You need several nutrients to support your vision, immune function, and your overall health; but did you know there is one essential nutrient so important to your health that it was given the name "the anti-infective vitamin" in the year 1928? In this episode, we shine the spotlight on a nutrient that can be overlooked in many Western countries but is no less critical for human development and daily function - Vitamin A.
First, we will look at the different forms of vitamin A as part of the "retinoid" family - differentiating between preformed vitamin A (active and stored) and provitamin A compounds, their roles in promoting human health and the consequences of vitamin A deficiency in the following bodily functions:
We will look to understand the prevalence of vitamin A deficiency in lower and middle-income countries, as well as the United States, and the impact deficiency has on women and children (i.e., groups at the highest risk of deficiency worldwide).
Next, we will examine vitamin A requirements and sources (from plant and animal foods). We will gather an understanding of how provitamin A from food and supplements contribute differently to vitamin A status, how not all provitamin A compounds were created equal, and how/why some food sources might be better than others for extracting provitamin A to be converted into active vitamin A in the body.
We conclude this episode by exploring the toxicity of retinoid compounds and how specific studies suggest that high doses of preformed vitamin A may increase the risk of certain cancers in the body (we will also attempt to understand why that is).
Be sure to subscribe for future episodes covering specific nutrients and strategies for achieving optimal nutrient adequacy.
You need several nutrients to support your vision, immune function, and your overall health; but did you know there is one essential nutrient so important to your health that it was given the name "the anti-infective vitamin" in the year 1928? In this episode, we shine the spotlight on a nutrient that can be overlooked in many Western countries but is no less critical for human development and daily function - Vitamin A.
First, we will look at the different forms of vitamin A as part of the "retinoid" family - differentiating between preformed vitamin A (active and stored) and provitamin A compounds, their roles in promoting human health and the consequences of vitamin A deficiency in the following bodily functions:
We will look to understand the prevalence of vitamin A deficiency in lower and middle-income countries, as well as the United States, and the impact deficiency has on women and children (i.e., groups at the highest risk of deficiency worldwide).
Next, we will examine vitamin A requirements and sources (from plant and animal foods). We will gather an understanding of how provitamin A from food and supplements contribute differently to vitamin A status, how not all provitamin A compounds were created equal, and how/why some food sources might be better than others for extracting provitamin A to be converted into active vitamin A in the body.
We conclude this episode by exploring the toxicity of retinoid compounds and how specific studies suggest that high doses of preformed vitamin A may increase the risk of certain cancers in the body (we will also attempt to understand why that is).
Be sure to subscribe for future episodes covering specific nutrients and strategies for achieving optimal nutrient adequacy.
Hello everyone, my name is William Wallace and I will be your host today as we take an overview. Look at a nutrient of global importance and one that I'm not sure is appreciated enough, and that is the essential micronutrient known as vitamin A. Specifically, we're going to cover the major forms of vitamin A, as there are several. We will discuss the significance of vitamin A in human health and disease, and this includes its role in vision, under both dim and bright light conditions. We'll also briefly discuss its role in immune function, red blood cell formation and fetal development. We will also talk about ways that vitamin A performs those roles and what happens when we don't get enough vitamin A. From there, we're going to go into vitamin A deficiency as well as how it's treated and identified. The last few topics we'll discuss today will include population and individual requirements of vitamin A, sources of vitamin A and problems that can occur when taking in excess vitamin A. There may be specific topics or information that I won't go into great detail on and will say for future episodes dedicated to vitamin A, as covering all aspects in great detail could leave us here for hours on end, and I don't want to do that to any of us. But before I go any further, I must preface with this disclaimer that this podcast is being generated purely for educational purposes. The contents of this broadcast do not constitute medical advice and are not meant to substitute for standard medical practice. Please consult with your primary healthcare practitioner before beginning any nutrition or supplement-based protocols that may be mentioned in this episode. Now, with that out of the way, let's get into the bulk of the episode.
