritis to multiple chemical sensitivities and Gulf War Illness. A lack of vitamin A hormone (retinoic acid) appears to play a key role in autoimmune disease. The deficit may be the result of a genetic deficiency in synthesis of the hormone, of exposure to environmental chemicals which interfere with hormone synthesis, or of a combination of the two. Prevention may be achieved by the use of vitamin A-rich diets and/or by avoidance of exposures to appropriate environmental chemicals.
INTRODUCTION
Vitamin A (retinol) and vitamin A hormone (retinoic acid) comprise one of the major human hormone systems. The importance of vitamin A in regulating visual accommodation as measured by both dark adaptation and photosensitivity has been known for many years.
Additional roles for vitamin A/retinoic acid have been recognized more recently. These include activation of synthesis of immune system proteins, activation of enzyme synthesis relative to apoptosis (killing off old cells) and drug metabolism, activation of protein synthesis related to neurotransmission, and activation of protein synthesis relating to reproduction. These findings suggest that quantitative changes in the vitamin A system may relate to health problems involving these areas. Without normal levels of vitamin A hormone, these systems are not fully functional.
Variations between individuals in levels of vitamin A are known to occur in human populations and, as described below, deficiency in vitamin A may relate to increased frequencies of autoimmune diseases as compared to the general population. Sub-populations such as those who served in the 1990-1991 Persian Gulf War also seem to be at greater risk than the general population. In addition, exposure of humans to various environmental chemicals such as pesticides and other endocrine disrupters may result in poisoning both the transport and synthesis of vitamin A. Individuals at greatest risk of autoimmune disease appear to be those who combine the genetic deficiency with chemical exposures. Material in support of this hypothesis follows.
VITAMIN A AND HUMAN DISEASE
The occurrence of diseases associated with malnutrition/vitamin A deficiency is well established in developing countries. Vitamin A deficiency is clearly associated with blindness in children (xerophthalmia) (see ref. 1). Higher infant mortality rates (2) and morbidity and mortality associated with infectious diseases (3) have also been demonstrated in vitamin A deficient children.
Vitamin A deficiency is associated with a predisposition to Staphylococcus aureus infection in rats (4). The authors also reported that host defense mechanisms are “profoundly affected” by Vitamin A deficiency.
Vitamin A deficiency is “strongly associated” with impaired immunity and infectious disease (5). Vitamin A deficiency impairs innate immunity and is also related to adaptive immunity (6).
Examples of autoimmune diseases associated with vitamin A deficiency include rheumatoid arthritis (7), juvenile arthritis (, Lyme disease (9), systemic lupus (7), and insulin dependent diabetes mellitus (10, 11). Evidence has been reported from several studies that low vitamin A levels occurred in affected individuals before they became ill. In other words, the lack of vitamin A is associated with development of the disease and is not a consequence of them.
Several human cancers have been reported to be associated with vitamin A deficiency (e.g. 12). Similarly, vitamin A levels are depleted in individuals with HIV/AIDS (13).
A number of neurological conditions may also relate to vitamin A deficiency. Lack of retinoic acid depresses synthesis of dopamine D2 receptors in mice suggesting a key role for retinoic acid in central nervous system gene expression (14). Further, a lack of retinoic acid induces a Parkinsonism-like condition in rats (15). The mouse hippocampus is a site of robust retinoid synthesis and retinoids are essential competence factors in the adult mouse brain (16). Similarly, retinoids are required for normal brain signaling in aged mice (17), suggesting a role for retinoids in optimal brain functioning in older individuals.
As described above, a possible role of vitamin A deficiency seems well established for a number of human illnesses. To the best of my knowledge, there have not been studies directly investigating the relationships between vitamin A and any of the several Gulf War Illnesses. Similarly, there seem to be a dearth of studies involving vitamin A and more recently recognized conditions as chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity. I propose such studies are badly needed. At the very least, the ideas presented here represent testable hypotheses and thus, are amenable to scientific study.
CHEMICAL EXPOSURES CAUSING VITAMIN A DEFICIENCY
Deficiency of vitamin A occurs frequently in humans and wildlife exposed to a wide array of environmental chemicals. Several processes appear to be involved. One is the binding of environmental chemicals to transthyretin, the protein which transports thyroid hormones and the retinol-retinol binding protein complex from sites of synthesis to sites of action. Evidence for poisoning of this process by environmental chemicals was first reported by Brouwer and Van Den Berg (1. The second process, poisoning of proteins involved in the synthesis of vitamin A, has not been systematically investigated. The apparent crucial step is inhibition of the esterases that hydrolyze fat-soluble retinyl esters such as retinyl acetate and retinyl palmitate. This inhibition blocks the conversion of these esters to retinol.
The third process involves interference with the oxidation of retinol, the product of retinyl ester hydrolysis, to retinoic acid, the active hormone. Retinol is oxidized via a two step process. The first step converts retinol to retinaldehyde and the second step converts retinaldehyde to retinoic acid (19,20). This step is also subject to poisoning. The synthetic chemicals, formaldehyde and acetaldehyde, both used in resin components of building products such as plasterboard and carpeting, are oxidized by the same process that converts retinaldehyde to retinoic acid. The presence of these competitors blocks the final step in hormone production and may be responsible for the human illness known as Sick Building Syndrome.
Different types of chemicals are involved in the different poisoning processes. Chlorinated phenoxyphenyls such as tetrachlorodioxin (TCDD), the major chemical involved in Agent Orange poisoning in Viet Nam, and polychlorinated biphenyls (PCB), a widely used plasticizer, both bind to transferrin and are well known as causes of human health problems. Hepatic vitamin A depletion in TCDD-treated rodents is a sensitive marker of TCDD exposures (21). Similar findings have been reported with exposures to PCBs and polybrominated biphenyls (22). Several types of insecticides, notably diphenyl ethanes such as DDT, and the phenoxybenzyl chlorinated pyrethroids such as permethrin and cypermethrin are potential transferrin poisons, but have not apparently been evaluated in this regard.
The second process, inhibition of retinyl ester hydrolysis by chemicals used in the Persian Gulf, has not been evaluated. It is well known that organophosphate and carbamate insecticides are poisons of many esterases, blocking reactions ranging from hydrolysis of acetylcholine to hydrolysis of long chain fatty acid esters. Pyrethroid insecticides are known as substrates for multiple esterases and may reduce esterase activity via competition for active sites.
Human exposure to subacute doses of esterase inhibitors is widespread in both military and civilian populations. Permethrin aerosol formulations were routinely made available to personnel in the Persian Gulf for self treatment of uniforms to protect against biting and disease carrying insects. I have not been able to determine if pretreated uniforms were issued to personnel in the Gulf or if uniforms were retreated with these chemicals at military laundry facilities in the Gulf. However, it is well established that the military has been developing the use of permethrin for treatment of uniforms since the early 1980s.
High rates of Gulf War illnesses occurred in rear area personnel such as nurses. Sanitation and regular clothing changes are necessary for hospital service and laundry treatment of uniforms with permethrin is a possible cause of their health problems (personal communications with Gulf War veterans).
Exposures to residues of insecticides applied to interior living and working areas, and to lawns and gardens have produced similar responses in civilians (numerous personal communications). Based on my knowledge of the action of potential esterase inhibitors in combination with low dose exposures to chemical toxicants, these residue treatments offer a plausible explanation for health problems in civilians similar to those seen in Persian Gulf veterans.
PON1 AND VITAMIN A: IS THERE A RELATIONSHIP?
The only biochemical variations clearly shown to relate to Gulf War Illness are the several mutations in the sequence of the esterase gene PON-1, also known as paraoxonase or paraoxonase-1, as well as mutations in upstream promoter regions. PON1 is an esterase capable of metabolizing paraoxon, the active form of the organophosphate insecticide parathion, as well as oxon forms of other phosphorothionate insecticides. Sick Gulf War veterans from a small test population were shown to have lower levels of PON1 activity than their healthy peers (23) and also to have a greater frequency of the less frequent R allele as compared to the Q allele than healthy veterans. Low PON1 activity is also characteristic of individuals with type 1 diabetes (24). Evidence of mutations in promoter sequences has been reported (25) along with evidence the mutations can cause large changes in PON1 activity.
The natural function of the PON1 esterase is not known. The idea it evolved in order to react with insecticides developed in the 20th century is not evolutionarily sound. There are suggestions that PON1 functions to protect against oxidative damage associated with high and low density lipoproteins (26) and other evidence it may relate to coronary disease (27). Alternative functions such as hydrolyzing lipophilic hormone precursors, e.g. retinyl esters, seem not to have been considered. It may be worthwhile to determine if competition between endogenous hormone-related chemicals and xenobiotics could increase our knowledge of the esterase and its possible role in Gulf War Syndrome and other autoimmune diseases.
REFERENCES
1. McLaren DS. 1999, J Indian Med Assoc 97:320
2. Semba RD et al. 1998, J Trop Pediatr 44:232
3. Donald PR et al. 1995, S Afr Med J 85:373
4. Wiedermann U et al. 1996, Infect Immun 64:209
5. Harbige LS. 1996, Nutr Health 10:285
6. Stephenson CB. 2001, Annu Rev Nutr 21:167
7. Comstock GW et al. 1997, Ann Rheum Dis 56:323
8. Helgeland M et al. 2000, Clin Exp Rheumatol 18:637
9. Cantorna MT, Hayes CE. 1996, J Infect Dis 174:747
10. Krill D et al. 1997, Hum Biol 69:89
11. Baena N et al. 2002, Eur J Clin Nutr 56:44
12. Sun SY, Lotan R. 2002, Crit Rev Oncol Hematol 41:41
13. Kafwembe EM et al. 2001, East Afr Med J 78:451
14. Samad TA et al. 1997, Proc Natl Acad Sci 94:14349
15. Wolf G. 1998, Nutr Rev 56:354
16. Misner DL et al. 2001, Proc Natl Acad Sci 98:11714
17. Etchamendy N et al. 2001, J Neurosci 21:6423
18. Brouwer A, van den Berg KJ. 1986 Toxicol Appl Pharmacol 85:301
19. LaBrecque J et al. 1993, Biochem. Cell Biol. 71:85
20. Tomita S et al. 1993, FEBS Lett. 336,272
21. Fletcher N et al 2001, 62:166
22. Hallgren S et al. 2001, Arch Toxicol 75:200
23. Haley RW et al. 1999, Toxicol Appl Pharmacol 157: 227
24. Mackness B et al. 2002, Eur. J Clin Invest 32:259
25. Furlong CE et al. 2000, Neurotoxicology 21:91
26. Brophy VH et al. 2001, Pharmacogenetics 11:77
27. Mackness B et al. 2000, Eur J Clin Invest 30:4
(c) 2002 Frederick W. Plapp, Jr. Ph.D. Reprinted with permission from the author. |
http://www.immunesupport.com/library/bulletinarticle.cfm?ID=4089&PROD=P208
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Wally
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| Posted: Sat Sep 20, 2003 5:22 pm Post subject: 6 |
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Detailed and scientfic. Its really good, but I had to read it three or four times to absorb it all.  . There are several graphs/pictures, so going to the link might be better than trying to read all of it here!
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The vitamin A spectrum: from deficiency to toxicity1,2,3,4
Robert M Russell
1 From the US Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston.
2 The contents of this article do not necessarily reflect the views or policies of the US Department of Agriculture.
3 Supported by the US Department of Agriculture, Agricultural Research Service (contract 53-3-06-5-10).
4 Address reprint requests to RM Russell, USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: russell@hnrc.tufts.edu.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
FUNCTIONAL TESTING
RETINOIC ACID DEFICIENCY
STABLE ISOTOPES
VITAMIN A TOXICITY
{beta}-CAROTENE TOXICITY
REFERENCES
Dark adaptation has been used as a tool for identifying patients with subclinical vitamin A deficiency. With this functional test it was shown that tissue vitamin A deficiency occurs over a wide range of serum vitamin A concentrations. However, serum vitamin A concentrations >1.4 µmol/L predict normal dark adaptation 95% of the time. Other causes of abnormal dark adaptation include zinc and protein deficiencies. Stable isotopes of vitamin A and isotope-dilution techniques were used recently to evaluate body stores of vitamin A and the efficacy of vitamin A intervention programs in field settings and are being used to determine the vitamin A equivalences of dietary carotenoids. Vitamin A toxicity was described in patients taking large doses of vitamin A and in patients with type I hyperlipidemias and alcoholic liver disease. Conversely, tissue retinoic acid deficiency was described in alcoholic rats as a result of hepatic vitamin A mobilization, impaired oxidation of retinaldehyde, and increased destruction of retinoic acid by P450 enzymes. Abnormal oxidation products of carotenoids can cause toxicity in animal models and may have caused the increased incidence of lung cancer seen in 2 epidemiologic studies of the effects of high-dose ß-carotene supplementation. Major issues that remain to be studied include the efficiency of conversion of carotenoids in whole foods to vitamin A by using a variety of foods in various field settings and whether intraluminal factors (eg, parasitism) and vitamin A status affect this conversion. In addition, the biological activity of carotenoid metabolites should be better understood, particularly their effects on retinoid signaling.
Key Words: Vitamin A • retinoids • vitamin A deficiency • vitamin A toxicity • vitamin metabolism • stable isotopes • Robert H Herman Memorial Award in Clinical Nutrition
INTRODUCTION
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INTRODUCTION
FUNCTIONAL TESTING
RETINOIC ACID DEFICIENCY
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VITAMIN A TOXICITY
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This article covers some of the recent advances in the field of vitamin A deficiency and toxicity.
FUNCTIONAL TESTING
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INTRODUCTION
FUNCTIONAL TESTING
RETINOIC ACID DEFICIENCY
STABLE ISOTOPES
VITAMIN A TOXICITY
{beta}-CAROTENE TOXICITY
REFERENCES
My involvement in the field of vitamin A began when Alex Krill, an ophthalmologist at the University of Chicago, approached me about his interest in developing a new visual function test for studying vitamin A deficiency. He wanted to study some patients with inflammatory bowel disease or celiac sprue at the gastroenterology clinics at the University of Chicago hospitals. I was eager to participate because I was interested in the prevalence of micronutrient deficiencies in these disease states. The first group of patients that we studied had relatively mild malabsorption due to chronic small-intestinal disease (1). In these patients, although fat malabsorption was relatively mild (mean fecal fat: 10 g/d with a 100-g-fat diet), the prevalence of reversible dark-adaptation abnormalities via vitamin A supplementation was in the range of 60%. Dark-adaptation curves for one of these patients, whose final threshold was grossly elevated at the beginning of study when his serum vitamin A concentration was 1.1 µmol/L, are shown in Figure 1. This patient's final dark-adapted threshold became normal after 30 d of treatment with 50000 IU (15 mg) vitamin A/d orally. The study pointed out a high frequency of vitamin A deficiency in patients with small-intestinal disease. The fact that many of these patients were taking routine vitamin supplements and that none of them was complaining of any kind of subjective symptom (eg, night blindness) suggested that this type of subclinical micronutrient deficiency was quite common in patients with Crohn disease and other chronic gastrointestinal diseases. Subsequent work showed that high prevalences of subclinical vitamin A deficiency also occur in clinic populations with alcoholic cirrhosis, primary biliary cirrhosis, a history of small-intestinal bypass surgery (which was once commonly performed for obesity), and pancreatic insufficiency (2–6).
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FIGURE 1. Dark-adaptation curves obtained from a vitamin A–deficient patient before (•) and after () treatment with 50000 IU (15 mg) vitamin A for 30 d. As time in the dark increased, luminance of smaller intensity was perceived. On treatment, the normal dark-adapted threshold decreased to the normal range, as indicated by the vertical bar, within 35–45 min. Adapted from reference 1.
In the meantime, Loerch et al (7) developed a new and unique way to diagnose vitamin A deficiency—the relative-dose-response test. This test requires 2 blood tests to be conducted 0 and 5 h after a physiologic dose of vitamin A. The test is based on the fact that in vitamin A–deprived states, resulting from an acute or chronic dietary deficiency, the plasma transport protein for vitamin A, retinol binding protein (RBP), accumulates in the liver (. However, when vitamin A is made available from a dietary source, it becomes bound to the accumulated RBP and is promptly released into blood. Thus, in vitamin A–depleted organisms, the rise in serum retinol after a small dose of vitamin A is rapid, large, and sustained over a 5-h period. In contrast, in the vitamin A–sufficient state the rise in serum retinol reaches a lower and earlier apex, presumably because of a lower amount of accumulated apo-RBP and because the newly ingested dose goes into body storage pools rather than into the circulation. Thus, individuals with high relative dose responses are in a vitamin A–deficient state. The formula to calculate the relative dose response is as follows:
where A5 is the serum retinol concentration 5 h after the vitamin A dose and A0 is the vitamin A value at baseline. This formula had been well worked out in animals, but Mobarhan et al (9) conducted the first human study to evaluate the relative-dose-response test for vitamin A nutriture in patients with alcoholic cirrhosis. In these subjects, serum retinol concentrations were <0.7 µmol/L and final dark-adapted thresholds were also abnormal. The relative dose response diagnosed vitamin A deficiency in 5 of 8 patients despite the fact that these patients had profound liver failure, and thus impaired vitamin A processing, as well as low hepatic protein synthesis, including that of RBP and transthyretin. These 5 patients responded to vitamin A treatment, as shown in Table 1. The relative-dose-response test has since been used in many developing countries to ascertain the severity of vitamin A deficiency and has been useful in assessing the benefits of vitamin A intervention programs (10–14).
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TABLE 1. Relative-dose-response test results before and after vitamin A supplementation (3 mg/d for 4 wk) in patients with alcoholic cirrhosis1
The effect of zinc deficiency on dark adaptation in humans was also of interest. It had been theorized that zinc deficiency could cause clinical night blindness by causing a state of functional vitamin A deficiency (15, 16). That is, it was thought that a person could become functionally vitamin A deficient if he or she was unable to synthesize RBP because of zinc deficiency or because of the inability to synthesize rhodopsin. The first demonstration of zinc deficiency causing abnormal dark adaptation in humans is illustrated in Figure 2. Ten patients with vitamin A deficiency, based on serum vitamin A concentrations <1.1 µmol/L and abnormally elevated final dark-adapted thresholds, were studied. In 2 of these patients, serum zinc concentrations were also <9.2 µmol/L. The middle panel of Figure 2 shows the response of these patients to oral vitamin A treatment alone (10000 IU/d, or 3 mg/d) over a 2–4 wk period. Final dark-adapted thresholds in the 2 zinc-deficient patients remained abnormal. These 2 patients were then additionally treated with 220 mg ZnSO4/d for 2 wk, after which their dark-adapted thresholds returned to normal.
