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Naqibullah jogezai
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Date Posted: 00:10:33 10/20/06 Fri
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zahid
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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]
Discovery
In 1913, Elmer McCollum, a biochemist at the University of Wisconsin, and colleague Marguerite Davis identified a fat-soluble nutrient in butterfat and cod liver oil. Their work confirmed that of Thomas Osborne and Lafayette Mendel, at Yale, which suggested a fat-soluble nutrient in butterfat, also in 1913 [1]. Vitamin A was first synthesized in 1947.
Structure
Many different geometric isomers of retinol, retinal and retinoic acid are possible as a result of either a trans or cis configuration of the four double bonds found in the polyene chain. The cis isomers are less stable and can readily convert to the all-trans configuration. Nevertheless, some cis isomers are found naturally and carry out essential functions. For example, the 11-cis-retinal isomer is the chromophore of rhodopsin, the vertebrate photoreceptor molecule. Rhodopsin is comprised of the 11-cis-retinal covalently linked via a Schiff base to the opsin protein (either rod opsin or blue, red or green cone opsins). The process of vision relies on the light-induced isomerisation of the chromophore from 11-cis to all-trans resulting in a change of the conformation and activation of the photoreceptor molecule.
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.
Sources
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. 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 food composition database to check foods for their content of several different carotenoids, including lycopene, lutein and zeaxanthin.
Food Serving Vitamin A, RAE Vitamin A, IU Retinol, mcg Retinol, IU
Cod liver oil 1 teaspoon 1,350 mcg 4,500 IU 1,350 mcg 4,500 IU
Fortified breakfast cereals 1 serving 150-230 mcg 500-767 IU 150-230 mcg 500-767 IU
Egg 1 large 91 mcg 303 IU 89 mcg 296 IU
Butter 1 tablespoon 97 mcg 323 IU 95 mcg 317 IU
Whole milk 1 cup (8 fl ounces) 68 mcg 227 IU 68 mcg 227 IU
2% fat milk (vitamin A added) 1 cup (8 fl ounces) 134 mcg 447 IU 134 mcg 447 IU
Nonfat milk (vitamin A added) 1 cup (8 fl ounces) 149 mcg 500 IU 149 mcg 500 IU
Sweet potato 1/2 cup, mashed 959 mcg 3,196 IU 0 0
Carrot (raw) 1/2 cup, chopped 385 mcg 1,283 IU 0 0
Cantaloupe 1/2 medium melon 466 mcg 1,555 IU 0 0
Spinach 1/2 cup, cooked 472 mcg 1,572 IU 0 0
Squash, butternut 1/2 cup, cooked 572 mcg 1,906 IU 0 0
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)(2).
The Visual Cycle
Retinol is transported to the retina via the circulation, where it moves into retinal pigment epithelial cells. There, retinol is esterified to form a retinyl ester that 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 to the rod cell, where it binds to a protein called opsin to form the visual pigment, rhodopsin (visual purple). 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.
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
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).
Disease Prevention
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
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. The majority of epidemiological studies have failed to find significant associations between retinol intake and breast cancer risk in women (8-9), 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. 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, two recent prospective studies did not observe significant associations between blood retinol levels and the subsequent risk of developing breast cancer. Presently, there is little evidence in humans that increased intake of preformed vitamin A or retinol reduces breast cancer risk
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 (10).
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(11)
Deficiency
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. 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).
1-Keratomalacia
A condition associated with vitamin A deficiency and protein-calorie malnutrition, characterized by a hazy, dry cornea that becomes denuded.Corneal ulceration with secondary infection is common. The lacrimal glands and conjunctiva are also affected. Lack of tears causes extreme dryness of the eyes, and foamy Bitot's spots appear on the bulbar conjunctiva. Night blindness may be associated.
2-Nyctalopia,
This also known as moon blink, was a temporary night blindness believed to be caused by sleeping in moonlight in the tropics. (Greek for "night blindness") is a condition making it difficult or impossible to see in the dark. It is a symptom of several eye diseases. Night blindness may exist from birth, or be caused by injury or malnutrition (for example, a lack of vitamin A).The most common cause of nyctalopia is retinitis pigmentosa, a disorder in which the rod cells in the retina gradually lose their ability to respond to the light. Patients suffering from this genetic condition have progressive nyctalopia and eventually their daytime vision may also be affected. In congenital stationary night blindness, the rods do not work / work very little from birth, but as the name implies, sufferers do not get worse.