Speaker 1:The term vitamin A is actually a generic descriptor for a family of compounds that share structural similarities, and, in some cases, functional similarities, to the chemical compound called retinol. This class of fat-soluble compounds collectively are known as retinoids and, if you recall from the first podcast episode that I did, that was an overview of all vitamins and their significance. Most vitamins as we know them, like vitamin A, come in multiple different chemical forms that are related to one another in some way. We use the term vitaminers to describe these different compounds that fall into the same vitamin family. In this case we're talking about retinoid vitaminers, all being referred to as and falling under the parent compound, vitamin A. So, as stated, vitamin A comes in many different forms, but it has three primary forms, with the first being known as retinol. This is the alcohol form of vitamin A. The second is called retinol. That's spelled with an A as opposed to an O, like used in retinol. Retinol is short for retinoldehyde. This is the aldehyde form of vitamin A. And the third is retinoic acid. This is the acid form of vitamin A. So we have retinol, retinol and retinoic acid. These three retinoids and their corresponding derivatives are responsible for nearly all vitamin A activity in the body.
Speaker 1:When talking about diet, vitamin A in those forms I just mentioned are what we call preformed vitamin A, because they display vitamin A like activities in the body as they are. In addition to those forms of vitamin A, there are forms of vitamin A known as retinol esters. These retinol esters are the storage form of vitamin A, predominantly stored in the liver, but also adipose tissues as well as other tissues of the body. The liver is the primary storage form and that holds anywhere from 50 to 90% of whole body vitamin A, mostly as retinol palmitate. Retinol palmitate is the primary storage form of vitamin A. As such, that is the most abundant form of vitamin A found in food derived from animal products like milk, different meats, eggs, etc. You might also notice that retinol palmitate is a widely used form of vitamin A in dietary supplements as well. Retinol esters, like retinol palmitate, even though they require conversion to retinol and retinol to display biological vitamin A activity, are also considered preformed vitamin A.
Speaker 1:Next to preformed vitamin A, we have another classification of compounds called pro vitamin A. These compounds do not start out as active or stored forms of vitamin A, but they can be converted into active or stored forms of vitamin A. These compounds are what we call carotenoids, which are pigments primarily found in plants, but animals can also store them in tissues if they eat plant materials. As of now, there are approximately 600 different known carotenoids in the world found in plants, and around 50 of them are considered pro vitamin A. So just under 10% of carotenoids that we know of can convert into active vitamin A in the body, but really only 5 or 6 of these are actually common in the foods that we eat.
Speaker 1:The main pro-vitamin A carotenoids in human diet are beta-carotene, alpha-carotene and beta-crypto-Xanthan, with beta-carotene, a red-orange pigment, being the most abundant and having the highest conversion ability to vitamin A, as I'll explain later when I talk specifically about beta-carotene. So, to summarize these points, the human diet consists of two classifications of vitamin A. We have preformed vitamin A and pro-vitamin A. Preformed vitamin A consists of active or stored forms of vitamin A found in dairy products, fish, eggs and meats, and you have pro-vitamin A that's the term typically used to refer to plant pigments known as carotenoids that we convert to active or stored forms of vitamin A after we ingest them. It's important to note that pro-vitamin A carotenoids also display biological activity that are unique to their structure as carotenoids, but not involving the formation of vitamin A, and I'm going to save that for a later episode dedicated to carotenoids, as they have pretty fascinating implications for health in their own right, outside of their vitamin A activity.
Speaker 1:The discovery of vitamin A and the earliest known functions of some retinoid compounds are hinted at in the name. Retinoid Carotenoids were given their name due to vitamin A's role in light sensing and vision through the production of pigments in the retina of the eye. It's important to note, actually, that vitamin A existed as a chemical long before it was considered a vitamin, and it even acted as a light sensor in nature before organisms ever developed retinas. But because of when and how vitamin A was discovered, we named it after the retina. The retina, as we know, is a layer of tissue at the back of the eye that contains different cells and cell types that are sensitive to light and that, when acted upon by light, photons, trigger nerve impulses that pass up the optic nerve and into the brain to initiate image and non-image vision. Vitamin A plays an important role in both image and non-image vision, but plays a more direct role in image vision. One of the primary roles of non-image vision is essentially to tell time, in other words, to adjust and fine tune circadian rhythms. Vitamin A plays an indirect but important role in fine tuning circadian rhythms because the cells that we are about to talk about use vitamin A for light sensing and actually send input to other cells that are primarily responsible for non-image vision.