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FIGURE 2. Final dark-adapted thresholds in 2 vitamin A– and zinc-deficient () and 8 vitamin A–deficient (•) patients before and after treatment with vitamin A alone (10000 IU/d, or 3 mg/d) for 2–4 wk or in conjunction with zinc sulfate (220 mg/d) for 2 wk.
In the absence of zinc deficiency or severe protein deficiency, dark adaptation is a reliable and highly reproducible functional indicator of vitamin A nutritional status; however, it was learned that abnormal dark adaptation can occur over a fairly wide range of serum vitamin A concentrations in clinic populations (17). Because the lower and upper limits of serum vitamin A indicating normal and abnormal retinal function had not been determined, we studied dark-adaptation responses in 67 patients with a variety of hepatic and gastrointestinal diseases and in chronic alcoholic individuals who were sober. It was found that a serum vitamin A concentration >1.4 µmol/L predicted normal dark adaptation 95% of the time. Patients with low serum zinc concentrations were excluded from this study as were patients with severe protein malnutrition. This was an important study because previous studies conducted to determine adequate serum vitamin A concentrations in individuals had not used dark adaptation as a second measurement of vitamin A adequacy. Thus, on the basis of these test results, a serum vitamin A concentration >1.4 µmol/L can be safely interpreted as indicating normal vitamin A–dependent retinal function in almost all adult patients. These data were subsequently used to help interpret the vitamin A status of the American population from the first and second National Health and Nutrition Examination Surveys (1.
RETINOIC ACID DEFICIENCY
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ABSTRACT
INTRODUCTION
FUNCTIONAL TESTING
RETINOIC ACID DEFICIENCY
STABLE ISOTOPES
VITAMIN A TOXICITY
{beta}-CAROTENE TOXICITY
REFERENCES
There has been recent interest in the effects of local tissue retinoic acid deficiency; thus, an alcoholic animal model was used to study this. Ethanol can compete with retinol for alcohol dehydrogenase, which catalyzes retinol oxidation to retinaldehyde, which then can be further oxidized to retinoic acid. It is possible that local tissue retinoic acid deficiency could be a molecular mechanism contributing to alcohol-induced liver injury (eg, proliferative activation of hepatocytes or hepatic fibrosis).
In work conducted by Wang et al (19), rats were fed a diet containing 36% of energy as alcohol or an isoenergetic diet containing maltose dextrin and no alcohol. Animals were pair fed for 4 wk; they were then killed and their tissues removed for analysis. Retinoic acid concentrations in rat liver and plasma after treatment with or without alcohol for 1 mo are shown in Table 2. It was found that treatment with a high dose of alcohol led to significant reductions in retinoic acid concentrations in both the liver and plasma. Because retinoic acid concentrations were significantly lower in the alcohol-fed animals, the authors hypothesized that alcohol ingestion can result in abnormal gene expression (19). Work from many groups showed that retinoic acid exerts profound effects on cellular growth and differentiation. Moreover, 2 families of nuclear retinoic acid receptors had been cloned (RAR and RXR) and were shown to be active in the receptor-mediated control of gene transcription. One of the proposed mechanisms for the antiproliferative effect of these retinoic acid receptors is through an interaction with the activator protein 1 (AP-1) complex made up of c-Fos and c-Jun. AP-1 mediates signals from several growth factors, inflammatory peptides, oncogenes, and tumor promoters, usually resulting in cell proliferation. AP-1–induced gene transcription can be inhibited by RAR and RXR when bound to retinoic acid.
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TABLE 2. Concentration of retinoic acid in rat liver and plasma after treatment with or without (control) alcohol for 1 mo1
Thus, from this study, an intriguing hypothesis arises of how ethanol could result in proliferative activation of hepatic cells (Figure 3). Ethanol could inhibit retinoic acid synthesis by providing competition for alcohol dehydrogenase–catalyzed retinol oxidation. In addition, there might be increased destruction of the retinoic acid that is formed by increased P450 enzyme activity. Finally, ethanol might have an indirect effect in reducing retinoic acid concentrations in liver cells by increasing the mobilization of vitamin A to peripheral tissues (20). The decrease in tissue all-trans-retinoic acid concentrations could interfere with normal retinoid signal transduction by causing a functional down-regulation of RAR activity. As mentioned previously, RARs act as regulators of AP-1–responsive genes because RARs bound to retinoic acid can combine with the c-Fos–c-Jun complex and sequester it, thereby preventing it from binding to the AP-1 binding site. In the absence of retinoic acid, RARs can no longer bind to the c-Fos–c-Jun complex; thus, AP-1 can bind to DNA sequence motifs, resulting in the transactivation of target genes and cell proliferation. Such a mechanism could, in part, be responsible for alcohol-induced cell injury as well as malignant transformation. The tools of molecular biology are opening up new approaches for understanding the mechanisms whereby vitamin A deficiency and retinoic acid deficiency wreak havoc with tissues.
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FIGURE 3. Ethanol results in decreased liver retinoic acid concentrations by 1) increasing the mobilization of vitamin A from hepatic stores, 2) blocking the oxidation of retinol by inhibiting alcohol dehydrogenase (ADH), and 3) stimulating the hydrolysis of retinoic acid by cytochrome P450.
STABLE ISOTOPES
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INTRODUCTION
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RETINOIC ACID DEFICIENCY
STABLE ISOTOPES
VITAMIN A TOXICITY
{beta}-CAROTENE TOXICITY
REFERENCES
Relatively new technologies are being used to determine how best to combat vitamin A deficiency in a field setting: the use of stable isotopes and the analysis of samples with gas chromatography–mass spectrometry. De Pee et al (21) and Bulux et al (22) questioned the effectiveness of plant carotenoids in combating vitamin A deficiency. Each of these groups found no evidence of benefit on vitamin A nutritional status from the increased consumption of dark-green or yellow vegetables. Tang et al (23) reported the use of tetra- and octadeuterated retinyl acetate at different time points to assess changes in vitamin A status in Chinese children fed high-vegetable diets for 10 wk. To assess baseline vitamin A status, each child was fed octadeuterated retinyl acetate in corn oil on day 0; blood samples obtained on day 21 were used as the equilibration point. From days 22 to 92, carotenoid-rich, dark-green and yellow vegetables were fed to one kindergarten class, whereas light-colored vegetables were fed to children in a second kindergarten class. During this intervention period, conducted in the autumn, the 2 groups of children consumed 3 meals at school daily, 5 d/wk for 10 wk. After the intervention was complete on day 95, tetradeuterated retinyl acetate was administered to the children in each group to measure changes in body stores of vitamin A. The nutrient contents of both diets were equivalent except for the carotenoid content: the calculated retinol equivalents were 4 times higher in the dark-green and yellow-vegetable diet than in the light-colored-vegetable diet. After 95 d, serum retinol concentrations were not significantly different from baseline in the dark-green and yellow-vegetable group, but fell significantly (by 20%) in the light-colored-vegetable group. Mean serum vitamin A concentrations in these 2 groups of children were low, 1.0 µmol/L. Likewise, total liver reserves before and after the intervention did not change significantly in the dark-green and yellow-vegetable group, whereas they fell significantly (by 27 µmol) in the light-colored-vegetable group. Because the dark-green and yellow-vegetable group consumed 4.7 mg provitamin A carotenoids in their daily diet and the light-colored-vegetable group consumed only 0.7 mg provitamin A carotenoids in their daily diet, it was calculated that the provitamin A carotenoid intake by the dark-green and yellow-vegetable group prevented a loss of 7.4 mg retinol from the liver. With use of this estimate, it was calculated that ß-carotene from vegetable origin (under these study conditions) provided an estimated vitamin A equivalence of 25 to 1 by weight or a molar ratio of 13 to 1. Thus, in that study, vitamin A nutrition was sustained in Chinese kindergarten children who consumed dark-green and yellow vegetables with their meals. However, the vitamin A equivalence (by wt) of dietary carotenoids was less than the presently assumed ratios of 1 to 6 for ß-carotene and of 1 to 12 for other provitamin A carotenes. This issue is in need of far greater study.
VITAMIN A TOXICITY
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ABSTRACT
INTRODUCTION
FUNCTIONAL TESTING
RETINOIC ACID DEFICIENCY
STABLE ISOTOPES
VITAMIN A TOXICITY
{beta}-CAROTENE TOXICITY
REFERENCES
Now I will turn to the opposite end of the vitamin A spectrum—vitamin A toxicity. My interest in vitamin A toxicity was sparked after treating a patient when I was a gastroenterology fellow at the University of Chicago. This patient had liver disease of obscure origin, but also had some odd symptoms: thinning of eyebrows; sparse, coarse hair; cheilosis; and bulging eyes (Figure 4). On careful questioning, she admitted to taking large doses of vitamin A, an average of 400000 IU (120 mg/d) for 8 y. Her liver biopsy showed hepatic congestion and fibrosis, particularly around the central vein. A second similar patient was identified within 2 mo. These patients were unique in that they showed a distinctive pattern of fibrosis and lipid disposition in their biopsy specimens. The report of these patients alerted the medical community that vitamin A toxicity may be more prevalent in clinic populations than recognized previously (24). Ellis et al (25) subsequently described other patients with vitamin A intoxication due to abnormal metabolism of vitamin A, specifically in patients with type I hyperlipidemia. Carpenter et al (26) described a familial clustering of vitamin A–intoxicated patients despite histories of only modest ingestion of the vitamin, thus implicating a possible genetic predisposition.
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FIGURE 4. A 58-y-old woman with vitamin A intoxication after taking on average 400000 IU (120 mg) vitamin A/d for 8 y. Note the dry skin, brittle hair, and cheilosis. This patient also had liver fibrosis.
Krasinski et al (27) were the first to point out the possible relation of age alone to a predisposition to vitamin A intoxication. These investigators showed that serum concentrations of vitamin A after a physiologic dose of vitamin A reached higher peaks in old people than in young people. As for the reason, it had been reported by Hollander and Morgan (2 that vitamin A was absorbed more readily in old rats than in young rats. However, Krasinski et al approached the problem somewhat differently. They fed humans high-fat, high–vitamin A meals and then conducted plasmapheresis several hours later. Chylomicrons and chylomicron remnants were laden with vitamin A esters and 24 h later the plasma was reinfused and the fall-off in serum retinyl esters was tracked in both old and young individuals. The fall-off in blood retinyl esters was significantly delayed 2-fold in older individuals than in younger individuals, which allowed for a transfer of vitamin A esters from chylomicrons into other lipoprotein particles such as LDLs. Once in LDL, potentially toxic retinyl esters are able to exist for 1 wk in the circulation as opposed to hours. In another study, Krasinski et al (29) showed that elderly people taking vitamin A supplements in amounts greater than the recommended dietary allowance tended to accumulate more retinyl esters in their fasting serum as the dose of vitamin A increased. Furthermore, they found that the longer the individuals took the vitamins containing vitamin A (ie, 5 y compared with <5 y), the greater the tendency for concentrations of potentially toxic retinyl esters to be high.
ß-CAROTENE TOXICITY
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{beta}-CAROTENE TOXICITY
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About the same time that these studies were published, ß-carotene toxicity was described by Leo et al (30) in the livers of alcohol-fed animals, which showed swollen mitochondria after ß-carotene feeding. Of interest is the possibility that retinoid metabolites of ß-carotene could also have biological and possibly toxic potential. Wang et al (31) showed that ß-carotene molecules in an in vitro system, in addition to splitting into retinal, could also be split at several double bonds, yielding apo carotenals and apo carotenoic acids. They showed that at low doses, these carotenoic acids could be converted directly to retinoic acid (32–34). That is, for retinoic acid to be formed, ß-carotene need not be converted to retinal first because in the presence of citral, which blocks the oxidation of retinal to retinoic acid, retinoic acid was still detected (35). Yeum et al (36) showed that this eccentric cleavage of ß-carotene could occur by a cooxidation mechanism in the cytosol. These investigations showed that when lipoxygenase was incubated with ß-carotene alone, very small amounts of eccentric cleavage products of ß-carotene appeared; however, when the substrate linoleic acid was added to the system, the cleavage metabolites of ß-carotene increased dramatically. Thus, it appears that eccentric cleavage can be initiated in tissues by a cooxidation mechanism and then possibly completed by either conversion to retinaldehyde to form retinoic acid or by a mitochondrial mechanism, as Wang et al (37) described, to form retinoic acid. However, the question arises as to what happens when these eccentric cleavage products accumulate in large amounts? Do they have biological activity of their own? Could these metabolites interfere with the action of retinoic acid? This may, in fact, partially explain the results from 2 carotene intervention trials in which the effects of high doses of ß-carotene supplements were studied in smokers and in asbestos-exposed workers (38, 39). These studies showed a higher incidence of lung cancer in smokers who consumed high doses of ß-carotene than in smokers who did not take ß-carotene supplements.
An animal model was used to try to mimic the results of these studies in humans (40). Ferrets were divided into 2 groups: ß-carotene supplemented and non-ß-carotene supplemented (control group). The dose of ß-carotene used was equivalent to 30 mg/d in the human intervention trials. The ß-carotene–supplemented and non-ß-carotene–supplemented groups were further divided into smoke-exposed and non-smoke-exposed groups. The smoke-exposed group was exposed to cigarette smoke within a chamber twice in the morning and twice in the afternoon for 30 min each time, providing an exposure equivalent to that from 1.5 packs of cigarettes/d in humans. The animals tolerated this exposure well; they experienced no decrease in appetite or weight and behaved no differently from non-smoke-exposed animals. Animals were treated for 6 mo and then killed. ß-Carotene concentrations in the plasma and lungs were greater in the ß-carotene–supplemented ferrets than in the nonsupplemented ferrets; however, ß-carotene concentrations in the lungs were significantly lower in the smoke-exposed ferrets than in the non-smoke-exposed ferrets in both the ß-carotene–supplemented and nonsupplemented control animals. Retinoic acid concentrations in the lung tissue were also significantly lower in all 3 treatment groups than in the control group (Table 3). The dramatic decreases in lung and blood ß-carotene concentrations as a result of smoke exposure correlated with the enhanced breakdown of ß-carotene into eccentric cleavage oxidation products.
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TABLE 3. Concentrations of ß-carotene and retinoic acid in lung tissue of ferrets after 6 mo of treatment1
When the lung sections of the 4 groups of ferrets were examined, it was found that smoke exposure alone caused mild aggregation and proliferation of macrophages. However, localized proliferation of alveolar cells and alveolar macrophages and keratinized squamous epithelial cells were observed in the ferrets in the 2 ß-carotene–supplemented groups. The most severe proliferation of alveolar cells and squamous metaplasia was observed in the ß-carotene–supplemented, smoke-exposed ferrets. Keratinized squamous metaplasia was confirmed by immunohistochemical staining with anti-keratin antibody in the lung sections of all ferrets in the ß-carotene–supplemented, smoke-exposed and non-smoke-exposed groups. Retinoic acid concentrations were lower in the smoke-exposed ferrets than in the non-smoke-exposed ferrets, presumably because of increased oxidative breakdown. In turn, the expression of RAR ß (a subtype of RAR) activity was down-regulated in the lungs of the 3 treatment groups compared with that in the control group. RAR ß is known to play an important role in normal lung development, and primary lung tumors and lung cancer cell lines lack RAR ß expression (41–46). Thus, a role for RAR ß as a tumor suppressor gene in the lung has been proposed (47). Because lung carcinogenesis is also associated with an alteration in retinoid signaling involving the AP-1 complex, AP-1 transcriptional activity was studied in these ferrets (4. c-Fos and c-Jun expression were up-regulated in the ß-carotene–supplemented, smoke-exposed group. Additionally, AP-1 expression in this study was positively correlated with squamous metaplasia and inversely with RAR ß expression in these animals.
Thus, it appears that high doses of ß-carotene under highly oxidative conditions result in many eccentric cleavage oxidative breakdown products, which could have biological activity of their own. One possibility is that these products interfere with retinoic acid binding to retinoid receptors, but another likely possibility is that these metabolites induce local enzymes in the lung, such as P450 enzymes, which increase the catabolism of retinoic acid and thus diminish retinoic acid signaling. A local deficiency of retinoic acid can then result in squamous metaplasia. Salgo et al (49) reported that ß-carotene oxidation products promote the binding of benzo[a]pyrene (a smoke-borne carcinogen) to calf thymus DNA. Incubation of DNA with intact ß-carotene decreased such binding, whereas incubation with ß-carotene oxidation products (eg, 5,6-epioxide) for 1, 2, 3, and 4 h significantly increased the binding. These are all possible explanations for why toxicity occurs after high doses of ß-carotene and may explain the increased incidence of lung cancers observed in the 2 large intervention trials mentioned previously (38, 39).
What then are some major issues remaining concerning vitamin A deficiency and toxicity? With regard to deficiency, the efficiency of conversion of carotenoids in whole foods to vitamin A by using a variety of foods in various field settings and whether intraluminal factors (eg, parasitism) and vitamin A status affect this conversion should be studied. These issues are of utmost importance in developing countries. With regard to the toxicity of retinoids, the biological activity of carotenoid metabolites must be better understood in terms of their possible beneficial as well as harmful effects. Are these metabolites able to induce local tissue deficiencies of retinoic acid and thus diminish retinoid signaling? Do these metabolites have gene transcription activity of their own? These are both pertinent and important questions as we move into the 21st century and questions that I believe will be answered with use of available new technologies. |
http://www.ajcn.org/cgi/content/full/71/4/878
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Wally
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Here are the references for the last article. Quite a mouthful! If you go to the link, you can even get some of the full articles for free. I haven't been to any of them, but judging by the title, there ought to be some really good info!