Another cause of night blindness is a deficiency of retinol, or vitamin A, found in fish oils, liver and dairy products. In the Second World War, pilots flying night missions were encouraged to eat plenty of carrots, which contain carotenoids and can be converted into retinol.The opposite problem, known as hemeralopia, is much rarer.
The outer area of the retina is made up of more rods than cones. The rod cells are the cells that enable us to see in poor illumination. This is the reason why loss of side vision often results in night blindness. Individuals suffering from night blindness not only see poorly at night, but also require some time for their eyes to adjust from brightly lit areas to dim ones. Contrast vision may also be greatly reduced.
Vitamin A excess
1-Osteoporosis
It is a disease of bone in which the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is changed. Osteoporotic bones are more susceptible to fracture. Osteoporosis is defined by the World Health Organization (WHO) as either a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old person standard) as measured by DXA, or any fragility fracture. While treatment modalities are becoming available, prevention is still the most important way to reduce fracture. Due to its hormonal component, more women, particularly after menopause, suffer from osteoporosis than men.
Osteoporosis can be thought of as analogous to "sarcopenia", which is the age-related loss of skeletal muscle. The combination of sarcopenia and osteporosis results in the significant frailty often seen in the elderly population
Risk factors
Risk factors for osteoporotic fracture can be split between modifiable and non-modifiable:
Nonmodifiable: history of fracture as an adult, family history of fracture, female sex, advanced age, European or Asian ancestry, and dementia
Potentially modifiable: prolonged intake of the prescription drug prednisone, tobacco smoking, intake of soft drinks (containing phosphoric acid), low body weight <58 kg (127 lb), estrogen deficiency, early menopause (<45 years) or bilateral oophorectomy, premature ovarian failure, prolonged premenstrual amenorrhea (>1 year), low calcium and vitamin D intake, alcoholism, impaired eyesight despite adequate correction, recurrent falls, inadequate physical activity (i.e. too little or also if done in excess), high risk of falls, poor health/frailty. Coeliac disease can lead those with an otherwise adequate calcium intake to develop osteoperosis due to the inability to absorb calcium. Osteoporotic fracture may indeed be the event that leads to diagnosis that coeliac disease (which affects around one in a hundred people in the West[1]) has affected the patient for many years.
A strong association between cadmium, lead and osteoporosis has also been established. Low level exposure to cadmium is associated with an increased loss of bone mineral density readily in both genders, leading to osteoporosis and increased risk of fractures, especially in elderly and in females. [2] [3] [4]
Diagnosis
Dual energy X-ray absorptiometry (DXA, formerly DEXA) is considered the gold standard for diagnosis of osteoporosis. Diagnosis is made when the bone mineral density is less than or equal to 2.5 standard deviations below that of a young adult reference population. This is translated as a T-score. The World Health Organization has established diagnostic guidelines as T-score -1.0 or greater is "normal", T-score between -1.0 and -2.5 is "low bone mass" (or "osteopenia") and -2.5 or below as osteoporosis. A low trauma or osteoporotic fracture, defined as one that occurs as a result of a fall from a standing height, is also diagnostic of osteoporosis regardless of the T-score.
In order to differentiate between "primary" (post-menopausal, regardless of age, or senile - related to age) and "secondary" osteoporosis, blood tests and X-rays are usually done to rule out cancer with metastasis to the bone, multiple myeloma, Cushing's disease and other causes mentioned above.
Pathogenesis
The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. Either bone resorption is excessive, and/or bone formation is diminished. Bone matrix is manufactured by the osteoblast cells, whereas bone resorption is accomplished by osteoclast cells. The mechanisms influencing the formation of the disease are complex. Most cases do not result from inadequate calcium intake, but include other factors affecting bone matrix formation and reabsorption. These include: (1) cigarette smoking, which inhibits the activity of osteoblasts; (2) sedentary lifestyle with little weight bearing exercise, such as walking; (3) a family history of osteoporosis; and being age 30 or older. Both men and women are at equal risk starting at age 30. Trabecular bone is the sponge-like bone in the center of long bones and vertebrae. Cortical bone is the hard outer shell of bones. Because osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more active, more subject to bone turnover, to remodeling. Long before any overt fractures occur, the small spicules of trabecular bone break and are reformed in the process known as remodeling. Bone will grow and change shape in response to physical stress. The bony prominences and attachments in runners are different in shape and size than those in weightlifters. It is an accumulation of fractures in trabecular bone that are incompletely repaired that leads to the manifestation of osteoporosis. Common osteoporotic fracture sites, the wrist, the hip and the spine, have a relatively high trabecular bone to cortical bone ratio. These areas rely on trabecular bone for strength.