Speaker 1:In the retina, vitamin A is primarily found in photoreceptor cells, which include rod and cone cells. Rod cells are primarily responsible for image vision under low light conditions, but also contribute to vision in intermediate light conditions, like those at dusk or dawn. These cells contain a pigment called rhodopsin, which is also called visual purple because of its purple hue. Rhodopsin is a two-part complex that contains a protein called opsin and a metabolite of retinal. That's the aldehyde form of vitamin A that I brought up a little bit ago, the specific vitamin A metabolite is 11-cis retinal, but it's not so important to get into that kind of detail for the sake of this episode, so we're just going to call it retinal for now.
Speaker 1:The other set of photoreceptor cells that use vitamin A to detect light for image vision are what we call cone cells. Cone cells are responsible for color vision and high acuity vision in bright light, but those are also activated by intermediate light conditions. Just like rod cells are Like rod cells, cone cells contain opsin proteins. In cone cells these proteins combine with retinal to detect different wavelengths of light. So in cone cells different opsin proteins sense different wavelengths of light and we ultimately perceive these different wavelengths as colors. Because of this interaction between light and opsin in cone cells. The opsins in cone cells are called S-cone opsins and those stand for short wavelength opsin, which we perceive as the color blue. We have M-cone opsin, which stands for medium wavelength opsin opsin, and we perceive that as the color green, and L-cone opsin, which stands for long wavelength opsin, which we perceive as the color red. Red, green and blue are considered the primary colors in physics under the additive primary color model. I believe because of these three photoreceptor pigments and their specific sensitivities to certain wavelengths of light.
Speaker 1:Without being bound to vitamin A, these proteins are not as capable of signal transduction and vision would suffer from that. When someone shifts to rod vision under dim light conditions and rod cells activate, there is a shift in wavelength sensitivity such that blue colors appear brighter than red colors. Under normal conditions, this shift to rod vision should take less than 10 minutes. However, abnormal dark adaptation or abnormal adaptation to dim light conditions is one of the earliest signs and symptoms of a vitamin A deficiency and can present itself in the subclinical phase of deficiency. If you want to learn more about phases of deficiency, then please go back to see the first episode of this podcast.
Speaker 1:If not corrected with vitamin A intake, this can lead to complete night blindness, also called nyctalopia. Interestingly, the inability to see under low light settings is one of the first ever recorded medical conditions. Writing is from ancient Greek, roman and Arab physicians all discussed the condition and explained that animal liver had been a known prevention and cure of this particular disease. Actually, ancient Egyptian writings dated back to 1550 BC described treating night blindness by squeezing liquid from lamb's liver directly into the eye of the affected patient, which I'm not suggesting anybody do, but I do find it interesting that ancient civilizations were actually making the connection between the liver and eye health, although at the time they didn't specifically know about vitamin A being the driver of that particular ailment. It was in the 1880s that cod liver oil was found to be effective at curing night blindness and corneal lesions known as Bittitz spots. So not quite ancient times, just over a hundred years ago. These Bittitz spots develop as vitamin A deficiency progresses into something called xerothalamia, which is a spectrum of eye disorders caused by more severe vitamin A deficiency.
Speaker 1:The dietary nature of night blindness and xerothalamia started to become more understood in the early 1990s when one group of researchers, led by the American biochemist Elmer McCollum, extracted a compound from egg and butterfat that was initially found to be necessary to sustain the growth of rats. Mccollum called this fat soluble A because it seemed to be found in high amounts in more fatty foods. Later studies by the same group did find that ocular disorders developed by animals fed fat free diets, that those could be cured by feeding them cod liver oil, butter or preparations of this extracted compound called fat soluble A. Now, in 1920, a fat soluble A was renamed to vitamin A. This factor, present in cod liver oil had been shown to prevent night blindness and xerothalamia nearly 40 years prior to vitamin A being recognized as its own unique compound in cod liver oil. So again, impaired dark adaptation and night blindness are some of the most well known and earliest signs of vitamin A deficiency.