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Russell RM, Multack R, Smith V, Krill A, Rosenberg IH. The use of dark adaptation as a reversible indicator of subclinical vitamin A deficiency in patients with chronic small intestinal disease. Lancet 1973;2:1161–4.[Medline]
Russell RM, Morrison SA, Smith FR, Oaks EV, Carney EA. Vitamin A reversal of abnormal dark adaptation in cirrhosis. Study of effects on the plasma retinol transport system. Ann Intern Med 1978;88:622–6.[Medline]
Rogers EL, Douglass W, Russell RM, Bushman L, Hubbard TB, Iber FL. Deficiency of fat soluble vitamins after jejunoileal bypass surgery for morbid obesity. Am J Clin Nutr 1980;33:1208–14.[Abstract]
Herlong HF, Russell RM, Garrett M, Maddrey WC. Vitamin A deficiency in primary biliary cirrhosis. Hepatology 1981;1:348–51.[Medline]
Dutta SK, Russell RM, Lakhanpal V. Abnormal dark adaptation associated with low plasma levels of vitamin A transport proteins; correction by protein repletion. Nutr Res 1981;1:461–6.
Dutta SK, Bustin MP, Russell RM, Boniface SC. Deficiency of fat soluble vitamins in treated patients with pancreatic insufficiency. Ann Intern Med 1982;97:549–74.[Medline]
Loerch JD, Underwood BA, Lewis KC. Response of plasma levels of vitamin A to a dose of vitamin A as an indicator of hepatic vitamin A reserves in rats. J Nutr 1979;109:778–86.[Medline]
Muto Y, Smith JE, Milch PO, Goodman DS. Regulation of retinol binding protein metabolism by vitamin A status in the rat. J Biol Chem 1972;247:2542–50.[Abstract/Free Full Text]
Mobarhan S, Russell RM, Underwood BA, Wallingford J, Mathieson RD, Al-Midani H. Evaluation of the relative dose response test for vitamin A nutriture in cirrhotics. Am J Clin Nutr 1981; 34:2264–70.[Abstract]
Udomkesmaleee E, Dhanamitta S, Sirisinha S, et al. Effect of vitamin A and zinc supplementation on the nutriture of children in Northeast Thailand. Am J Clin Nutr 1992;56:50–7.[Abstract]
Tanumihardjo SA, Muherdiyantiningsih, Permaesih D, et al. Assessment of the vitamin A status in lactating and nonlactating, nonpregnant Indonesian women by use of the modified-relative-dose-response (MRDR) test. Am J Clin Nutr 1994;60:142–7.[Abstract]
Tanumihardjo SA, Muhilal, Yuniar Y, et al. Vitamin A status in preschool-age Indonesian children as assessed by the modified relative-dose-response assay. Am J Clin Nutr 1990;52:1068–72.[Abstract]
Campos F, Flores H, Underwood BA. Effect of an infection on vitamin A status of children as measured by the relative dose response (RDR). Am J Clin Nutr 1987;46:91–4.[Abstract]
Flores H, Campos F, Araujo C, Underwood BA. Assessment of marginal vitamin A deficiency in Brazilian children using the relative dose response procedure. Am J Clin Nutr 1984;40:1281–9.[Abstract]
Parisi AF, Vallee BL. Zinc metalloenzymes: characteristics and significance in biology and medicine. Am J Clin Nutr 1969;22:1222–39.[Medline]
Huber AM, Gershoff SN. Effects of zinc deficiency on the oxidation of retinol and ethanol in rats. J Nutr 1975;105:1486–90.[Medline]
Carney EA, Russell RM. Correlation of dark adaptation test results with serum vitamin A levels in diseased adults. J Nutr 1980;110:552–7.[Medline]
Pilch SM, ed. Assessment of the vitamin A nutritional status of the U.S. population based on data collected in the Health and Nutrition Examination Surveys. Bethesda, MD: Life Sciences Research Office, 1985.
Wang XD, Liu C, Chung J, Stickel F, Seitz HK, Russell RM. Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 expression in liver. Hepatology 1998;28:744–50.[Medline]
Mobarhan S, Seitz HK, Russell RM, et al. Age related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats. J Nutr 1991;121:510–7.[Medline]
De Pee S, West CE, Muhilal, Karyadi D, Hautvast JGAJ. Lack of improvement in vitamin A status with increased consumption of dark-green leafy vegetables. Lancet 1995;346:75–81.[Medline]
Bulux J, Quan de Serrano J, Giulian A, et al. Plasma response of children to short-term chronic ß-carotene supplementation. Am J Clin Nutr 1994;59:1369–75.[Abstract]
Tang G, Gu X-F, Hu S-M, et al. Green and yellow vegetables can maintain body stores of vitamin A in Chinese children. Am J Clin Nutr 1999;70:1069–76.[Abstract/Free Full Text]
Russell RM, Boyer JL, Bagheri S, Hruban Z. Hepatic toxicity from chronic hyper-vitaminosis. A unique morphologic lesion resulting in portal hypertension and ascites. N Engl J Med 1974;291:435–40.[Medline]
Ellis JK, Russell RM, Makrauer FL, Schaefer EJ. Increased risk of vitamin A toxicity in severe hypertriglyceridemia. Ann Intern Med 1986;105:877–9.[Medline]
Carpenter TO, Pettifor JM, Russell RM, et al. Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake. J Pediatr 1987;111:507–12.[Medline]
Krasinski SD, Cohn JS, Schaefer EJ, Russell RM. Postprandial plasma retinyl ester response is greater in older subjects compared with younger subjects. J Clin Invest 1990;85:883–92.[Medline]
Hollander D, Morgan D. Aging: its influence on vitamin A intestinal absorption in vivo by the rat. Exp Gerontol 1979;14:301–5.[Medline]
Krasinski SD, Russell RM, Otradovec CL, et al. Relationship of vitamin A and E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, -tocopherol, and cholesterol among elderly people and young adults increased plasma retinyl esters among vitamin A–supplemented users. Am J Clin Nutr 1989;49:112–20.[Abstract]
Leo MA, Aleynik SI, Aleynik MK, Lieber CS. ß-Carotene beadlets potentiate hepatotoxicity of alcohol. Am J Clin Nutr 1997;66:1461–9.[Abstract]
Wang XD, Tang GW, Fox JG, Krinsky NI, Russell RM. Enzymatic conversion of ß-carotene into ß-apo-carotenals and retinoids by human, monkey, ferret and rat tissue. Arch Biochem Biophys 1991;121:510–7.
Wang XD, Russell RM, Marini RP, et al. Intestinal perfusion of ß-carotene in the ferret raises retinoic acid level in portal blood. Biochim Biophys Acta 1993;1167:159–64.[Medline]
Wang XD, Krinsky NI, Benott PN, Russell RM. Biosynthesis of 9-cis-retinoic acid from ß-carotene in human intestinal mucosa. Arch Biochem Biophys 1994;313:150–5.[Medline]
Hebuterne X, Wang XD, Smith DE, Tang GW, Russell RM. In vivo biosynthesis of retinoic acid from ß-carotene involves an excentric cleavage pathway in ferret intestine. J Lipid Res 1996;37:482–92.[Abstract]
Wang XD, Krinsky NI, Tang GW, Russell RM. Retinoic acid can be produced from excentric cleavage of ß-carotene in human intestinal mucosa. Arch Biochem Biophys 1992;293:298–304.[Medline]
Yeum KJ, Lee YC, Yoon S, et al. Similar metabolites formed from ß-carotene by either lipoxygenase or human gastric mucosal homogenate. Arch Biochem Biophys 1995;321:167–74.[Medline]
Wang XD, Russell RM, Liu C, Stickel F, Smith DE, Krinsky NI. A type of ß-oxidation in rabbit liver in vitro and in the perfused ferret liver contributes to retinoic acid biosynthesis from ß-apocarotenoic acids. J Biol Chem 1996;271:26490–8.[Abstract/Free Full Text]
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in males smokers. N Engl J Med 1994;330:1029–35.[Abstract/Free Full Text]
Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996;88:1550–9.[Abstract/Free Full Text]
Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell RM. Alteration of retinoid signaling and AP1 expression by ß-carotene supplements in smoke exposed ferrets. J Natl Cancer Inst 1999; 91:60–6.[Abstract/Free Full Text]
Geberg JF, Moghal N, Frangioni JV, Sugar-Baker DJ, Neel BG. High frequency of retinoic acid receptor ß abnormalities in human lung cancer. Oncogene 1991;6:1859–68 (published erratum appears in Oncogene 1992;7:821).[Medline]
Dolle P, Ruberte E, Leroy P, Morriss-Kay G, Chambon P. Retinoic acid receptors and cellular retinoid binding proteins. 1. A systematic study of their differential pattern of transcription during mouse organogenesis. Development 1990;11:1133–51.
Nervi C, Vollberg TM, George MD, Zelent A, Chambon P, Jetten AM. Expression of nuclear retinoic acid receptors in normal tracheobronchial cells and in lung carcinoma cells. Exp Cell Res 1991;195:163–70.[Medline]
Lotan R. Retinoids in cancer chemoprevention. FASEB J 1996; 10:1031–9.[Abstract]
Zhang XK, Liu Y, Lee MO. Retinoid receptors in human lung cancer and breast cancer. Mutat Res 1996;350:267–77.[Medline]
Xu XC, Sozzi G, Lee JS, et al. Suppression of retinoic acid receptor ß in non-small-cell lung cancer in vivo: implications for lung cancer development. J Natl Cancer Inst 1997;89:624–9.[Abstract/Free Full Text]
Houle B, Rochette-Egly C, Bradley WE. Tumor-suppressive effect of the retinoic acid receptor ß in human epidermoid lung cancer cells. Proc Natl Acad Sci U S A 1993;90:985–9.[Abstract]
Lee HY, Dawson MI, Claret FX, et al. Evidence of a retinoid signaling alteration involving the activator protein 1 complex in tumorigenic human bronchial epithelial cells and non-small cell lung cancer cells. Cell Growth Differ 1997;8:283–91.[Abstract]
Salgo MG, Cueto R, Winston GW, Pryor WA. Beta carotene and its oxidation products have different effects on microsome mediated binding of benzo[a]pyrene to DNA. Free Radic Biol Med 1996;26:162–73. |
http://www.ajcn.org/cgi/content/full/71/4/878
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| Posted: Sat Sep 20, 2003 5:44 pm Post subject: 7 |
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This article talks about tests to identify the amounts of Vitamin A in the body.
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Scientists Get A's for Vitamin Testing
Iowa State University Office of Biotechnology
November 20, 1997
AMES, Iowa -- Count yourself lucky if your mother made you eat your vegetables. Childhood reminders to eat carrots can pay off. Healthy, well-nourished adults and children have several times more vitamin A than they need stored in their livers to ward off blindness, disease and death.
Unfortunately, the problem of vitamin A deficiency exists in the United States as well as underdeveloped countries. According to Dr. James Olson, an ISU biochemistry and biophysics professor, many people around the world are deficient in vitamin A, particularly children and pregnant and nursing mothers. Olson and his research team at ISU are working on ways to improve the testing of vitamin A levels in persons already affected by illnesses, as well as developing new methods for measuring vitamin A deficiency in humans.
The liver is responsible for housing about 90% of the body's reserves of vitamin A. When organs and tissues draw on liver reserves, vitamin A travels to its new destination through the bloodstream. However, testing the liver's reserves is the best way to obtain an accurate measure of a person's vitamin A status.
Dr. Olson and his colleague Dr. Sherry Tanumihardjo want to improve the test that assesses marginal levels of vitamin A. Even marginal levels of the nutrient can lead to illness and death. During the test, a person receives a small dose of a special form of vitamin A termed A2 . Blood tests monitor the amounts of A2 and standard vitamin A bound to a protein secreted by the liver. This protein builds up in the liver when vitamin A reserves are low. When the ratio of A2 to standard vitamin A is greater than 3 parts to 100, a person's vitamin A status is considered inadequate. However, infections can reduce the amount of protein secreted and make readings inaccurate. Olson's team has determined that increasing the dosage of A2 counters the effects of infection on the test and increases the accuracy of readings.
In a new test, Dr. Olson and his colleague Dr. Arun Barua measure the blood level of a chemical known as retinoic acid. Retinoic acid is converted from a complex form of vitamin A more rapidly when the vitamin A status of an individual is poor. A positive reading indicates the presence of vitamin A deficiency because retinoic acid formation is higher when the vitamin is scarce.
According to Olson, a combination of the two tests would be ideal in measuring an individual's vitamin A reserves. "The information gained would be much better when combining these two tests than for any test alone," he said.
"With this research, we hope to find better ways of identifying groups of people who have vitamin A deficiency, as well as better ways to evaluate the effectiveness of nutritional education programs. We also hope to improve methods of evaluating the availability of vitamin A ffound in foods," he commented
Dr. Olson's research is funded by the U.S. Department of Agriculture.
(Contacts: James A. Olson, Biochemistry and Biophysics, 515-294-6116, or Danelle Baker, Office of Biotechnology, 515-294-7356) |
http://www.biotech.iastate.edu/news_releases/Nov_20_97.html
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| Posted: Sat Sep 20, 2003 6:05 pm Post subject: |
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Vitamin A Deficiency-talks about some of the possible reasons for Vitamin A deficiency.
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Vitamin A Deficiency
Last Updated: July 2, 2003 Rate this Article
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Synonyms and related keywords: VAD, retinoic acid, retinol, beta carotene, beta-carotene, Aquasol A, Palmitate-A, Oleovitamin A, carotenoids, provitamin A, 11-cis-retinol, vision, dark adaptation, nyctalopia, retinol-binding protein, RBP, cellular retinol-binding protein, CRBP, cystic fibrosis, sprue, pancreatic insufficiency, inflammatory bowel disorder, IBD, inflammatory bowel disease, cholestasis, alcoholism, Bitot spots, nyctalopia, dry skin, dry hair, pruritus, broken fingernails, keratomalacia, xerophthalmia, follicular hyperkeratosis, phrynoderma, vitamin deficiency, malnutrition, retinoids, retinoid deficiency, deficiency of vitamin A
AUTHOR INFORMATION Section 1 of 10
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Author: Jigna Thakore, MD, Staff Physician, Department of Internal Medicine, Miami Valley Hospital, Wright State University School of Medicine
Coauthor(s): N Gopalswamy, MD, Chairman, Professor of Internal Medicine, Department of Gastroenterology, Wright State University / Veterans Affairs Medical Center
Jigna Thakore, MD, is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, and American Medical Association
Editor(s): Udaya M Kabadi, MD, Professor, Department of Medicine, University of Iowa School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Romesh Khardori, MD, Chief, Division of Endocrinology, Metabolism and Molecular Medicine, Professor, Department of Internal Medicine, Southern Illinois University School of Medicine; Alex J Mechaber, MD, FACP, Director of Clinical Skills Program, Assistant Professor, Department of Internal Medicine, Division of General Internal Medicine, University of Miami School of Medicine; and George T Griffing, MD, Director, Division of General Internal Medicine, Professor, Department of Internal Medicine, St Louis University
INTRODUCTION Section 2 of 10
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Background: The word vitamin was originally derived from Funk’s term "vital amine." In 1912, he was referring to Christian Eijkman’s discovery of an amine extracted from rice polishings that could prevent beriberi. Funk’s recognition of the antiberiberi factor as vital for life was indeed accurate. Researchers have since found that vitamins are essential organic compounds that the human body cannot synthesize. Vitamins A, D, K, and E are classified as fat-soluble vitamins, whereas others are classified as water-soluble vitamins.
Vitamin A was the first fat-soluble vitamin to be discovered. Two independent research teams, Osborne and Mendel at Yale University and McCollum and Davis at the University of Wisconsin, simultaneously discovered it in 1913. Vitamin A comprises a family of compounds called the retinoids. The retinoid designation resulted from finding that vitamin A had the biologic activity of retinol, which was originally isolated from the retina.
In nature, the active retinoids occur in 3 forms: alcohol (retinol), aldehyde (retinal or retinaldehyde), and acid (retinoic acid). The inactive retinoids, known as provitamins A, are produced as plant pigments and are called carotenoids. Several hundred carotenoids occur in foods, but only approximately 50 can be metabolized into the active retinoid forms; among these 50 compounds, beta-carotene, a retinol dimer, has the most significant provitamin A activity.
In the human body, retinol is the predominant form, and 11-cis-retinol is the active form. Retinol-binding protein (RBP) binds vitamin A and regulates its absorption and metabolism. Vitamin A is essential for vision (especially dark adaptation); immune response; epithelial cell growth and repair; bone growth; reproduction; maintenance of the surface linings of the eyes; and epithelial integrity of respiratory, urinary, and intestinal tracts. Vitamin A is also important for embryonic development and regulation of adult genes. It functions as an activator of gene expression by retinoid alpha-receptor transcription factor and ligand-dependent transcription factor.
Deficiency of vitamin A is found among malnourished, elderly, and chronically sick populations in the United States, but it is more prevalent in developing countries. Abnormal dark adaptation, dry skin, dry hair, broken fingernails, and decreased resistance to infections are among the first signs of vitamin A deficiency (VAD).
Pathophysiology: Once ingested, provitamins A are released from proteins in the stomach. These retinyl esters are then hydrolyzed to retinol in the small intestine because retinol is more efficiently absorbed. Carotenoids are cleaved in the intestinal mucosa into molecules of retinaldehyde, which is subsequently reduced to retinol and then esterified to retinyl esters. The retinyl esters of both retinoid and carotenoid origin are transported via micelles in the lymphatic drainage of the intestine to the blood and then to the liver as components of chylomicrons. Of vitamin A in the body, 50-80% is stored in the liver, where it is bound to the cellular RBP. The remaining vitamin A is deposited into adipose tissue, lungs, and kidneys as retinyl esters, most commonly as retinyl palmitate.