Low peak bone mass is important in the development of osteoporosis. Bone mass peaks in both men and women between the ages of 25 and 35, thereafter diminishing. Achieving a higher peak bone mass through exercise and proper nutrition during adolescence is important for the prevention of osteoporosis.
Bone remodeling is heavily influenced by nutritional and hormonal factors. Calcium and vitamin D are nutrients required for normal bone growth. Parathyroid hormone regulates the mineral composition of bone, with higher levels causing resorption of calcium and bone. Glucocorticoid hormones cause osteoclast activity to increase, causing bone resorption. Calcitonin, estrogen and testosterone increase osteoblast activity, causing bone growth. The loss of estrogen following menopause causes a phase of rapid bone loss. Similarly, testosterone levels in men diminish with advancing age and are related to male osteoporosis. In addition to estrogen, follicle-stimulating hormone (FSH) affects BMD. In mice, lower levels of FSH mean less resorption by osteoclasts.[5]
Physical activity causes bone remodeling. People who remain physically active throughout life have a lower risk of osteoporosis. Conversely, people who are bedridden are at a significantly increased risk. Physical activity has its greatest impact during adolescence, affecting peak bone mass most. In adults, physical activity helps maintain bone mass, and can increase it by 1 or 2%. However, excessive exercise can lead to constant damages to the bones which can cause exhaustion of the structures as described above. There are numerous examples of marathon runners who developed severe osteoporosis later in life.
Lastly, osteoporosis on its own would not be a significant disease, were it not for the falls which precipitate fractures. Age-related sarcopenia, or loss of muscle mass, loss of balance and dementia contribute greatly to the increased fracture risk in patients with osteoporosis. Physical fitness in later life is associated more with a decreased risk of falling than with an increased bone mineral density.
Treatment
Patients at risk for osteoporosis (e.g. steroid use) are generally treated with vitamin D and calcium supplements. In renal disease, a different form of Vitamin D (1,25-dihydroxycholecalciferol or calcitriol which is the main biologically active form of vitamin D) is used, as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol) which is the storage form of vitamin D.
In osteoporosis (or a very high risk), bisphosphonate drugs are prescribed. The most often prescribed bisphosphonates are presently sodium alendronate (Fosamax®) 10 mg a day or 70 mg once a week, risedronate (Actonel®) 5mg a day or 35mg once a week or and ibandronate (Boniva® once a month).
Other medicines prescribed for prevention of osteoporosis include raloxifene (Evista®), a selective estrogen receptor modulator (SERM). Estrogen replacement remains a good treatment for prevention of osteoporosis but, at this time, is not recommended unless there are other indications for its use as well.
Recently, teriparatide (Forteo®, recombinant parathyroid hormone 1-34) has been shown to be effective in osteoporosis. It is used mostly for patients who have already fractured, have particularly low BMD or several risk factors for fracture or cannot tolerate the oral bisphosphonates. It is given as a daily injection with the use of a pen-type injection device. Teriparatide is only licensed for treatment if bisphosphonates have failed or are contraindicated (however, this differs by country).
Oral Strontium ranelate (Protelos® - Servier) is the first in a new class of drugs called a Dual Action Bone Agents (DABA's), and has proven efficacy in the prevention of vertebral and non-vertebral fractures (including hip fracture). Strontium Ranelate works by stimulating the proliferation of osteoblast (bone building) cells, and inhibiting the proliferation of osteoclast (bone absorbing) cells. This means that strontium Ranelate increases BMD by forming new bone, rather than just preserving existing bone. In comparison to bisphosphonates which only act on one aspect of bone remodeling, strontium ranelate also preserves bone turnover, allowing the microarchitecture of the bone to be continuously repaired as it would in healthy bone. Strontium ranelate is taken as a 2g oral suspension daily, and is licenced for the treatment of osteoporosis to prevent vertebral and hip fracture (this may differ by country). Strontium ranelate has show significant efficacy at reducing both vertebral, and non-vertebral fractures in patients over the age of 80, who are the most at risk where osteoporosis is concerned. This is unique to strontium ranelate as bisphosphonates can only show efficacy in vertebral fracture reduction, not non-vertabral. Strontium ranelate has side effect benefits over the bisphosphonates, as it does not cause any form of upper GI side effect, which is the most common cause for medication withdrawal in osteoporosis.