Speaker 1:Some researchers believe there's good evidence to actually suggest that vitamin A's first function in humans was as a light sensor in the eyes and that through evolution, other organ systems gradually developed a dependence on different forms of vitamin A for different functions. However, despite the growing dependence of other organs on vitamin A, the human eye actually remains the organ that is the most dependent on vitamin A and is more sensitive than any other organ to a vitamin A deficiency. Although the eye is the most sensitive organ to vitamin A deficiency, the extra retinal functions of vitamin A are actually of greater physiological importance than the visual functions that vitamin A contributes to. Even though it has been hypothesized that vitamin A's first use in humans was directed towards visual function, retinoid compounds began to be used for other processes in the body. As human beings continue to develop. Many of these vitamin A-affected processes are considered more recent on an evolutionary timeline compared to the visual ones and most of the newer processes are mediated by the acid form of vitamin A, and again that would be retinoic acid and its derivatives.
Speaker 1:It might be important to mention here that retinol and retinol that's the alcohol and aldehyde form of vitamin A that those can actually convert back and forth to one another. However, once the aldehyde form, retinol, now converts into retinoic acid, there's no conversion back to the alcohol or aldehyde forms, and retinoic acid is metabolized to form isomers that have different biological activity, or it's metabolized for excretion. The primary function of retinoic acid and its isomers is to affect gene expression. In this way, retinoic acid, and so vitamin A, acts like a hormone in the body, affecting over 500 different genes. Vitamin A, along with vitamin D, are two of the only known vitamins to actually have what we call a nuclear receptors in the body. It's also possible that vitamin E has these, but that's really neither here nor there at the moment.
Speaker 1:You can think of these receptors as a switch that can be turned on or off by specific molecules, usually in the form of hormones, to regulate and influence the activity of certain genes. Vitamin A has two classes of these receptors and those are known as retinoid X receptors and retinoic acid receptors. Two primary acid forms of vitamin A bind to these receptors. There's nine cis retinoic acid which can bind to both receptor types, and then you have all trans retinoic acid, which primarily binds to the retinoic acid receptor. Now the retinoid X receptor is at times what we call a promiscuous receptor because of its ability to dimerize with other receptor types in the body. When I say dimerize, what I mean is that the retinoid X receptor and retinoic acid receptors, those sometimes join together with each other or other receptor types to form what is kind of like a single unit where several compounds, and not just retinoids, might be able to bind to and activate them. For example, the retinoid X receptor often joins with the thyroid hormone receptor on the thyroid stimulating hormone gene. Vitamin thyroid stimulating hormone depends on triiodothironine, that's T3, and nine cis retinoic acid binding to their receptors on the thyroid stimulating hormone gene.
Speaker 1:Animal models here have shown that vitamin A deprivation impairs thyroid signaling in the brain. Vitamin A deficient conditions cause dysregulated secretion of thyroid stimulating hormone from the pituitary gland. Dysregulated gland will also increase in size, reduce its iodine uptake and increase circulating concentrations of certain thyroid hormones. As such, it's been proposed that a vitamin A deficiency can be a contributing factor to some cases of hypothyroidism. There was actually one study in 2004 that looked at 138 children with vitamin A and iodine deficiency and found that vitamin A deficiency severity was associated with higher concentrations of circulating thyroid stimulating hormone, thyroid hormones and the severity of goiter, which is an abnormal enlargement of the thyroid gland. These children were given two different, very large doses of vitamin A, along with some iodine, and after five months thyroid stimulating hormone and thyroid gland size had actually begun to normalize. Another study in a similar population showed that vitamin A supplementation alone actually reduced volume of the thyroid gland and helped to normalize thyroid hormone levels.
Speaker 1:Another important receptor that retinoid X receptors interact with is the vitamin D receptor. In this way, vitamin A actually plays a role alongside vitamin D and bone metabolism. It's very common for retinoid X receptors and retinoic acid receptors to form a complex with one another, and this plays a very large role in the maturation and function of the immune system. In fact, one of vitamin A's best characterized functions is its role in the immune system. Two years after vitamin A was isolated as a compound, but 14 years before its structure was ever determined, there was a paper published in 1928 in a coin vitamin A, the anti-infective vitamin, because of its proposed importance in normal immune function. Lymph nodes, the skin mucosal cells, linings of the digestive tract, the respiratory tract and the urinary tract are all considered first lines of defense against infection.