Vitamin A can be mobilized from the liver to peripheral tissue by a process of de-esterification of the retinyl esters. In blood, vitamin A is bound to RBP, which transports it as a complex with transthyretin. The hepatic synthesis of RBP is dependent on the presence of zinc and amino acids to maintain its narrow serum range of 40-50 mcg/dL. The retinol is taken up by the peripheral tissues from the RBP-transthyretin complex by a receptor-mediated process.
VAD may be secondary to decreased ingestion, defective absorption and altered metabolism, or increased requirements. An adult liver can store up to a year's reserve of vitamin A, whereas a child’s liver may have enough stores to last only several weeks. Serum retinol concentration reflects an individual’s vitamin A status. Because serum retinol is homeostatically controlled, its levels do not drop until the body’s stores are significantly limited. The serum concentration of retinol is affected by several factors, including RBP synthesis in the liver, infection, nutritional status, and an adequate level of other nutrients such as zinc and iron.
In zinc deficiency, impaired synthesis of proteins occurs with rapid turnover (eg, RBP). In turn, this impairment affects retinol transport by RBP from the liver to the circulation and other tissues. The mechanism by which iron affects vitamin A metabolism has not been identified, but randomized, double-blind studies have shown that vitamin A supplementation alone is not sufficient to improve VAD in the presence of coexisting iron deficiency.
The bioavailability of the carotenoids varies and depends on absorption and their yield of retinol. Only 40-60% of ingested beta-carotene from plant sources is absorbed by the human body, whereas 80-90% of retinyl esters from animal proteins are absorbed. Carotenoid absorption is affected by dietary factors such as zinc deficiency, abetalipoproteinemia, and protein deficiency.
Because vitamin A is a fat-soluble vitamin, any GI diseases affecting the absorption of fats also affect vitamin A absorption. Patients with cystic fibrosis, sprue, pancreatic insufficiency, inflammatory bowel disorder (IBD), cholestasis, and small-bowel bypass surgery are at increased risk for VAD. These patients should be advised to consume vitamin A.
One factor affecting the metabolism of vitamin A is alcoholism. Alcohol dehydrogenase catalyzes the conversion of retinol to retinaldehyde, which is then oxidized to retinoic acid. The affinity of alcohol dehydrogenase to ethanol impedes the conversion of retinol to retinoic acid.
Increased requirements of vitamin A most commonly occur among sick children. In the United States, the American Academy of Pediatrics recommends vitamin A supplementation for infants aged 6-24 months who are hospitalized with measles and for all hospitalized children older than 6 months. In the 1960s, the World Health Organization (WHO) undertook the first global survey of VAD with associated xerophthalmia and complicated measles. In 1973, an international vitamin A board was set up to alleviate global malnutrition. The WHO and United Nations International Children’s Emergency Fund (UNICEF) have issued joint statements recommending vitamin A administration for all children, especially those younger than 2 years, who are diagnosed with measles. Coexistent VAD in young children increases the risk of death. The Cochrane Database Systemic Review concluded that daily treatment with 200,000 IU of vitamin A for at least 2 days reduces mortality rates (D’Souza, 2002).
Pregnant women do not require increased vitamin A supplementation. In fact, the Teratology Society advocates that women should be informed of the possible risk of cranial neural crest defects and other malformations resulting from excessive use of vitamin A shortly before or during pregnancy. The recommended daily allowance (RDA) of 800 mcg for all adult females is also appropriate for pregnant women because their stores of vitamin A meet the fetal accretion rate. The requirements for lactating women have been debated, but the current RDA is 1300 mcg in the first 6 months and 1200 mcg in the second 6 months.
The RDAs of vitamin A for various age groups are as follows:
Infants aged 1 year or younger - 375 mcg
Children aged 1-3 years - 400 mcg
Children aged 4-6 years - 500 mcg
Children aged 7-10 years - 700 mcg
All males older than 10 years - 1000 mcg
All females older than 10 years - 800 mcg
Frequency:
In the US: Statistics from the US Centers for Disease Control and Prevention from the 1988-1991 survey show that age-specific intakes of carotenes were higher among males than females and were higher among adults than children (see Vitamin Intake). Significant differences in intake existed among different ethnic groups.
Internationally: Clinical and subclinical VAD are problems in at least 75 countries. In 1994, the WHO classified countries as having clinical or subclinical, severe, moderate, or mild VAD. Most countries with clinical VAD (children demonstrate eye signs and symptoms, including blindness) are in Southeast Asia and sub-Saharan Africa (see Vitamin A: Advocacy). Severe VAD is also found in persons in refugee settlements and in displaced populations.
Mortality/Morbidity:
United States: VAD is uncommon in the general population, but subgroups of patients with fat malabsorption, cholestasis, small-bowel bypass, or IBD may have subclinical deficiency with dark-adaptation abnormalities in the range of 60%. Vegans, refugees, persons with alcoholism, toddlers and preschool children living below the poverty line, and recent immigrants or refugees from developing countries all have increased risk of VAD secondary to decreased ingestion.
Developing countries: An estimated 250 million children are at risk for vitamin deficiency syndromes. The most widely affected group includes up to 10 million malnourished children who develop xerophthalmia and an increased risk of complications and death from measles. Each year, 250,000-500,000 children become blind because of VAD. Improving the vitamin A status of children with deficiencies (aged 6-59 mo) can reduce rates of death from measles by 50%, rates of death from diarrhea by 33%, and risk rates from of all causes of mortality by 23%.
CLINICAL Section 3 of 10
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History: Subclinical forms of VAD may not cause any symptoms, but the risk of developing respiratory and diarrheal infections is increased, the growth rate is decreased, and bone development is slowed. Patients may have a recent history of increased infections, infertility secondary to impaired spermatogenesis, or recent spontaneous abortion secondary to impaired embryonic development. The patient may also report increased fatigue as a manifestation of VAD anemia.
Physical: Signs and symptoms include Bitot spots, poor dark adaptation (nyctalopia), dry skin, dry hair, pruritus, broken fingernails, keratomalacia, xerophthalmia, and follicular hyperkeratosis (phrynoderma) secondary to blockage of hair follicles with plugs of keratin. Other signs include excessive deposition of periosteal bone secondary to reduced osteoclastic activity, anemia, and keratination of mucous membranes.
Causes: The risk of VAD is increased in patients with fat malabsorption, cystic fibrosis, sprue, pancreatic insufficiency, IBD, cholestasis, and/or small-bowel bypass surgery. It is also increased in vegans, refugees, recent immigrants, persons with alcoholism, and toddlers and preschool children living below the poverty line. These patients should be advised to consume vitamin A. DIFFERENTIALS Section 4 of 10
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Hypothyroidism
Other Problems to be Considered:
Refractory errors
Zinc deficiency
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WORKUP Section 5 of 10
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Lab Studies:
A serum retinol study is a costly but direct measure using high-performance liquid chromatography. A value of less than 0.7 mg/L in children younger than 12 years is considered low.
A serum RBP study is easier to perform and less expensive than a serum retinol study because RBP is a protein and can be detected by an immunologic assay. RBP is also a more stable compound than retinol with respect to light and temperature. However, RBP levels are less accurate because they are affected by serum protein concentrations and types of RBP cannot be differentiated.
A zinc level is useful because zinc deficiency interferes with RBP production.
An iron panel is useful because iron deficiency can affect the metabolism of vitamin A.
Albumin levels are indirect measures of vitamin A levels.
Obtain a CBC count with differential if anemia, infection, or sepsis is a possibility.
An electrolyte evaluation and liver function studies should be performed to evaluate for nutritional and volume status.
Imaging Studies:
In children, x-ray films of the long bones may be useful to evaluate for bone growth and excessive deposition of periosteal bone.
Procedures:
Dark-adaptation threshold should be tested.
TREATMENT Section 6 of 10
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Medical Care:
In the United States, VAD can easily be prevented by consuming foods recommended in the Diet section below.
Treatment of subclinical VAD includes consumption of vitamin A–rich foods, including liver, beef, chicken, eggs, fortified milk, carrots, mango, sweet potatoes, and leafy green vegetables.
For VAD syndromes, treatment includes daily oral supplements of 600 mcg (2000 IU) for children aged 3 years or younger, 900 mcg (3000 IU) for children aged 4-8 years, 1700 mcg (5665 IU) for children aged 9-13 years, 2800 mcg (9335 IU) for persons aged 14-18 years, and 3000 mcg (10,000 IU) for all adults.
Therapeutic doses for severe disease include 60,000 mcg (200,000 IU), which has been shown to reduce child mortality rates by 35-70%.
Consultations:
Consult endocrinologists, gastroenterologists, ophthalmologists, nutritionists, infectious disease specialists, and dermatologists as indicated.
Diet:
The 2000 US Department of Agriculture and Department of Health and Human Services Dietary Guidelines for Americans recommend consumption of a variety of foods for a comprehensive nutrient intake.
Liver, beef, chicken, eggs, whole milk, fortified milk, carrots, mango, orange fruits, sweet potato, spinach, kale, and other green vegetables are among foods rich in vitamin A.
Eating at least 5 servings of fruits and vegetable per day is recommended in order to provide a comprehensive distribution of carotenoids.
A variety of foods, such as breakfast cereals, pastries, breads, crackers, and cereal grain bars, are often fortified with 10-15% of the RDA for vitamin A.
MEDICATION Section 7 of 10
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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Vitamins -- Essential for normal DNA synthesis and metabolism of proteins, carbohydrates, and fats. May also work as cofactors used in aerobic cellular respiration.Drug Name
Vitamin A (Del-Vi-A, Del-Vi-A) -- Cofactor in many biochemical processes.
Adult Dose 3000 mcg (10,000 IU) PO qd
Severe disease: 60,000 mcg (200,000 IU) PO for at least 2 d
Pediatric Dose <3 years: 600 mcg (2000 IU) PO qd
4-8 years: 900 mcg (3000 IU) PO qd
9-13 years: 1700 mcg (5665 IU) PO qd
14-18 years: 2800 mcg (9335 IU) PO qd
Severe disease: 60,000 mcg (200,000 IU) PO for at least 2 d
Contraindications Documented hypersensitivity; hypervitaminosis A; pregnancy (if dose >800 mcg/d)
Interactions Cholestyramine, neomycin, and mineral oil may decrease absorption
Pregnancy A - Safe in pregnancy
Precautions Risk of teratogenicity increases in pregnant women at doses >800 mcg/d (not recommended); parenteral vitamin A in infants of low birth weight may be associated with thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension, and metabolic acidosis (E-Ferol syndrome)
FOLLOW-UP Section 8 of 10
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Further Inpatient Care:
Patients with VAD seldom need to be admitted to the hospital unless they also have a serious associated condition. Patients with sepsis, severe dehydration, and/or metabolic derangements should be admitted to the hospital.
Further Outpatient Care:
Follow-up care with a primary care physician is recommended.
In/Out Patient Meds:
Patients should take oral vitamin A at prescribed doses until the deficiency resolves.
Deterrence/Prevention:
Liver, beef, chicken, eggs, whole milk, fortified milk, carrots, mango, orange fruits, sweet potato, spinach, kale, and other green vegetables are among foods rich in vitamin A.
Eating at least 5 servings of fruits and vegetable per day is recommended in order to provide a comprehensive distribution of carotenoids.
A variety of foods, such as breakfast cereals, pastries, breads, crackers, and cereal grain bars, are often fortified with 10-15% of the RDA for vitamin A.
Prognosis:
Prognosis is good if patients are treated when the deficiency is subclinical.
Morbidity increases once blindness has progressed or an infection is acquired.
Irreversible conditions include punctate keratopathy, keratomalacia, and corneal perforation.
Patient Education:
Eating at least 5 servings of fruits and vegetable per day is recommended in order to provide a comprehensive distribution of carotenoids.
Patients may visit the US National Institutes of Health (NIH) web site for more information (see Facts About Dietary Supplements).
MISCELLANEOUS Section 9 of 10
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Medical/Legal Pitfalls:
Evaluation for subclinical symptoms is important in high-risk groups (eg, patients with small-bowel disease or surgery, malabsorption syndromes, alcoholism, or low socioeconomic status). Follow-up care upon completion of all standard vaccination regimens, especially for the measles, is imperative in children.
Special Concerns:
Studies comparing the association of vitamin A and cancer have yielded mixed results. Two randomized, controlled trials have shown an increased risk of lung cancer associated with beta-carotene supplementation. No convincing data exist concerning a reduction in the risk of colorectal cancer with beta-carotene supplementation. Similarly, clinical data on an association between vitamin A and breast cancer are lacking.
BIBLIOGRAPHY Section 10 of 10
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Alaimo D, McDowell MA, Briefel RR, et al: Dietary Intake of Vitamins, Minerals, and Fiber of Persons Ages 2 Months and Over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91. In: Advance Data. Atlanta, Ga: Vital and Health Statistics, Centers for Disease Control and Prevention; 1994: (258) 1-28. Available at: http://www.cdc.gov/nchs/data/ad/ad258.pdf[Full Text].
Combs GF Jr: Vitamins. Chapter 4. In: Mahan LK, Escott-Stump S, eds. Krause's Food, Nutrition, & Diet Therapy. 10th ed. Philadelphia, Pa: WB Saunders; 2000.
D'Souza RM, D'Souza R: Vitamin A for treating measles in children. Cochrane Database Syst Rev 2002; (1): CD001479[Medline].
de Pee S, Dary O: Biochemical indicators of vitamin A deficiency: serum retinol and serum retinol binding protein. J Nutr 2002 Sep; 132(9 Suppl): 2895S-2901S[Medline].
Department of Health and Human Services, Department of Agriculture: Health and Nutrition: Dietary Guidelines for Americans. Available at: http://www.health.gov/dietaryguidelines/dga2000/document/frontcover.htm. 5th ed. Washington, DC: US Government Printing Office; 2000.[Full Text].
Fairfield KM, Fletcher RH: Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002 Jun 19; 287(23): 3116-26[Medline].
Fletcher RH, Fairfield KM: Vitamin supplementation in disease prevention II. Up To Date 2002.
Munoz EC, Rosado JL, Lopez P, et al: Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers. Am J Clin Nutr 2000 Mar; 71(3): 789-94[Medline].
NIH Clinical Center: Facts About Dietary Supplements: Vitamin A and Carotenoids. Clinical Nutrition Service. Office of Dietary Supplements. Available at: www.cc.nih.gov/ccc/supplements/vita.html. Bethesda, Md: National Institutes of Health.[Full Text].
Pazirandeh S, Burns DL: Overview of fat-soluble vitamins I. Up To Date 2002.
Reddy V: History of the International Vitamin A Consultative Group 1975-2000. J Nutr 2002 Sep; 132(9 Suppl): 2852S-2856S[Medline].
Russell RM: The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr 2000 Apr; 71(4): 878-84[Medline].
Russell RM: Vitamin and trace mineral deficiency and excess. In: Braunwald E, Fauci A, Kasper D, Hauser S, Longo D, Jameson J, eds. Harrison's Principals of Internal Medicine. Vol 1. 15th ed. New York, NY: McGraw-Hill; 2001: 465-6.
World Health Organization: Vitamin A: Advocacy. In: Vitamin A. Available at: http://www.who.int/vaccines-diseases/en/vitamina/advocacy/index.shtml. Geneva, Switzerland: 2003.[Full Text].
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| Posted: Sat Sep 20, 2003 6:23 pm Post subject: / |
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This is one of my favorites. It talks about how RDA levels are incorrect and how beta carotene isn't the best source of Vitamin A. GREAT ARTICLE!!!!!
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By Sally Fallon and Mary G. Enig, PhD
The discovery of vitamin A and the history of its application in the field of human nutrition is a story of bravery and brilliance, one that represents a marriage of the best of scientific inquiry with worldwide cultural traditions; and the suborning of that knowledge to the dictates of the food industry provides a sad lesson in the use of power and influence to obfuscate the truth.
A key player in this fascinating story is Weston A. Price, who discovered that the diets of healthy traditional peoples contained at least ten times as much vitamin A as the American diet of his day. His work revealed that vitamin A is one of several fat-soluble activators present only in animal fats and necessary for the assimilation of minerals in the diet. He noted that the foods held sacred by the peoples he studied, such as spring butter, fish eggs and shark liver, were exceptionally rich in vitamin A.
All traditional cultures recognized that certain foods were necessary to prevent blindness. In his pioneering work, Nutrition and Physical Degeneration, Weston Price tells the story of a prospector who, while crossing a high plateau in the Rocky Mountains, went blind with xerophthalmia, due to a lack of vitamin A. As he wept in despair, he was discovered by an Indian who caught him a trout and fed him “the flesh of the head and the tissues back of the eyes, including the eyes.”1 Within a few hours his sight began to return and within two days his eyes were nearly normal. Several years previous to the travels of Weston Price, scientists had discovered that the richest source of vitamin A in the entire animal body is that of the retina and the tissues in back of the eyes.
Many cultures used liver, another excellent source of vitamin A, for various types of blindness.2 The liver was first pressed to the eye and then eaten, a ritual through which the patient directed the healing powers of liver to the afflicted sense organ. The Egyptians described this cure at least 3500 years ago. Similar practices have been described in 18th-century Russia, rural Java in 1978 and among the inhabitants of Newfoundland in 1929. Other cultures used the liver of shark. Hippocrates (460-327 BC) prescribed liver soaked in honey for blindness in malnourished children. Assyrian texts dating from 700 BC and Chinese medical writings from the 7th century AD both call for the use of liver in the treatment of night blindness. A 12th-century Hebrew treatise recommends pressing goat liver to the eyes, followed by eating of the liver. In the Middle Ages, the Dutch physician Jacob van Laerlandt (1235-1299) wrote the following:
Who does not at night see right
Eats the liver of goat
He will then see better at night.
VITAMIN-A BRAVERY
Night blindness was a recurring problem among sailors on long voyages but by the advent of the great European navies, the wisdom of traditional liver therapy was largely ignored. It took brave dedication to the scientific method to confirm the validity of the ancient treatments. The first to do this was Eduard Schwarz (1831-1862), a ship’s doctor on an Austrian frigate that was sent around the world on a scientific exploration. Before his departure from Vienna, several physicians had asked Schwartz to test the old folk remedy of boiled ox liver against night blindness. On the voyage, 75 of the 352 men developed the condition. Every evening when dusk came, they lost their vision and had to be led about like the blind. Schwartz fed them ox or pork liver and found that the night vision in all of the afflicted was restored.