Changes to lifestyle factors and diet are also recommended; the "at-risk" patient should include 1500mg of calcium daily either via dietary means (for instance, an 8 oz glass of milk contains approximately 300 mg of calcium) or via supplementation. The body will absorb only about 500 mg of calcium at one time and so intake should be spread throughout the day. However, the benefit of supplementation of calcium alone remains, to a degree, controversial since several nations with high calcium intakes through milk-products (e.g. the USA, Sweden) have some of the highest rates of osteoporosis worldwide. A few studies even suggested an adverse effect of calcium excess on bone density and blamed the milk industry for misleading customers. Some nutrionists assert that excess consumption of dairy products causes acification, which leeches calcium from the system, and argue that vegetables and nuts are a better source of calcium and that in fact milk products should be avoided. In any case, thirty minutes of weight-bearing exercise such as walking or jogging, three times a week, has been shown to increase bone mineral density, and reduce the risk of falls by strengthening the major muscle groups in the legs and back.
In a recent study that examined the relationship between calcium supplementation and clinical fracture risk in an elderly population, there was a significant decrease in fracture risk in patients that received calcium supplements versus those that received placebo. However, this benefit only applied to patients who were compliant to their treatment regimen. [6]
Increasing vitamin D intake has been shown to reduce fractures up to twenty-five percent in older people, according to recent studies.
There is some evidence to suggest bone density benefits from taking the following supplements (in addition to calcium and vitamin D): boron, magnesium, zinc, copper, manganese, silicon, strontium, folic acid, and vitamins B6, C, and K. [7] [8]
2-Teratogenesis
It is a medical term from the Greek, literally meaning monster-making, which derives from teratology, the study of the frequency, causation, and development of congenital malformations—misleadingly called birth defects. These include gross morphological abnormalities, such as cleft lip and/or palate, anencephaly, or ventricular septal defect, but may also include phenomena such as increased risk of cervical cancer or discoloration of tooth enamel. These malformations can arise from genetic abnormalities of the fetus, from adverse environmental circumstances (termed teratogens or tetragens), or a combination of these factors. Teratogenesis has gained a more specific usage for the development of abnormal cell masses during fetal growth (see pregnancy), causing physical defects in the fetus.
Isotretinoin (13-cis-retinoic-acid)
Often used to treat severe acne, is such a strong teratogen that just a single dose taken by a pregnant woman may result in serious birth defects. Because of this effect, most countries have systems in place to ensure that it is not given to pregnant women, and that the patient is aware of how important it is to prevent pregnancy during and at least one month after treatment. Medical guidelines also suggest that pregnant women should limit vitamin A intake to about 700 μg/day, as it has teratogenic potential when consumed in excess.[3][
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)
Safety
Safety in pregnancy
Although normal fetal development requires sufficient vitamin A intake, consumption of excess preformed vitamin A (retinol) during pregnancy is known to cause birth defects. No increase in the risk of vitamin A-associated birth defects has been observed at doses of preformed vitamin A from supplements below 3,000 mcg/day (10,000 IU/day) (18). Since a number of foods in the U.S. are fortified with preformed vitamin A, pregnant women should avoid multivitamin or prenatal supplements that contain more than 1,500 mcg (5,000 IU) of vitamin A . Vitamin A from beta-carotene is not known to increase the risk of birth defects. 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
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 (18)
Chronic alcohol consumption results in depletion of liver stores of vitamin A, and may contribute to alcohol-induced liver damage. 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 . 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
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.
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
Dietary Reference Intakes for Vitamin A
Children (< 4 yrs): 300 μg
Children (4+ yrs): 400 - 600 μg
Women: 700 μg
Men: 600 μg
Lactation: 1200 μg
References
1 Barker ME, Blumsohn A. Is vitamin A consumption a risk factor for osteoporotic fracture?. Proc Nutr Soc. 2003;62:845-850. [Medline].
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