Speaker 1:Vitamin A plays a necessary role in helping to maintain these physical barriers against infectious agents. Within these barriers, what you'll find are cells called antigen presenting cells, which are a type of immune cell that captures a piece of a foreign or non-indigenous substance, like certain bacteria, for instance, that's somewhere in the body that it should not be. These cells then deliver these pieces to other cells to alert and activate them and to have them respond to the invader substance. Basically, these antigen presenting cells basically bridge the gap between innate and adaptive immunity. Three such cells are dendritic cells, macrophages and B cells. All these cells exhibit retinoic acid and retinoid X receptors. Retinoic cells and macrophages are interesting because they can effectively convert retinol to retinoic acid, which then binds these antigen presenting cells and helps regulate their capacity to deliver these invader fragments to other immune cells. Retinoic acid metabolized by these cells can also act on other immune cells, like immature T cells, and this allows them to properly mature into what we call a helper T cell, which is a type of effector T cell. These cells basically mobilize and coordinate other immune cells for and during an immune response.
Speaker 1:Because of the role that vitamin A plays in infectious disease prevention, vitamin A deficiency is considered a nutritionally acquired immunodeficiency, and some researchers claim that retinoic acid itself may help prevent the development of autoimmunity later in life. But please note that I'm not making the claim that this is 100% the case, nor am I suggesting that retinoic acid can cure autoimmune disorders. Other physiological processes that retinoids influence include red blood cell formation. Cell studies in this area suggest that vitamin A plays a role in the ability of erythropoietic progenitor cells, which are red blood precursor cells, to commit and mature into red blood cells. Some research does suggest that vitamin A is actually needed to stimulate erythropoietin release from the kidneys. This is a hormone that stimulates red blood cell formation.
Speaker 1:Vitamin A also seems to be able to help liberate and mobilize stored iron from ferritin for its incorporation into hemoglobin, and may even mobilize iron from what's called hemo-siderin. Iron found in this particular pigment is typically more difficult and time consuming for the body to draw from. Iron must be mobilized from storage to be incorporated into hemoglobin. Hemoglobin is the protein complex found in red blood cells, whose main role is to carry oxygen from the lungs to all other tissues of the body, but it cannot do so or form without iron, because iron in hemoglobin is actually what binds to oxygen, allowing that oxygen to be transported. Vitamin A's role in red blood cell formation seems to be a dynamic, but its role in liberating stored iron has tied vitamin A deficiency closely to iron deficiency anemia.
Speaker 1:Now, interestingly, a 2019 meta-analyses analyzed studies conducted on children, teenagers, pregnant and breastfeeding women and found that vitamin A supplementation actually reduces the risk of iron deficiency anemia by 26%, or did in that case at least, as well as raised hemoglobin levels. I need to pause here and add that the consensus opinion of experts is that pregnant women should not be taking in preformed vitamin A in doses that exceed the upper limit without being directed by and under the supervision of a medical doctor and for a particular reason, as is the case with these studies looking at anemia associated with vitamin A deficiency. I'm going to go over upper limits and toxicity later in the podcast, so I will stress and reiterate this point there. But anyways, back to the meta-analyses. The researchers had concluded that vitamin A supplementation alone may reduce the risk of iron deficiency anemia in individuals who were considered to have low serum vitamin A levels.
Speaker 1:The intake of supplemental vitamin A associated with these effects varies quite a bit from study to study, and it usually depends on the prevalence and the extent of vitamin A deficiency present in the groups that are being investigated. For instance, studies looking at vitamin A's ability to lower the risk for iron deficiency anemia. They use dosing schemes between 500 and 200,000 international units of vitamin A, and that's equivalent to a range of about 150 and 60,000 micrograms. 60,000 micrograms in one day is 20 times the upper limit for vitamin A intake set by the Food and Nutrition Board at the National Academy of Medicine. However, doses that large, under supervision and direction of a medical professional, are a common treatment strategy for actual clinical vitamin A deficiency, but dose and frequency need to be considered with a special consideration for the age of the person or population being treated. For instance, the World Health Organization recommends this 60,000 micrograms supplemental treatment to people between 12 and 59 years old once every 4 to 6 months for certain purposes, always in people at risk of deficiency and usually in parts of the world where vitamin A intake is considered a public health concern. A 2006 study published in the American Journal of Clinical Nutrition used supplemental vitamin A doses of 60,000 micrograms, that's 200,000 international units, where I use either once every 5 months or every 2 to 3 months in Moroccan school children with poor iron and vitamin A status and found that vitamin A supplementation alone increased hemoglobin concentrations, lower the prevalence of iron deficiency anemia from 54 to 38% in these children, largely through helping to mobilize iron from existing stores.