The cure was “a true miracle,” said Schwartz in his published report, which stated emphatically that night blindness was a nutritional disease. For this he was viciously attacked by the medical profession, which accused him of “frivolity” and “self-aggrandizement.” Three years after his return from the expedition, the discredited physician died of TB. He was 31. The use of vitamin-A-rich foods for tuberculosis had not yet been discovered.
In 1904, the Japanese physician M. Mori described xerophthalmia in undernourished children whose diet consisted of rice, barley, cereals “and other vegetables.” Xerophthalmia is a condition that progresses from night blindness to dissolution of the cornea and finally the bursting of the eye. He treated the children with liver and also cod liver oil with excellent results. In fact, he found that cod liver oil was even more effective than liver in restoring visual function. Mori described it as “an excellent, almost specific medication. . . Indeed, in most cases, the effect is so rapid that by evening the children with night blindness are already dancing around briskly, to the joy of their mothers.” Cod liver oil also helped reverse keratomalacia, a condition associated with severe nutritional deficiencies and characterized by corneal ulceration, extreme dryness of the eyes and infection.
At the end of the First World War, a physician named Bloch discovered that a diet containing whole milk, butter, eggs and cod liver oil cured night blindness and keratomalacia. In one important experiment, Bloch compared the results when he fed one group of children whole milk and the other margarine as the only fat. Half of the margarine-fed children developed corneal problems while the children receiving butterfat and cod liver oil remained healthy.
The actual discovery of vitamin A is credited to a researcher named E. V. McCollum. He was curious why cows fed wheat did not thrive, became blind and gave birth to dead calves, while those fed yellow corn had no health problems. The year was 1907 and by this time, scientists were able to determine the levels of protein, carbohydrate, fat and minerals in food. The wheat and corn used in McCollum’s experiments contained equal levels of minerals and macronutrients. McCollum wondered whether the wheat contained a toxic substance, or whether there was something lacking in the wheat that was present in yellow maize?
In order to solve the puzzle, McCollum hit upon the idea of using small animals like mice or rats rather than cows for nutrition experiments—they ate less, took up less space, reproduced rapidly and could be given controlled diets. Like many good ideas, this one met with considerable opposition. McCollum worked in the Wisconsin College of Agriculture and was told by the dean “to experiment with economically valuable animals—the rat was a pest to farmers!” McCollum was forced to work secretly in the basement of the Agriculture Hall where he studied the effects of various diets on colonies of rats. He discovered that rats fed pure protein, pure skim milk, sugar, minerals and lard or olive oil for fat failed to grow. When he added butterfat or an extract of egg yolk to their diets, their health was restored. He discovered a fat-soluble factor in certain foods that was essential for growth and survival. This was named “fat-soluble factor A” as opposed to other accessory dietary factors, called “water-soluble B.”
Research by Osbourne and Mendel, published just five months after McCollum’s study, found that cod liver oil produced the same results as butter in rat studies, thus confirming the early work of Mori in Japan. Continued experiments helped scientists determine that vitamin A was colorless, but often associated in foods with beta-carotene, which was yellow. In the 1930s, researchers discovered that vitamin A is formed by the conversion of beta-carotenes in the intestinal mucosa of animals and humans.
The scientific term for vitamin A is retinol, because of its presence in the retina of the eye. The role of retinol in vision was elucidated by a number of brilliant scientists, beginning in 1877 with a German, W. Kuhne, who discovered that the purple retinas from dark-adapted frogs turned yellow when exposed to light. The purple color is restored in a complex biochemical cycle involving vitamin A, which makes vision possible. Other scientists demonstrated the role of vitamin A in cell differentiation, bone development, reproduction and immune system function. Weston Price confirmed the value of vitamin A in traditional diets during his studies of primitive peoples carried out during the 1930s and 1940s.
Due to the outstanding scientific work of these and many other researchers, the administration of cod liver oil to growing children—a tradition found among Arctic peoples such as the Scandanivians and Eskimos—became standard practice until after the Second World War. Ironically, as Americans have stopped giving cod liver oil to their children, programs to administer vitamin A to children in Africa and Asia have had astonishing success in preventing blindness and infectious disease. This vitamin-A-treatment program was the brainchild of yet another brave researcher, Alfred Sommer, an ophthalmologist at Johns Hopkins University, who patiently lobbied for an international program after observing the wonderful effects of vitamin-A supplementation in Indonesia and Nepal.
In recent decades, much vitamin-A research has focussed on its role in preventing cancer, and its use in combination with nontoxic therapies in the treatment of cancer. Unfortunately, research on the anticarcinogenic properties of vitamin A has not been widely adopted. Perhaps the most tragic example is Dr. Max Gerson, who treated many cases of terminal cancer with excellent results using raw liver juice, a rich source of vitamin A. In 1946, he testified before a US congressional committee on the success of his treatment, but it was subsequently ignored.3 In 1973, Dr. Kanematsu Sigiura of the Sloan Kettering Institute published the results of studies on mammary tumors in mice using high doses of vitamin A and a derivative of seeds called laetrile. He observed complete regression of all the tumors in a total of five mice. The final report noted that “Dr. Sigiura has never observed complete regression of these tumors in all his cosmic experience with other chemotherapeutic agents.” Nevertheless, just a few months later, spokesmen for Sloan Kettering flatly denied that there was any value in the therapy.4
VITAMIN-A VAGARY
While the ongoing process of research into vitamin A and its effects is a boon to children and adults throughout the world, modern agriculture and food processing conglomerates gain nothing from this knowledge. Confinement farming practices effectively prevent vitamin A from incorporation into animal foods and the processing industry would rather use vegetable oils than animal fats. Some vegetable oils contain carotenes but they do not contain true vitamin A. Only animal fats contain vitamin A and vitamin A is present in large amounts only when the animals have a source of carotenes or vitamin A in the diet, such as green pasture, insects and fish meal.
Unfortunately, the vast majority of popular books on nutrition insist that humans can obtain vitamin A from fruits and vegetables. Even worse, FDA regulations allow food processors to label carotenes as vitamin A. The label for a can of tomatoes says that tomatoes contain vitamin A, even though the only source of true vitamin A in the tomatoes is the microscopic insect parts. The food industry, and the lowfat school of nutrition that the industry has spawned, benefit greatly from the fact that the public has only vague notions about vitamin A. In fact, most of the foods that provide large amounts of vitamin A—butter, egg yolks, liver, organ meats and shellfish—have been subject to intense demonization.
Under optimal conditions, humans can indeed convert carotenes to vitamin A. This occurs in the upper intestinal tract by the action of bile salts and fat-splitting enzymes. Of the entire family of carotenes, beta-carotene is most easily converted to vitamin A. Early studies indicated an equivalency of 4:1 of beta-carotene to retinol. In other words, four units of beta-carotene were needed to produce one unit of vitamin A. This ratio was later revised to 6:1 and recent research suggests an even higher ratio.5 This means that you have to eat an awful lot of vegetables and fruits to obtain even the daily minimal requirements of vitamin A, assuming optimal conversion.
But the transformation of carotene to retinol is rarely optimal. Diabetics and those with poor thyroid function, a group that could well include at least half the adult US population, cannot make the conversion. Children make the conversion very poorly and infants not at all — they must obtain their precious stores of vitamin A from animal fats6— yet the low-fat diet is often recommended for children. Strenuous physical exercise, excessive consumption of alcohol, excessive consumption of iron (especially from “fortified” white flour and breakfast cereal), use of a number of popular drugs, excessive consumption of polyunsaturated fatty acids, zinc deficiency and even cold weather can hinder the conversion of carotenes to vitamin A,7 as does the lowfat diet.
Carotenes are converted by the action of bile salts, and very little bile reaches the intestine when a meal is low in fat. The epicure who puts butter on his vegetables and adds cream to his vegetable soup is wiser than he knows. Butterfat stimulates the secretion of bile needed to convert carotenes from vegetables into vitamin A, and at the same time supplies very easily absorbed true vitamin A. Polyunsaturated oils also stimulate the secretion of bile salts but can cause rapid destruction of carotene unless antioxidants are present.
It is very unwise, therefore, to depend on plant sources for vitamin A. This vital nutrient is needed for the growth and repair of body tissues; it helps protect mucous membranes of the mouth, nose, throat and lungs; it prompts the secretion of gastric juices necessary for proper digestion of protein; it helps to build strong bones and teeth and rich blood; it is essential for good eyesight; it aids in the production of RNA; and contributes to the health of the immune system. Vitamin-A deficiency in pregnant mothers results in offspring with eye defects, displaced kidneys, harelip, cleft palate and abnormalities of the heart and larger blood vessels. Vitamin A stores are rapidly depleted during exercise, fever and periods of stress. Even people who can efficiently convert carotenes to vitamin A cannot quickly and adequately replenish vitamin A stores from plant foods.
Foods high in vitamin A are especially important for diabetics and those suffering from thyroid conditions. In fact, the thyroid gland requires more vitamin A than the other glands, and cannot function without it.8 And a diet rich in vitamin A will help protect the diabetic from the degenerative conditions associated with the disease, such as problems with the retina and with healing.
Weston Price considered the fat-soluble vitamins, especially vitamin A, to be the catalysts on which all other biological processes depend.9 Efficient mineral uptake and utilization of water-soluble vitamins require sufficient vitamin A in the diet. His research demonstrated that generous amounts of vitamin A insure healthy reproduction and offspring with attractive wide faces, straight teeth and strong sturdy bodies. He discovered that healthy primitives especially value vitamin-A-rich foods for growing children and pregnant mothers. The tenfold disparity that Price discovered between primitive diets and the American diet in the 1940s is almost certainly greater today as Americans have forsworn butter and cod liver oil for empty, processed polyunsaturates.
In Third World communities that have come into contact with the West, vitamin-A deficiencies are widespread and contribute to high infant mortality, blindness, stunting, bone deformities and susceptibility to infection.10 These occur even in communities that have access to plentiful carotenes in vegetables and fruits. Scarcity of good quality dairy products, a rejection of organ meats as old fashioned or unhealthful, and a substitution of vegetable oil for animal fat in cooking all contribute to the physical degeneration and suffering of Third World peoples.
Supplies of vitamin A are so vital to the human organism that mankind is able to store large quantities of it in the liver and other organs. Thus it is possible for an adult to subsist on a fat-free diet for a considerable period of time before overt symptoms of deficiency appear. But during times of stress, vitamin A stores are rapidly depleted. Strenuous physical exercise, periods of physical growth, pregnancy, lactation and infection are stresses that quickly deplete vitamin A stores. Children with measles rapidly use up vitamin A, which can result in irreversible blindness. An interval of three years between pregnancies allows mothers to rebuild vitamin A stores so that subsequent children will not suffer diminished vitality.
One aspect of vitamin A that deserves more emphasis is its role in protein utilization. Kwashiorkor is as much a disease of vitamin-A deficiency, leading to impaired protein absorption, as it is a result of absence of protein in the diet. High-protein, lowfat diets are especially dangerous because protein consumption rapidly depletes vitamin-A stores. Children brought up on high-protein, lowfat diets often experience rapid growth. The results—tall, myopic, lanky individuals with crowded teeth, and poor bone structure, a kind of Ichabod Crane syndrome—are a fixture in America. High-protein, lowfat diets can even cause blindness as occurred once in Guatemala where huge amounts of instant nonfat dry milk were donated in a food relief program.11 The people who consumed the dried milk went blind. Primitive peoples understood this principle instinctively, which is why they never ate lean meat and always consumed the organ meats of the animals that served them for food.
Growing children actually benefit from a diet that contains considerably more calories as fat than as protein.12 A high-fat diet that is rich in vitamin A will result in steady, even growth, a sturdy physique and high immunity to illness.
The great discrepancy between what science has discovered about vitamin A and what nutrition writers promote in the popular press contributes to awkward moments. The New York Times has been a strong advocate for lowfat diets, even for children, yet a recent NYT article noted that vitamin-A-rich foods like liver, egg yolk, cream and shellfish confer resistance to infectious diseases in children and prevent cancer in adults.13 A Washington Post article hailed vitamin A as “cheap and effective, with wonders still being (re)discovered,” noting that recent studies have found that vitamin-A supplements help prevent infant mortality in Third World countries, protect measles victims from severe complications and prevent mother-to-child transmission of HIV virus.14 The article lists butter, egg yolk and liver as important sources of vitamin A, but claims, unfortunately, that carotenes from vegetables are “equally important.”
Vitamin-A vagary confuses the public and contributes to continued acceptance of lowfat dogma, even among science writers.
VITAMIN -A KNAVERY
Even worse than vitamin-A vagary is vitamin-A knavery in the form of concerns that vitamin A may be toxic in more than the minuscule RDA-recommended amounts. In fact, so great is the propaganda against the vitamin that obstetricians and pediatricians are now warning patients to avoid foods containing vitamin A!
Recently an “expert” panel recommended lowering the RDA (recommended daily allowance) for vitamin A from 5000 IU daily to about 2500 IU and has set an upper limit of about 10,000 IUs for women. The panel was headed by Dr. Robert Russell of Tufts University, who warned that intake over the “upper limit” may cause irreversible liver damage and birth defects—a ridiculous statement in view of the fact that just a few decades ago pregnant women were routinely advised to take cod liver oil daily and eat liver several times per week. One tablespoon of cod liver oil contains at least 15,000 IU and one serving of liver can contain up to 40,000 IU vitamin A. Russell epitomizes the establishment view when he insists that vitamin-A requirements can be met with one-half cup of carrots daily.
The anti-vitamin-A campaign began in 1995 with the publication of a Boston University School of Medicine study published in the New England Journal of Medicine.15 “Teratogenicity of High Vitamin A Intake,” by Kenneth J. Rothman and his colleagues, correlates vitamin-A consumption among more than 22,000 pregnant women with birth defects occurring in subsequent offspring. The study received extensive press coverage in the same publications that had earlier extolled the benefits of vitamin A. “Study Links Excess Vitamin A and Birth Defects” by Jane Brody appeared on the front page of the New York Times on October 7, 1995; on November 24, 1995, the Washington Times reported: “High doses of vitamin A linked to babies’ brain defects.”
When a single study receives front-page coverage, it’s important to take a closer look, especially as earlier research discovered the importance of vitamin A in preventing birth defects. In fact, the defects listed as increasing with increased vitamin A dosage—cleft lip, cleft palate, hydrocephalus and major heart malformations—are also defects of vitamin A deficiency.
In the study, researchers asked over 22,000 women to respond to questionnaires about their eating habits and supplement intake before and during pregnancy. Their responses were used to determine vitamin-A status. As reported in the newspapers, researchers found that cranial-neural-crest defects increased with increased dosages of vitamin A; what the papers did not report was the fact that neural tube defects decreased with increased vitamin A consumption, and that no trend was apparent with musculoskeletal, urogenital or other defects. The trend was much less pronounced, and less statistically significant, when cranial-neural-crest defects were correlated with vitamin-A consumption from food alone.
The study is compromised by a number of flaws. Vitamin-A status was assessed by the inaccurate method of recall and questionnaires; and no blood tests were taken to determine the actual usable vitamin-A status of the mothers. Researchers did not weight birth defects according to severity; thus we do not know whether the defects of babies born to mothers taking high doses of vitamin A were serious or minor compared to those of mothers taking lower amounts.
The most serious flaw was that researchers failed to distinguish between manufactured vitamin A in the form of retinol, found in supplements and added to fabricated foods, from natural vitamin-A complex, present with numerous co-factors, from vitamin-A-containing foods. It is well known that synthetic vitamins are less biologically active, hence less effective, than naturally occurring vitamins. This is especially true of the fat-soluble vitamins like vitamin A, because these tend to be more complex molecules, with numerous double bonds and a multiplicity of forms. Natural vitamin A occurs as a mixture of various isomers, aldehydes, esters, acids and alcohols. Pure retinoic acid, a metabolite of vitamin A used to treat adult acne, is well known to cause birth defects. Apparently pure retinol has teratogenic properties in high amounts as well.
Researchers found that cranial-neural-crest defects increased in proportion to the amount of retinol from supplements consumed during the first trimester of pregnancy (although the total number of defects remained stable up to 15,000 IU daily). Research into vitamin A has indicated that many factors interfere with its absorption and utilization. Inadequate fat in the diet, poor production of bile salts, low enzyme status, and compromised liver function can all interfere with the uptake and usage of vitamin A, especially when given as a supplement in the form of retinol, rather than as a component of whole foods. It may be that the teratogenic effects of commercial vitamin-A preparations are exacerbated in women whose dietary practices and general health status are poor. Some researchers believe that synthetic vitamin A interferes with the proper utilization of natural vitamin A from foods.
Pure retinol is added to many fabricated foods like margarine, breakfast cereals and pizza. The study made no distinction between those women whose vitamin A was supplied by whole animal foods and those who ingested retinol added to margarine, white flour and extruded breakfast cereals—foods which contain many other factors that can cause birth defects. Natural vitamin A provided by liver, eggs, butter, cream and cod liver oil is well recognized as providing excellent protection against birth defects.
Distinctions between synthetic and natural vitamin A have been absent in the extensive media coverage of this study—on the contrary, the newspaper reports contain implied warnings against pregnant women eating liver, dairy products, meat and eggs, but none against eating fabricated foods like margarine and breakfast cereals to which synthetic vitamin A is added. And there has been no media coverage for subsequent studies, which found that high levels of vitamin A did not increase the risk of birth defects. A study carried out in Rome, Italy found no congenital malformations among 120 infants exposed to more than 50,000 IU of vitamin A per day.16 A study from Switzerland looked at blood levels of vitamin A in pregnant women and found that a dose of 30,000 IU per day resulted in blood levels that had no association with birth defects.17
VITAMIN-A SLAVERY
While scientists in America are creating confusion and fear about vitamin A, WHO and UNICEF vitamin-A-distribution programs in Africa and Asia have been extremely successful in reducing blindness and death among both children and adults. Vitamin A is more cost effective in saving lives and preventing suffering than immunizations and drugs and it can be administered with 2-cent capsules. The program does not undermine traditional cultures or foodways and is easily carried out on the village level.
But this kind of success doesn’t sit well with the food and pharmaceutical industries because it strengthens village life and lessens the market for drugs and processed foods. Fulsome with praise, the “big guns of the international food supply system” have joined in a “public-private partnership” to get in on the program.18 Kellogg, Cargill, Monsanto and Procter & Gamble have pioneered the addition of vitamin A to margarine, vegetable oil, wheat flour, sugar and breakfast cereals—even to MSG! At a formal luncheon hosted by Hillary Clinton, the corporate executives and leaders of various relief groups announced their goal of showing “indigenous food companies. . . how to add vitamin A to foods that low-income people eat.” In other words, vitamin A will be used to promote processed foods to villagers in Africa and Asia in the guise of humanitarian relief. Low income people in America eat margarine and other processed foods, but low-income people in the Third World eat foods grown by farmers and processed locally by artisans.
And when people refuse to eat processed foods, the “big guns” have devised another stratagem—genetically engineering rice to produce carotenes. Those who promote the so-called “golden” rice as a solution to the vitamin-A problem are either woefully ignorant or unabashedly corrupt. Golden rice containing carotenes can’t provide true vitamin A to the world’s children but it will further the trend of pushing their parents off the farm and into ghastly slums.
In the process of showing “indigenous food companies. . . how to add vitamin A to foods. . .” and of inserting genes for producing carotenes into rice, the multinational corporations will strengthen their grip on the world’s food supply, leading to a disruption of village life and what Indian writer Vandana Shiva calls “food dictatorship.” If the conglomerates have their way, programs to promote golden rice and “enriched” processed foods will replace programs to distribute vitamin-A capsules, increasing the suffering of children and worldwide economic slavery.
What can we in the west do to foil the nefarious plans of the food-and-pharmaceutical-complex in nations less prosperous than our own? The answer is simple: cut off their funding at the source by refusing to spend money on their products. Boycott processed foods; avoid pharmaceutical drugs. The better way to physical and economic health is through foods containing vitamin A.
Note: Your donations can help support the campaign to provide vitamin A capsules to children in Africa and Asia. For details see www.the childsurvivalsite.com.
REFERENCES
WA Price. Nutrition and Physical Degeneration. Price-Pottenger Nutrition Foundation, San Diego, CA, p 280.
The history outlined here has been expertly compiled by G Wolf. “A History of Vitamin A and Retinoids.” The FASEB Journal, July 1996, 10:1102-1107.
M Gerson, MD. A Cancer Therapy: Results of Fifty Cases. Totality Books, Del Mar, CA, 1958.
GE Griffin. World Without Cancer. American Media, Westlake Village, CA, 1974, pp 462-3.
NW Solomons, J Bulus. “Plant sources of provitamin A and human nutriture.” Nutrition Review, Springer Verlag New York, Inc, July 1993, 51:1992-4.
IW Jennings. Vitamins in Endocrine Metabolism. Charles C. Thomas Publisher, Springfield, Illinois.
LJ Dunne. Nutrition Almanac, Third Edition, McGraw-Hill Publishing Company, 1990.
Jennings, Op Cit.
WA Price. Op Cit.
Solomons, Op Cit.
Personal Communication, Ruth Rosevear
Protein calories should comprise about 15 percent of the diet. Fat calories in children’s diets should be greater than 40 percent of total calories.
Natalie Angler. “Vitamins Win Support as Potent Agents of Health,” New York Times, March 10, 1992.
David Brown. “It’s Cheap and Effective, With Wonders Still Being (Re)discovered.” The Washington Post, November 7,1994.
KJ Rothman and others. “Teratogenicity of high vitamin A intake.” New England Journal of Medicine. November 23, 1995 333(21):1414-5.
P Mastroiacovo and others. “High vitamin A intake in early pregnancy and major malformations: a multicenter prospective controlled study.” Teratology. January 1999 59(1):1-2.
UW Wiegand and others. “Safety of vitamin A: recent results.” International Journal of Vitamin and Nutrition Research. 1998, 68(6):411-6.
J Mann. “Saving Young Lives With a 2-Cent Capsule.” The Washington Post, March 17, 1999.
Sidebar Articles
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THE SUCCESS OF VITAMIN A
One of the most successful programs in the history of nutrition science is the global campaign to distribute high-dose vitamin-A capsules to children throughout Africa and Asia. Launched in 1997, the global campaign is a partnership between UNICEF and the World Health Organization (WHO) as well as the governments of Canada, the United Kingdom, the Netherlands, Japan and the United States Agency for International Development (USAID). The program has been particularly successful in Nepal where groups of local women known as Female Community Health Volunteers help distribute the capsules throughout the rugged terrain. In 2000, over 90 percent of Nepalese children had received their yearly dosage of vitamin A.
Although the vitamin A distributed is synthetic and not the natural form derived from fish oils, it is the animal form of vitamin A (retinol), not carotenes. Children six to twelve months old receive two doses of 100,000 units per year; children over 12 months receive two doses of 200,000 per year. According to Werner Schultink, head of the Nutrition Section at UNICEF headquarters in New York, infant and child mortality drops about 23 percent when vitamin A levels are adequate. The program in Nepal costs just over $2 million per year, less than $1 per child (Reuter’s 2/12/01).
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CONVERSION OF CAROTENES TO VITAMIN A
The many conditions that interfere with the conversion of carotenes in plant foods to vitamin A include:
Being an infant or child
Diabetes
Low Thyroid Function
Low Fat Intake
Intestinal Roundworms
Diarrhea
Pancreatic Disease
Celiac Disease
Sprue
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THE MYTH OF VITAMIN A TOXICITY
Typical of the orthodox medical view of vitamin A is the following statement, posted at WebMD.com: “Vitamin A can be very toxic when taken in high-dose supplements for long periods of time and can affect almost every part of the body, including eyes, bones, blood, skin, central nervous system, liver, and genital and urinary tracts. Symptoms include dizziness, nausea, vomiting, headache, skin damage, mental disturbances and, in women, infrequent periods. Severe toxicity can cause blindness and may even be life-threatening. Liver damage can occur in children who take RDA-approved adult levels over prolonged periods of time or in adults who take as little as five times the RDA-approved amount for seven to ten years. In children, chronic overdose can cause fluid on the brain and other symptoms similar to those in adults. Pregnant women who take amounts not much higher than RDA levels increase the risk for birth defects in their children. High consumption of vitamin A may also increase the risk of gastric cancer and the risk of osteoporosis and fractures in women.”
The Merck Manual describes vitamin-A toxicity in less hysterical terms. Acute vitamin-A poisoning can occur in children after taking a single dose of synthetic vitamin A in the range of 300,000 IU or a daily dosage of 60,000 IU for a few weeks. Two fatalities have been reported from acute vitamin-A poisoning in children, which manifests as increased intracranial pressure and vomiting. For the vast majority, however, recovery after discontinuation is “spontaneous, with no residual damage.”
In adults, according to the Merck Manual, vitamin-A toxicity has been reported in arctic explorers who developed drowsiness, irritability, headaches and vomiting, with subsequent peeling of the skin, within a few hours of ingesting several million units of vitamin A from polar bear or seal liver. Again, these symptoms cleared up with discontinuation of the vitamin-A rich food. Other than this unusual example, however, only vitamin-A from “megavitamin tablets containing vitamin A. . . when taken for a long time” has induced acute toxicity, that is, 100,000 IU synthetic vitamin-A per day taken for many months.
Unless you are an arctic explorer, it is virtually impossible to develop vitamin-A toxicity from food. The putative toxic dose of 100,000 IU per day would be contained in 3 tablespoons of high vitamin cod liver oil, 6 tablespoons of regular cod liver oil, two-and-one-half 100-gram servings of duck liver, about three 100-gram servings of beef liver, seven pounds of butter or 309 egg yolks. Even synthetic vitamin A is not toxic when given as a single large dose or in small amounts on a daily basis. Children in impoverished areas of the world are routinely given two 100,000-unit doses of retinol per year for infants and two 200,000-unit doses for children over 12 months.
The tragedy is that misplaced concern about vitamin-A toxicity has led doctors to advise pregnant women to avoid foods containing vitamin A, and parents to avoid giving cod liver oil to their babies. Yet the early books on the feeding of pregnant women and infants recommended generous doses of cod liver oil and frequent liver consumption for pregnant women and two teaspoons of cod liver oil per day for babies three months and older. A majority of our medical problems would clear up very quickly if the populace would return to eating liver and embrace the use of cod liver oil—our finest superfoods.
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GETTING IT WRONG
“Vitamin A can be found in fish liver oils, animal livers and green and yellow fruits and vegetables.” —Prescription for Nutritional Healing by James F. Balch, MD and Phillis A. Balch, CNC. (However, the authors include the following warning at the end of their section on vitamin A: “Diabetics should avoid beta-carotene as should hypothyroid individuals, because they cannot convert beta-carotene to vitamin A.”)
“Cod liver oil used to be taken routinely as a source of vitamin A. But many experts now believe that as a nutritional aid, the oil is obsolete. We can only consume vitamin A directly in the meat of animals—liver is the richest source. But bright orange fruits and vegetables and dark, leafy greens contain beta-carotene which our bodies convert into the vitamin. . . Before the days of refrigerated trucks and mass distribution of produce, vitamin A deficiency was an enormous problem. . . . But today most people have access to a wide range of produce year-round. What’s more, beta-carotene supplements are also widely available.” —Article on WebMD.com by Karen Cullen, RD, PhD
“Vitamin A is found in animal produce and beta-carotene, a vitamin-A-type compound. It is found in the yellow pigments of vegetables. . . If it is not needed, it remains as beta-carotene; if needed, it is converted into vitamin A. . . vitamin A supplements [are] not necessary.”—Enhancing Fertility Naturally by Nicky Wesson
“Vitamin A is found in the form of betacarotene in leafy green vegetables, carrots, sweet potatoes, winter squash and cantelope in adequate amounts to supply a child’s daily needs. . . “ —Dr. Attwood’s Low-Fat Prescription for Kids by Dr. Charles R. Attwood
“Vitamin A’s toxicity depends on its form. Only retinol and the other varieties found in animal foods are capable of doing much harm. Carotenoids, the vegetable sources of vitamin A, don’t seem to be toxic even when extraordinarily large amounts are consumed.” —The University of California San Diego Nutrition Book by Paul Saltman, PhD, Joel Gurin and Ira Mothner
”The carotenes. . . are the main source of vitamin A.” Basic Food Chemistry by Frank E. Lee, PhD “Yellow, deep orange/red and dark green vegetables and fruits. . . are high in vitamin A. . . “ —The Breast Cancer Survival Manual by John Link, MD
“Vitamin A taken too enthusiastically can be toxic, since it is stored in the liver. Beta-carotene, however, is not converted into vitamin A unless the body requires it, and you cannot suffer from toxic levels of it.” —The Endometriosis Answer Book by Niels H Lauersen and Constance deSwaan
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VITAMIN A—THE MIRACLE NUTRIENT
Vitamin A supplementation of children in Asia and Africa has been extremely effective in reducing the rates of infection, diarrhea, anemia and blindness (Reuter’s 2/12/01). African and Asian children receiving vitamin-A supplements grow faster, have better hemoglobin values and die 30-60 percent less frequently than nonsupplemented peers (J Nutr Jan 1989 119(1):96-100).
Vitamin A supplementation can reduce the incidence of malaria. Children in Papua New Guinea given high doses of vitamin A had a 30 percent lower incidence of malaria than those receiving a placebo (The Lancet, 1999, 354:203-9).
Vitamin A plays a vital regulating role in the immune system. Vitamin A deficiency leads to a loss of ciliated cells in the lung, an important first line defense against pathogens. Vitamin A promotes mucin secretion and microvilli formation by mucosa, including the gastrointestinal tract mucosa. Vitamin A regulates T-cell production and apoptosis (programmed cell death) (Nutrition Reviews 1998;56:S38-S48).
HIV transmission is closely correlated with levels of vitamin A in mothers. A study in Malawi, Africa found that mothers with the highest levels of vitamin A had an HIV transmission rate of just 7.2 percent (Celia Farber, “A Timely Firestorm,” www.ironminds.com).
Treatment with megadoses of vitamin A (100,000 IU per day) resulted in a 92 percent cure rate of menorrhagia (excessive menstrual bleeding) at Johannesburg General Hospital in South Africa (S Afr Med J 1977).
Lack of vitamin A interferes with optimal function of the hippocampus, the main seat of learning. Scientists at the Salk Institute for Biological Studies in San Diego, California, found that removing vitamin A from the diets of mice diminished chemical changes in the brain considered the hallmarks of learning and memory (Proc Natl Acad Sci, Sep 25, 2001 98(20):11714-9).
Natural vitamin A helps reconnect retinoid receptors critical for vision, sensory perception, language processing and attention in autistic children. Use of cod liver oil helps children recover from autism due to the DPT vaccine. The pertussis toxin interferes with retinoid receptors in the brain (Med Hypothesis, Jun 2000 54(6):979-83).
Vitamin A can be helpful in the treatment of psoriasis. Researchers found that patients suffering from severe psoriasis had low blood levels of vitamin A (Acta Derm Venereol Jul 1994 74(4):298-301).
In stroke victims, those with high levels of vitamin A are more likely to recover without damage (The Lancet, Mar 25, 1998, pp 47-50).
Vitamin A protects against lung and bladder cancers in men (Alt Cancer Inst Monogr Dec 1985 69:137-42). Fourteen out of 20 patients with prostate cancer achieved total remission and five achieved partial remission using vitamin A as part of a natural cancer therapy in Germany (Drugs Exp Clin Res 2000;26(65-6):249-52).
Vitamin A was used successfully by Dr. L. J. A. Loewenthal, to combat tropical ulcers in Uganda (S Afr Med J Dec 24 1983 64(27):1064-7).
Vitamin A has also been used successfully to treat a skin condition called Kyrle’s disease (Cutis Dec 1982 30(6):753-5, 759). Elderly persons who consume adequate vitamin A are less prone to leg ulcers (Veris Newsletter Dec 1999;15(4):5).
Chronic vitamin-A deficiency causes degeneration of the structures of the ear. Decreased auditory function in humans is associated with low vitamin-A levels. (Arch Otorhinolaryngol 1982;234(2):167-73).
Vitamin A inhibits the effects of phytic acid and increases absorption of iron from whole wheat. (Arch Latinoam Nutr Sep 2000;50(3):243-. Vitamin A supplementation increases absorption of iron and folic acid in women in Bangladesh (Am J Clin Nutr Jul 2001;74(1):108-15).
Use of vitamin A supplements reduces the risk of cataracts (Am J Ophthalmol Jul 2001;132(1):19-26).
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SOURCES OF VITAMIN A
Listed below are approximate levels of vitamin A in common foods, in IUs per 100 grams:
High-vitamin cod liver oil 230,000
Regular cod liver oil 100,000
Duck liver 40,000
Beef liver 35,000
Goose liver 31,000
Liverwurst sausage (pork) 28,000
Lamb liver 25,000
It should be noted that these amounts can vary according to how the animals are fed. Weston Price noted a huge variation in vitamin-A content of butter according to the season. In addition, absorption of vitamin A varies according to the food. Research carried out during the 1940s indicates that vitamin A is more easily absorbed from butter than from other foods.
The US Recommended Daily Allowance of vitamin A is currently 5,000 IU per day (and may possibly be lowered to 2500 IU per day). From the work of Weston Price, we can assume that the amount in primitive diets was about 50,000 IU per day, which could be achieved in a modern diet by consuming generous amounts of whole milk, cream, butter and eggs from pastured animals; beef or duck liver several times per week; and 1 tablespoon regular cod liver oil or 1/2 tablespoon high-vitamin cod liver oil per day.
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ARE CAROTENES SAFE?
Are carotenes safe in large doses, as claimed? Dependence on carotenes for vitamin A calls on large reserves of enzymes to make the conversion. In their fascinating book Nutrition and Evolution, Michael Crawford and David Marsh note that in animals, “if any function can be delegated to another organism it leaves the disk space free to perform some new function or to perform an old one better.” The cat species does not synthesize vitamin A from carotenes. “If they had to synthesize their own vitamin A . . . it would take up a significant amount of their disk space.” Cats get vitamin A from their prey, whose ability to synthesize vitamin A from carotenes compromises other functions, such as night vision and quickness of movement. While medical orthodoxy claims that consumption of large amounts of carotenes has no downside, it is possible that dependence on carotenes for vitamin A, even in those who are good converters, compromises other biochemical functions in subtle ways.
The so-called nontoxic betacarotene supplements contain a synthetic form of carotene, just one of 50 or 60 carotenes found in the typical diet. The biological activity of synthetic betacarotene is much lower than that of the natural complexes of carotenes and, in fact, may put stress on the immune system Studies with humans and rats given synthetic betacarotene found an increase in white blood cells. In cancer trials, synthetic betacarotenes were not found to be protective. In fact, in one study, patients given synthetic betacarotene had worse results than controls (NEJM April 1994 330:(15);891-895). |
http://www.westonaprice.org/vitamins/vitaminasaga.html
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Very detailed. Takes a couple reads, but thorough. pretty scientific
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A. Background
Description
Vitamin A is a general term that refers to fat-soluble compounds that are similar in structure and biologic activity to retinol. Vitamin A also refers to dietary precursors of vitamin A (6,11). The precursors of vitamin A (retinol) are the carotenoids (most commonly beta-carotene). The term retinoid refers to any compound that is structurally similar to retinal (aldehyde), retinol (alcohol), or any other substance that exhibits vitamin A activity (1). Retinoic acid, which is a metabolite of retinal (6), is such a substance that is often studied. Synthetic compounds within the vitamin A family have similar structures as the natural form, but may have few or no functions that the natural vitamin posses (11). Most compounds within the vitamin A family are soluble in fat and essential to numerous processes within the body. There have been several water-soluble retinoids, extracted from plasma, bile, and other tissue (11). For the purposes of this literature review any discussion of vitamin A will focus on those retinoids with fat-soluble properties. The main discussion will involve retinol. Retinol is chemically a "pale yellow crystalline solid" (6). The solid and its metabolites exist in nature as various isomers. The biologic metabolites of retinol are unique in that they contain five conjugated double bonds within their six-carbon ring (B-ionone) and isoform specific side chains (11). The double bonds contribute special properties; for example, the double bonding in retinol plays a unique role in multiple vision processes, which will be discussed in a subsequent section of this review. As mentioned earlier most retinoids are soluble in organic solvents and fat. However, oxidation and polymerization are all detrimental to retinoids; therefore, the compounds must be protected from light, oxygen and high temperature.