Speaker 1:Although vitamin A supplementation can have a beneficial effect on iron status in certain cases, iron deficiency is the primary cause of iron deficiency anemia and vitamin A supplementation cannot overcome severe iron deficiency by itself. There is evidence that points to the synergistic nature of combined supplemental vitamin A and iron, where the two together seem to be more effective in reducing anemia compared to vitamin A or iron supplemented alone. This was shown 3 decades ago when anemic pregnant women in Indonesia were given either 2,400 micrograms of vitamin A alone or 60 milligrams of elemental iron alone, or 2,400 micrograms of vitamin A and 60 milligrams of elemental iron together daily for 8 weeks, and the results showed that the number of women who became non-anemic with vitamin A alone was 35%. It was 68% in women given iron alone and in the combined vitamin A and iron group, 97% of women were actually considered no longer iron deficiency anemic by the end of that study. There are reasons that many studies investigating vitamin A supplementation and deficiency are conducted in women and children, and those are one, these groups are at the highest risk of vitamin A deficiency, especially in developing countries. And two, because vitamin A plays such a large role in mostly women-centered issues like iron deficiency, anemia, but also embryonic development.
Speaker 1:Actually, an organ that expresses one of the highest levels of a protein that regulates the cellular uptake of vitamin A is the female placenta. Obviously, that's the structure that, among some of its functions, transfers oxygen and nutrients to a growing fetus. Vitamin A signaling is highly important for a developing system as it plays a key role in the growth and division of cells, as well as differentiation of many different cell types, and the term differentiation refers to maturing cells committing to specialized functions in the body. In early development, retinoic acid signals the expression of genes directing organization of the trunk and development of the neuroectoderm. The neuroectoderm helps give rise to the entire nervous system. Basically, in the later development, retinoic acid signaling assists in the development of several organs, including the eyes, heart, ears and lungs.
Speaker 1:Its role in lung maturation is an interesting one, because past research published in the early 2000s showed that vitamin A status in preterm newborns is actually lower compared to full term infants. Approximately one third of preterm infants born between 22 and 28 weeks of gestation develop bronchopulmonary dysplasia. That is a lung disease that can be fatal to infants or it can also result in lifelong respiratory issues. Its well known that vitamin A is important for the development and maintenance of mucus secretion and mucus integrity in the respiratory tract, and this is crucial for preventing respiratory infections throughout our life.
Speaker 1:Once a child is born, human breast milk is the principal source of vitamin A intake if the infant is being breastfed. Even though infants get some vitamin A from the mother during gestation or their time in utero, they are likely to consume approximately 60 times more vitamin A from vitamin A adequate breast milk compared to the amount of vitamin that they get while in the womb. Vitamin A in breast milk is present in milk fat globules, so as such, vitamin A in breast milk varies with milk content, and that's obviously affected by the general nutrition status of the mother. In less economically sound areas of the world, breast milk is typically the only reliable source of vitamin A for infants in their first six months of life. Again, it's highly important to address both the women of reproductive age and children when talking about vitamin A inadequacy or deficiency, as they would be included in groups at the highest risk for inadequate vitamin A intake and or status. This is most generally the case in sub-Saharan Africa, southeast Asia and Central America. Central America includes places like Mexico, costa Rica, el Salvador, honduras and so on.