Dietary Function
Vitamin A is essential for numerous intrinsic processes. The most well-known and understood process is that of vision. The 11-cis retinal form of vitamin A is essential for the neural transmission of light into vision (11). Epithelial cells are highly dependent on retinoic acid and are commonly used to treat a variety of skin diseases. A developing fetus is also highly dependent on retinoic acid, as it is essential to the growth of the eyes, lungs, ears and heart (6). The retinoids are not only the most active form of vitamin A, but also a current area of interest to many scientists. The role of vitamin A as an antioxidant is debatable. Vitamin A has been shown to possibly have some antioxidant characteristics. However, the carotenoids such as beta-carotene have in recent years received more attention from the scientific community because of the harmful role they may play as pro-oxidants (14). A great deal more research is needed that addresses the role of vitamin A as an antioxidant to determine the exact role the vitamin and precursors play.
Sources
Retinol, the active form of vitamin A, is rarely found in foods. Instead, precursors to retinol, fatty acid retinyl esters, are found in the human diet. The esters are commonly found in foods of animal origin, such as egg yolks, liver, fish oil, whole milk and butter (6). Plants can synthesize the carotenoids, but cannot convert them to retinoids; this process occurs in the human body (11). The carotenoids are red, yellow, and orange in color and substantial in number (over 400 types). It is estimated that only 10% of the pigments have "vitamin A activity", with beta-carotene having the greatest activity, followed by the alpha and gamma forms (6). Fruits and vegetables that appear bright orange or yellow in color are usually high in carotenoids. All green vegetables also contain substantial amounts of carotenoids, but the orange or yellow color is masked by chlorophyll (6). The wide variety of vitamin A precursors allows for adequate amounts of the vitamin in all diet types.
B. Metabolism
Absorption and Bioavailability
Seventy to ninety percent of vitamin A from the diet is absorbed in the intestine. The efficiency of absorption for vitamin A continues to be high (60-80%) as intake continues to increase. Greater than 90% of the retinol store within the body enters as retinyl esters that are subsequently found within the lipid portion of the chylomicron (11). Absorption of vitamin A is very rapid, with maximum absorption occurring two to six hours after digestion (11). Within the intestinal lumen the vitamin is incorporated into a micelle and absorbed across the brush border into the enterocytes. Within the enterocyte, precursors of vitamin A (carotenoids) are converted to active forms of the vitamin. The newly formed products and additional precursors are then packaged into chylomicrons and readied for transport throughout the body (6).
Transport
After leaving the enterocytes chylomicrons, which carry retinyl esters, carotenoids, and unesterfired retinol along with triglycerides, are circulated first through the lymphatic system and then through the general circulation. Upon arriving at extra-hepatic cells chylomicrons release triglycerides, however vitamin A remains within the chylomicron. The vitamin A is then incorporated into a chylomicron remnant (6). The chylomicron remnant then travels back to the liver where it is taken up and further metabolized or stored. When needed retinol is mobilized from the liver and requires the use of a carrier for transport through the blood. Retinol-binding protein (RBP) is the specific carrier used to transport all-trans retinol in the plasma. The all-trans isoform accounts for more than 90% of all plasma vitamin A (11). This specific carrier is manufactured and secreted by the parenchymal cells of the liver (6,11). Each mole of retinol released binds equivocally with RBP to form holo-RBP. This compound then binds with a molecule of transthyretin (TTR), formerly known as prealbumin. This newly formed retinol-RBP-TTR complex is not filtered by the glomerulus, but instead freely circulates throughout the plasma. Tissues are then able to take the retinol up as needed via cellular retinoid-binding protein (11). Retinoic acid is believed to be manufactured by the cells as needed. Therefore, transport of retinoic acid is likely not substantial. Instead, the cell possesses intra-cellular proteins that regulate the amount of retinoic acid produced. The proteins also help to determine the intracellular usage of retinoic acid (6).
Storage
Approximately 50 to 85% of the total body retinol are stored in the liver when vitamin A status is adequate (11). Retinol returning to the liver is re-esterfied before storage. Because of this, over 90% of the retinol is stored in the form of retinyl esters. The retinol is stored in hepatic stellate (star-shaped) cells along with droplets of lipid (6,11). Thus constitutes the fat-soluble property of vitamin A. The size of stellate cells increase linearly with increasing retinol levels. Once hepatic stellate cells are saturated with all the retinol they can hold, hypervitaminosis can result. (11). The precursor to vitamin A, beta-carotene, can be stored in adipose cells of fat depots throughout the body (2). To date the only side effect of excess beta-carotene supplementation appears to be yellowing of the skin. Serum levels of beta-carotene are an indicator of recent intake and not body stores (6).
Excretion
The kidneys are the main paths of RBP and retinol excretion from the body. This is achieved manly via renal catabolism and glomerular filtration (11). Those persons suffering from renal disease often experience elevated serum levels of RBP and retinol and therefore must be more aware of vitamin A toxicity.
Physiological Role
As previously mentioned vitamin A is essential to vision. Within the photoreceptor cells of the retina are the rods, which detect small amounts of light and are specialized for motion detection and vision in dim light, and the cones that are specialized for color vision in bright light (11). Both rods and cones posses specialized outer segment disks that contain high amounts of rhodopsin and iodopsin respectively. These compounds are often referred to as the "visual pigment" (11). Photoreceptor cells detect light and undergo a series of reactions, which send signals to the brain, where they are deciphered as a particular visual image. A second very important function of vitamin A involves retinoic acid. Acting as a hormone, retinoic acid first binds to retinoic acid receptors. The receptors then interact with specific nucleotide sequences of DNA. The interaction directly affects gene expression and transcription, which in turn control cellular development and body processes (6). For example, epithelial cells depend on retinoic acid for structural and functional maintenance. This role of vitamin A is important for growth mechanisms in a manner that is not completely understood (6). Retinoic acid is especially important in heart, eye, lung and ear development (11). The development of gap junctions between cells is also affected by retinoic acid (6). Besides the previously mentioned functions, vitamin A plays a role in numerous other processes. Vitamin A is thought to play a key role in glycoprotein synthesis. Once formed, glycoproteins are important in multiple cellular processes including: communication, recognition, adhesion, and aggregation. Reproductive processes, bone development, along with maintenance, and immune system function (6,11) are dependent upon different isoforms of vitamin A. Retinoids are most commonly used in the treatment of skin diseases. The role the retinoids play in epithelial cell formation is very important in the treatment of skin cancer, acne, and acne-related diseases (11). Vitamin A also has antioxidant properties. However, beta-carotene has been noted as having pro-oxidant properties. Despite these discrepancies vitamin A is known to help repair damaged tissue and therefore may be beneficial in counter-acting free radical damage (11).
C. Daily Reference Intakes (DRI)
Current DRI
The Recommended Dietary Allowance (RDA) established in 1980 for vitamin A was set at 800-ug retinol equivalent (RE) for adult women and 1000 ug (1mg) retinol equivalent (RE) for adult men (6). It should be noted that 1 RE of vitamin A is equal to 3.33 IU of the vitamin. The levels (RDA) were not changed in 1989 when the RDAs were revised (6,11). One RE is equivalent to 1 ug of all-trans retinol, or 6 ug of all-trans beta-carotene (6). The RDA was based on the amount of vitamin needed to reverse night-blindness in vitamin A deficient subjects. The RDA has also been based on the amount needed to raise the plasma vitamin A levels to normal in depleted subjects. Starting in 2000 Dietary Reference Intakes (DRI) were developed to replace the RDA. A DRI for vitamin was not established. The DRI incorporates a safety ceiling into the recommendation, however due to a lack of evidence a safe upper limit could not established. The absence of a safe upper limit plus the numerous carotenoids has led the National Academy of Sciences to not establish a DRI at this time. The RDA is the current dietary guideline being used in place of the DRI. For men the RDA is 1000 mg of retinol equivalents (RE) and for women the RDA currently stands at 800 mg RE (10).
Deficiency
Deficiency of vitamin A is very rare in the United States, unless confounding malabsorption conditions such as steatorrhea, or diseases of the liver, pancreas, or gallbladder are present. In contrast vitamin A deficiency is prominent in young children (<5 years old) living in third world countries (6,11). At birth many neonates experience low plasma vitamin A content, but the levels are corrected with a diet sufficient in vitamin A (6). Symptoms of vitamin A deficiency include metaplasia (changing of normal tissue into abnormal tissue), poor growth, xerophthalmia (dry corneas), and keratinization of epithelial cells resulting in a loss of differentiation (6,11). If vitamin A deficiency has not been chronic leading to permanent debilitation the symptoms can often be reversed through supplementation.
Toxicity
The use of acne medicines (i.e. Acutane) has led to birth defects and even death (11) in children born to mothers using these compounds (6). This has helped make the public more aware of the toxic properties of vitamin A. In adults a condition known as hypervitaminosis exhibits itself after chronic ingestion of the vitamin in doses that are ten times the RDA (10 mg RE). Symptoms of vitamin A toxicity include: anorexia, headache, bone and muscle pain, vomiting, alopecia, liver damage, and coma. These symptoms slowly reside as vitamin A intake levels are reduced (6,11). To date the only side effect of excess beta-carotene has been yellowing of the skin, most commonly in the fatty areas of the hands and palms. The yellowing disappears as beta-carotene intake decreases. This commonly ingested dietary precursor to vitamin A has yet to exhibit any signs of toxicity even at levels as high as 180 mg per day (6). Researchers believe that the presentation of unbound retinol to the cell is a major factor in toxicity. Excessive intakes of vitamin A saturate RBP and instead of retinol being transferred bound to RBP, it is transferred to the tissue via plasma lipoproteins. When retinol reaches the tissue by a carrier other than RBP it is hypothesized that the retinol is released and causes toxic side effects (6).
D. Vitamim A and Exercise
Effects of Exercise on Vitamin A Requirements
Data addressing vitamin A and any aspect of exercise are lacking at best. A literature review done by Stacewicz-Sapuntzakis (12) reports that there has been essentially no evidence to suggest that the vitamin A needs of athletes and exercisers are increased above those of sedentary individuals. For example the author reports that cyclists in the Tour de France were found to consume adequate amounts of the vitamin during the race. The studies that have been performed have failed to account for training patterns or specify the percentages of vitamin A coming from meat and plant sources respectively. This has led to difficulty determining the carotenoid intake of individuals in these studies (12). In contrast, serum levels of retinol and beta-carotene have been studied in national teams from West Germany. The athletes tested came from a variety of sports: marathon runners, weightlifters, swimmers, and cyclists. The research showed that none of the athletes exhibited depressed retinol levels. Beta-carotene levels were distributed over a wide range of values (14.0-122.5 ug/dl). Results show that although there was a wide range of intakes none of the athletes were deficient in beta-carotene (12). Many athletes looking for a competitive edge will increase their daily vitamin intake. This has led to widespread vitamin A abuse among athletes. Toxic side effects from vitamin A consumption have so far only been documented in one subject. The subject, a high school soccer player, whose daily, two-month consumption of vitamin A was 100,000 IU vitamin A per day suffered from excessive leg pain (5).
The carotenoids, specifically beta-carotene has been shown to possess antioxidant properties. This precursor of vitamin A is considered the most efficient "quencher" of singlet oxygen (6). The antioxidant properties may actually be detrimental to the body however. The carotenoids may undergo oxidation, leaving byproducts in the lungs and arterial blood. This can result in additional oxidative damage and tumor growth in smokers and those exposed to either second-hand smoke or automobile fumes. Limited studies have been performed addressing the possible role of beta-carotene plays in prevention of muscle damage. Unfortunately the studies included vitamin A as part of antioxidant cocktail mixture (8,9). In a study by Kanter et al. (9) the antioxidant cocktails lowered markers of oxidative stress during exercise but not before or after the exercise bout. Use of the cocktail makes it virtually impossible to assess the effects of vitamin A on lipid oxidation. The evidence addressing beta-carotene has actually shown detrimental effects in some subjects. This body of inconclusive and somewhat detrimental evidence has led to the recommendation that those who exercise should refrain from beta-carotene supplementation (14).
Vitamin A in Exercise Recovery
The role vitamin A plays in exercise recovery has yet to be determined. There is an obvious lack of credible evidence suggesting vitamin A plays a role in enhancing exercise performance or preventing lipid peroxidation. However, due to the ability of vitamin to repair muscle tissue damage (12) the vitamin may aid in recovery. This is strictly a hypothesis as the possibility has yet to be proven or even investigated. In order to better understand the role of vitamin A in exercise recovery studies need to be designed that address the issue.
E. Summary & Current Recommendations
The level of vitamin A intake in all persons, regardless of exercise seems to be more than adequate. This is mainly due to the wide variety of foods that contain vitamin A and its precursors. Vitamin A research is a very tedious process that has little room for error. To date, no research has conclusively shown that vitamin A alone (not part of a cocktail mixture) in any way improves exercise capacity, recovery, or lipid peroxidation. Furthermore, vitamin A can be toxic and beta-carotene has pro-oxidant capabilities. In summary, any supplementation of vitamin A for improvements in exercise is unwarranted, dangerous, and may involve risks.
F. References
Anderson, K.N., L.E. Anderson, and W.D. Glanze, Mosby's Medical, Nursing, and Allied Health Dictionary. Mosby Publishing Company, St. Louis pp. 1415, 1716. [Abstract]
Bucci, L.R. Dietary Supplements As Ergogenic Aids. In: Nutrition in Exercise and Sport. 3rd Edition. Edited by Ira Wolinsky. New York: CRC Press, 1998, pp. 328-329. [Abstract]
Clarkson P. M. Antioxidants and physical performance. Crit.Rev. Food Sci. Nutr. 35: 131-141, 1995. [Abstract]
Dekkers, J. C., L. J. P. van Doornen, and Han C. G. Kemper. The Role of Antioxidant Vitamins and Enzymes in the Prevention of Exercise-Induced Muscle Damage. Sports Med. 21: 213-238, 1996. [Abstract]
Fumich, R.M., and G.W. Essig. Hypervitaminosis A. Case report in adolescent soccer player. Am J Sports Med. 11(1): 34-7, 1983. [Abstract]
Groff, J.L., S.S. Gropper, and S.M. Hunt. The Fat Soluble Vitamins. In Advanced Nutrition and Human Metabolism. Minneapolis: West Publishing Company, 1995, pp. 284-324. [Abstract]
Kanter, M.M. 1998. Dietary Supplements As Ergogenic Aids. In: Nutrition in Exercise and Sport. 3rd Edition. Edited by Ira Wolinsky. New York: CRC Press, 1998 p. 245-253. [Abstract]
Kanter, M.M. and D.E. Eddy. Effect of antioxidant supplementation on serum markers of lipid peroxidation and skeletal muscle damage following eccentric exercise. Med. Sci Sports Exerc. 24:S17, 1992. [Abstract]
Kanter, M., L.A. Nolte, and J. Holloszy. Effects of an antioxidant vitamin mixture on lipid peroxidation at rest and postexercise. J. Apply. Physiol. 14:965, 1993. [Abstract]
National Academy of Sciences. Dietary Reference Intakes:Recommended Intakes for Individuals. Food and Nutrition Board, Institute of Medicine. 2000.
Ross, A.C. Vitamin A. In: Modern Nutrition in Health and Disease. Ninth Edition. Edited by Maurice Shils, James Olson, Moshe Shike, and A. Catharine Ross. Baltimore,Williams & Wilkins, 1999, p. 305-313.
Stacewicz-Sapuntzakis, M. Vitamin A and Caroteniods. In: Sports Nutrition Vitamins and Trace Minerals. Edited by Ira Wolinsky and Judy A. Driskell. New York: CRC Press, 1997, p.101-110. [Abstract]
Viguie, C.A., L. Packer, and G.A. Brooks. Antioxidant supplementation affects indices of muscle trauma and oxidant stress in human blood during exercise. Med. Sci.. Sports. Exerc. 21:S16, 1989. [Abstract]
Volpe, S. Vitamins and minerals for active people. In: Sports Nutrition: A guide for the professional working with active people. Edited by C.A.
Rosenbloom. The American Dietetic Association: Chicago, 2000, p. 68-69.
Witt, E.H., A.Z. Reznick, C.A. Viguie, P. Starke-Reed, and L. Packer. Exercise, oxidative damage and effects of antioxidant manipulation. J. Nutr. 122:766, 1992. [Abstract]
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Wally
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Easy to read, brief but informative.
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VITAMIN A
Introduction
Major deficiency diseases of the world are: marasmus, kwashiorkor, xerophthalmia, night blindness, beriberi, scurvy, pellagra, anemia, iodine deficiency disorders, and osteoporosis
Xerophthalmia - Thousands in S.E. Asia - Most common cause of blindness in young children
Vitamin A may be considered most important vitamin from a practical standpoint
Vitamin A not found in plants (e.g. Carotene)
Vitamin A both deficiency and toxicity
Chemical Structure and Properties
Retinol - alcohol
Retinal - aldehyde
Retinoic acid - acid
Retinol Retinal
Retinal retinoic acid
Vitamin A, a colorless, fat-soluble, long-chain, unsaturated alcohol with five double bonds
Must possess -ionone ring to have vitamin A activity
Isoprene units with alternate double bonds
All-trans vitamin A most active form
Structural changes promoted by moisture, heat, light and catalysts (e.g. in hay making, ensiling, dehydrating and storage of crops)
Precursors of vitamin A are carotenes (over 500 isolated)
Carotenes, orange-yellow pigments mainly in green leaves and corn
Important carotenes are , , and cryptoxanthine (main carotenoid of corn)
-carotene most potent precursor of vitamin A
Lycopene an important carotenoid for antioxidant function
-carotene and lycopene predominate carotenoids in tissue.
Pure vitamin A, twice the potency of beta-carotene (weight basis)
Definitions
1 IU activity = 0.3 micrograms vitamin A
= 0.55 micrograms vitamin A palmitate
= 0.6 micrograms beta carotene
Retinol equivalents (RE) also expression of vitamin A activity
1 RE = 1 g of retinol
= 6 g of -carotene
= 12 g of other provitamin A carotenoids
Analytical Procedures
Biological methods - growth of rats or chicks, storage of vitamin A in liver, cell changes in vaginal smears
Chemical - color reactions with antimony trichloride (Carr-Price), gas chromatography, thin layer chromatography, high-pressure liquid chromatography (HPLC)
Recent procedures for retinol binding protein is radioimmunoassay (Vallet, 1994)
Metabolism
Digestion
Vitamin A and carotenoids are released from proteins by action of pepsin and S.I. proteolytic enzymes (Ong, 1993)
Bile salts break up fatty globules to smaller lipid congregates for more efficient digestion by pancreatic lipase, retinylester hydrolase, etc.
Digestion - affected by a number of factors:
dietary level;
month of forage harvest;
type of forage;
species of plant
Some amounts of carotene or vitamin A degraded in rumen
Absorption and Transport
Intestinal mucosa - conversion of beta-carotene to vitamin A
Conversion involves two enzymes:
Beta-carotene - 15',15' dioxygenase (enzymes not in cat or mink)
Retinaldehyde reductase
Two molecules of retinol for one of -carotene
Also random (excentric) cleavage resulting in retinoic acid and retinal (Wolf, 1995)
Species specificity in ability to absorb carotenoids
Carotene cleaved in intestine for rat, pig, goat, sheep, rabbit, buffalo and dog
Carotene absorbed for humans, cattle (some), horses and carp
A breed difference for cattle, why is Guernsey or Jersey milk yellow?
Poultry absorb some carotenoids (see Fig. 2-3) Absorb hydroxy carotenoids, convert hydrocarbon carotenoids
Cis-trans isomerism affects absorbability, trans best absorbed
Dietary fat important for absorption, small amounts of fat to Central African boys increased absorption from <5% to 50%
Vitamin E favors absorption of carotenoids
No absorption stomach, rather mucosa of proximal jejunum
Absorption 80% to 90% of vitamin A, 50% to 60% beta-carotene
Vitamin A occurs primarily as the palmitate ester hydrolyzed in S.I. by retinyl ester hydrolase
Bile salt required for enzyme activation and formation of lipid micelle
Micelle carries vitamin A to microvillus
Vitamin A absorbed as free alcohol
Within mucosal, retinol re-esterified is incorporated into chylomicra of the mucosa and secreted into lymph
For poultry more absorbed to portal blood
Transport with low density lipoprotein as a carrier to the liver
Deposited in hepatocytes, stellate and parenchymal cells
50-80% of retinyl esters stored in stellate cells
Retinol is released from the hepatocyte as a complex with retinol-binding protein (RBP)
Secretion of RBP from liver regulated by estrogen, A status, protein and Zn
In plasma RBP forms a 1:1 complex with transthyretin (thyroxine-binding protein)
Retinoic acid not transported by RBP, but tightly bound to albumin
When RBP and transthyretin reaches receptor site, retinol is released
Retinoids in cells are quickly bound by specific binding proteins
In cell cytoplasma retinol is oxidized to retinoic acid and other cpd's (e.g., 3, 4 dihydroretinoic acid and 9- cis retinoic acid
Purpose - protection against decomposition, solubilize, render nontoxic, transport, and presenting to appropriate enzymes
Important binding proteins: CRBP (I, II), CRABP (I and II), CRALBP, RAR (, , ) and RXR (, , )
CRALBP aids in oxidation-reduction of 11-cis-retinol to 11 cis-retinaldehyde in retina
The two classes of nuclear receptors are all-trans retinoic acid (the ligand for RAR) and 9-cis-retinoic acid (the ligand for RXR)
Receptors for 1,25(OH)2D, all-trans retinoic acid, and 9-cis-retinoic acid are members of the nuclear hormone super family (a gene family having at least 30 members) including receptors for estrogen, progesterone, glucocorticoids, androgens, and thyroid hormone.
Common feature - they control gene expression by interacting with specific DNA sequences
RAR and RXR- Function in nucleus by attaching to promoter regions of specific genes (transcription)
Excretion
Equal amounts feces and urine
Main elimination of Vitamin A is glucuronide conjugates in bile
A large portion of glucuronides reabsorbed, providing for A conservation
Retinol readily transferred to eggs in birds, but transfer across the placenta is poor, mammals born with low liver stores
Storage
Liver 90% of total body vitamin A
In stomach oils of certain seabirds and in the eyes of shrimp
Carotenoids more evenly distributed in species that have the ability to absorb and store
Grass-fed cattle, a yellow fat
Low correlation between liver and blood retinol
Measurement of liver store (slaughter or biopsy) indicates status
Functions
Growth, health and life
Four distinct lesions
loss of vision
defect in bone
reproduction
growth and differentiation of epithelial tissues, with deficiency keratinization
Retinoic acid unable to fulfill all vitamin A functions of vision and reproduction
However, retinoic acid is the active form (hormone form) of vitamin A in development, differentiation and metabolism
Retinoic acid as all-trans retinoic acid and 9-cis-retinoic acid performs as hormones
RAR and RXR receptor proteins attach to promoter regions of genes to stimulate transcription
RA receptors in cell nuclei function similar to receptors for other hormones
Therefore, functions as a hormone
Actions of vitamin A in development, differentiation and metabolism mediated by nuclear receptor proteins that bind retinoic acid with steroid and thyroid hormone receptors
Retinoic acid and triiodothyronine control overlapping networks of genes
Retinoic acid plays an important role in growth and defferentiation of embryonic tissues
It also regulates differentiation of epithelial, connective and hematopoietic tissues (Safonova et al. 1994)
Vision
11-cis-retinal + protein opsin = rhodopsin
All-trans retinaldehyde cannot form a stable complex with opsin. See Fig. 2.6
Night blindness (nyctalopia) - lack of resynthesis of rhodopsin
Outer segments of rods lose their opsin. leading to degeneration
Molecular basis of night blindness collagenase activity. Retinoic acid inhibited collagenase by forming inactive protein complex (Nut. Rev. 50:292, 1992)
Advanced stage of vitamin A deficiency is xerophthalmia (Latin word for "dry eye")
Dogs, foxes, rats and humans have a dry condition of cornea and conjunctiva, cloudiness and ulceration
Cows and horses - copious lacrimation
Chicken - tear glands dry up
Cell differentiation and normal epithelium
Needed for healthy epithelium, for protective linings. When deficient, normal mucus secreting cells replaced by stratified kertinized epithelium, cells fail to differentiate.
Tissues more susceptible to infection (e.g. colds, pneumonia, diarrhea) sloughed keratinized cells may form foci for kidney stones
Altered epithelium affects reproduction
Squamous metaplasia of parotid gland and elevated cerebrospinal fluid pressure, early signs of deficiency
Vitamin A responsible for formation of mucopolysaccharides (glucosamine)
Retinoic acid and its metabolite, 3,4-didehydroretinoic acid are morphogens.
Morphogens specify three-dimensional structure
Cell differentiation in developing chick limb bud differentiated into muscle, cartilage and bone cells via vitamin A morphogens.
Action in development, differentiation and metabolism via RARs and RXRs that bind retinoic acid with steroid and thyroid hormone receptors. RARs and RXRs interact with specific genes and regulate their transcription.
Reproduction
Part of reproductive effect relates to normal epithelium
Vitamin A deficiency - reproductive ability, hatchability, abortion
•Male - sexual activity and failure of spermatogenesis
•Female - resorption of fetus, abortion, birth of dead offspring
Bone development
Control osteoclast and osteoblast, disorganized bone growth. Constriction of openings for optic and auditory nerves
Congenital malformation
Immune response and disease conditions
Vitamin A and/or -carotene have important roles in protecting against numerous infections, including mastitis
Deficiency of A - severity of bacterial, protozoal and viral infections with deficiency production of antibodies, infections, lymphocytes
cancer of skin, lung, bladder, breast with synthetic analogs of retinoids
-carotene effective for some types of cancer
Skin diseases, e.g. Psoriasis, Cystic acne and Rosacea
Requirements
NRC requirements (Table 2.2)
Pregnancy, lactation and egg production requirement
See Table 2.3
Conversion of -carotene to A most efficient with rats and poultry
See Table 2.4
Rate of conversion depends on type of carotenoid, production level, genetics, carotene intake, stress
Other factors: nitrates, low protein, Zn, water temp.
Human females require 80% of males in retinol equivalents
Natural Sources
Richest sources-fish oils
Milk fat, egg yolk and liver are rich
Factors affecting vitamin A value
Green color good index
Maturity
Oxidation
Absence of air, no loss
Field curing of hay
Legume hays richer
Storage
Artificial curing 2 - 10 times vitamin A value
Yellow corn 1/8 value of green forage
Carotene in silage
Cooking and processing
Chemical stabilization and physical protection
Pelleting-moisture, heat and pressure
Running fines back through, more loss
History
For thousands of years, humans and animals suffered from vitamin A deficiency, night blindness and xerophthalmia.
1500 B.C. - Ancient Egypt recommended liver to cure
Jeremiah 14:6 - "and the asses did stand in high places, their eyes did fail, because there was no grass"
Blind Tobias cured by fish bile
1909 Hopkins and Stepp - fat-soluble substances (from milk) necessary for growth of mice and rats
1913-1915 - McCollum and Davis described "fat-soluble A"
1919 - Drummond suggested name of vitamin A
Vitamin A potency associated with yellow color, but some potent sources colorless
1929 Moore - proof that animal body transformed carotene into vitamin A
1922 - McCollum proved rickets not vitamin A deficiency
1930-1931 - Karrer et al. exact structures for vitamin A and -carotene
1935 - Wald obtained a specific form of vitamin A (retinal) from bleached retinas (Nobel Prize)
1947 - Isler et al. synthesized vitamin A
Deficiency
Vision, healthy epithelial tissues, bone, etc.
Ruminants
In cattle, F.I. and growth rough hair coat, edema, lacrimation, xerophthalmia, night blindness, slow growth, diarrhea, bone growth, etc.
Grazing goats may have less problems than cattle. Why?
Calves - blind, dead or weak, severe diarrhea, nasal discharge, staggering gait
Bulls - reduced libido, semen quality and sterility
Mastitis - both A and -carotene lower incidence
With deficiency, depressed activity of natural killer cells, antibody production, and susceptibility to infection
X-disease (a hyperkeratosis) - chlorinated naphthalene
Lack heat tolerance
Vitamin A deficiency could result from Zn deficiency
Swine
Unsteady gait, paralysis, eye lesions, embryonic mortality, estrus failure, resorption of young, cell differentiation problems
Litter size increased 0.6-1.5 pigs/litter with vitamin A injection (Whaley et al. 1997)
Poultry
Growth, lowered resistance, eye lesions, incoordination, ruffled feathers
Egg production, hatchability (embryonic mortality)
Viral infections impair vitamin A status of chickens (West et al. 1992)
Status of day-old chicks depends on hen's diet
Horses
Night blindness, lacrimation, keratinization of the cornea and respiratory system, reproduction
During the winter, vitamin A depletion in grazing horses (Greiwe-Crandell et al. 1997)
Other Species
Cats - growth, poor appetite, night blindness, bones become thickened and constrict central nervous system, males sterile, females fetus resorption
Dogs - growth, xerophthalmia, respiratory infection, deafness, etc.
Fish - growth, eye problems, high mortality
Foxes - nervous disorders
Laboratory animals - problems with vision, bone defects, reproductive failure
Humans
Deficiency - mostly developing countries
Alcohol consumption affects vitamin A status
Most common cause of blindness in children
Xerophthalmia -endemic in many countries
Bitot's spots common sign
Mortality rate high for A deficiency
Increased susceptibility to infections
Circumstances for deficiency and body stores
Drought
High concentrate diets
Corn silage and concentrates
Milk - low dam status, little colostrum
Lack yellow corn
Green color
Dry seasons 6 mo. or longer
Florida study 1982, fewer grazing days for cattle (Kiatoko et al. 1982)
Limited alfalfa meal
Deficiency of other nutrients
Australia - slow release of vitamin A
Status
Production response
Liver stores
Plasma vitamin A
Cerebrospinal fluid pressure (CFP)
Supplementation
As part of concentrate or liquid supplement
Free-choice mineral mixture
Injectable
Drinking water
Stabilized and protectively coated (or beaded) forms
Gelatin beadlet of vitamin A ester (palmitate or acetate)
Factors that affect stability (Table 2.
For grazing livestock, part of free-choice mineral mixture
Abrasion, moisture and prooxidant minerals destroy
Feedlot cattle - injection
Massive doses under intensive housing
Vitamin A is inexpensive
-carotene Independent of Vitamin A
Studies since 1978, dairy cattle receiving extra:
higher intensity of estrus,
conception
reduced follicular cysts
Corpus luteum, higher -carotene than other organs
Positive relationship between -carotene and luteal cell progesterone. Other researchers, no effect
Lower incidence of mastitis
Increased pregnancy and milk yield with -carotene (Aréchiga et al. 1998)
Human nutrition - -carotene inhibitor of some types of cancer
Health benefits of megavitamin doses of the antioxidant vitamins (C, E, and -carotene)
Lycopene an efficient quencher of singlet oxygen
Toxicity
Of all vitamins most likely to be toxic
Safe levels 4 to 10 times requirement
30 times for ruminants
Skeletal malformations, spontaneous fractures and internal hemorrhage
Extensive bone resorption
Destruction of cartilage matrix
High carotene in forages, no problem
Toxicity, not a practical problem
High vitamin A depressed vitamin E utilization
Humans - headache (intracranial pressure), skin rash, irritability, pain in arms and legs
Problem in eating polar bear and seal liver, 500g a toxic dose
Dogs may not eat liver
Gulls and ravens avoid polar bear liver
Hypervitamonosis A in humans - self medication |
http://www.animal.ufl.edu/ans6449/Vitamin%20A.htm
_________________
"Most of the important things in the world have been accomplished by people who have kept on trying when there seemed to be no hope at all."
Dale Carnegie |
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Wally
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| Posted: Sat Sep 20, 2003 6:52 pm Post subject: |
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Brief and to the point! 
| Quote: |
Vitamin A - Retinol, Retinal, Retinoic Acid
Vitamin A, is a fat-soluble vitamin and is involved in the formation and maintenance of healthy skin, hair, and mucous membranes. Vitamin A helps us to see in dim light and is necessary for proper bone growth, tooth development, and fertility and has been well documented for decades. It is also an important antioxidant.
During the Second World War, the British even covered up their new Radar invention by using propaganda that their ability to see enemy planes in the dark was due to the popularity of carrots in the British diet!
There are three active forms of Vitamin A:
Retinol
Retinal
Retinoic Acid
In food, most vitamin A is found in the form of Retinol. All three forms can be formed from the plant pigment carotenes (usually red or yellow plants, for example, carrots) . Most common form being beta-carotene.
Absorption and Metabolism
Requires bile salts
Very large quantities of Vitamin A can be stored in the liver (90 %)
Requires a transport protein, protein deficiency will have a negative impact on Vitamin A status.
Zinc is required to release the vitamin from the liver to other parts of the body where it is required and deficiency will also cause negative impact on Vitamin status.
Natural Sources of Vitamin A or Carotenoids
Little Vitamin A is lost in normal cooking, it oxidizes readily with heat. Animals take b-carotene and convert it into an active form of Vitamin A. Vitamin A is normally abundant within a balanced diet and can be obtained from the following sources:
Dark green vegetables
orange-yellow vegetables
whole milk
butter
cheese
eggs
fish liver oils
Liver
Deficiency
Deficiency is still remarkably widespread in developing countries, causing serious problems that could so easily be prevented by better nutrition, problems include:
Night blindness
Stunting of growth
Xeropthalmia
Problems with skin and epithelial cells that line respiratory, digestive and genitourinary tracts.
Abnormalities of enamel-forming cells of the teeth.
Increased incidence of infection, hard dry keratinized skin.
Requirements
1 International Unit (I.U.) = 0.3 mcg Retinol
= 0.34 mcg retinal acetate
= 0.6 mcg beta carotene
= 1.2 mcg other carotenes
Female 4,000 IU
Male 5,000 IU
Pregnancy 5,000 IU
Toxicity:
Excess carotene does not result in toxicity, however you should not consume more than 10,000 IU/day of retinal.
Warning from the UK Food Standards Agency:
Pregnant women, or women who are thinking of becoming pregnant, should not take supplements of vitamin A, except on the advice of their GP. This is because there is an association between very high levels of retinol (a source of vitamin A) consumption during pregnancy and the incidence of some birth defects. As an additional precaution, pregnant women should not eat liver or liver products as these are a very rich source of retinol.
Other
"Vitamin A is probably the most important of all vitamins, if any single vitamin can be so distinguished from another. Its great importance is demonstrated dramatically in that, more than any other vitamin, deficiencies of Vitamin A are still widespread throughout the world and involve millions of persons, especially children." - Briggs and Calloway in Nutrition and Physical Fitness
Sources:
Ohio State University
Vitamin A Deficiency - W.C. Edmundson and S.A. Edmundson |
http://www.1stvitality.co.uk/az/a/index.html
_________________
"Most of the important things in the world have been accomplished by people who have kept on trying when there seemed to be no hope at all."
Dale Carnegie |
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Wally
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Location: MIDWEST
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| Posted: Tue Sep 23, 2003 10:45 pm Post subject: > |
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I found another interesting article. It talks about the small intestine and Vitamin A. I'm just going to post the link because this post is already slow with all the info!
http://www.nutrition.org/cgi/content/full/127/1/13
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"Most of the important things in the world have been accomplished by people who have kept on trying when there seemed to be no hope at all."
Dale Carnegie |
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