Speaker 1:True vitamin A deficiency is actually quite rare in the United States. Now, in 2015, there was a polled analysis population based study done and published it, and what I mean by polled analysis is that population surveys were taken between the years 1991 and 2013 from 83 different lower and middle income countries. Those were looked at together. Basically, the results showed that nearly 30% of children six months to five years old were vitamin A deficient is late as 2013. Deficiency rates were the highest in Africa and Southeast Asia. There was another study published in 2015 suggesting that 10 to 20% of pregnant women in low income countries have a clinical vitamin A deficiency. This agrees with statistics from the World Health Organization suggesting that 15% of pregnant women worldwide have a true vitamin A deficiency.
Speaker 1:Some evidence suggests that one out of every five people in the world may be, at the very least, in a state of subclinical vitamin A deficiency. Approximately 46% of people in the United States report inadequate vitamin A intake, but it's really important to note that under reporting intake that's not the same thing as a deficiency. It's really only suggestive of what someone's vitamin A status could possibly be Because of these rates of deficiency. The World Health Organization has deemed vitamin A deficiency a public health problem in countries and parts of the world where serum retinol concentrations of less than 20 micrograms per deciliter, or 0.7 micromoles per liter, reaches 15% or more of a specific population. And again, that list of countries largely consists of less economically sound and developing countries.
Speaker 1:Now there are two very well known effects of vitamin A deficiency. One, as I had mentioned earlier, is night blindness. Remember that I had said impaired dark adaptation was one of the earliest signs of deficiency, due to the reliance of the eyes on vitamin A. The next clinical stage of deficiency would be the development of bitots spots. Deferred deficiency then progresses to xerothalmia, which is Greek for dry eye. This results in ulcers and scarring in the eye and further to full blindness if not corrected.
Speaker 1:In fact, vitamin A deficiency is one of the top causes of preventable blindness in children and the leading cause in low and middle income countries. Some researchers have even claimed that nutritional blindness due to vitamin A deficiency is a leading cause of blindness in the world, regardless of age. It's especially important and relevant in children because, if left untreated, two-thirds of children die within months of going blind due to their increased susceptibility to infectious disease. A second most well known effect of vitamin A deficiency is, unfortunately, increased childhood mortality and morbidity. As I mentioned earlier, true vitamin A deficiency is considered a nutritionally acquired immunodeficiency, so children who have only mild vitamin A deficiency have higher rates of respiratory disease, anemia, potentially fatal cases of diarrhea and higher rates of and mortality from infectious disease like measles, compared to children consuming enough vitamin A. Actually, 95% of deaths related to vitamin A deficiency do occur in parts of Africa and Asia where vitamin A deficiency rates are highest in the world, but in these areas, vitamin deficiency accounts for 2% of all death in children younger than 5 years old, which is honestly a pretty staggering statistic.
Speaker 1:It comes as no surprise at this point that infants, children, pregnant women and women of reproductive age are considered general groups at the highest risk of vitamin A deficiency, especially in these lower income countries. When it comes to infants and children, preterm infants are considered very high risk and tend to have low liver stores of vitamin A, probably due to interrupted accretion due to less time spent in the mother's womb. Of course, infants and children whose mothers were not getting enough vitamin A during pregnancy or lactation are very high risk for deficiency. Frequent alcohol use, especially alcoholism, places people in the high risk category for a deficiency as well. People with malabsorption conditions, like cystic fibrosis, are at risk because of their inability to absorb fat and, as we'll look at when we discuss requirements, dietary fat is needed to properly absorb vitamin A. In that same way, even without a malabsorption disorder, not getting enough dietary fat would hinder the uptake of vitamin A. People who are not taking in enough dietary protein are also at risk for vitamin A deficiency.
Speaker 1:Dietary protein is needed for us to synthesize retinal binding protein. This protein is needed to mobilize vitamin A from the liver and transport retinol through the blood to different tissues for use. There are other forms of retinol binding protein that transport different forms of vitamin A to different parts of the cell, depending on where in the body that is. Some evidence suggests that in cases of protein malnutrition, that serum retinol binding protein can actually drop by as much as 50%, which would limit the vitamin A able to make its way to tissues throughout the body. Dietary protein is also needed to form the enzyme which converts beta carotene to retinal, the aldehyde form of vitamin A.
Speaker 1:Now, another important nutrient whose absence would increase one's risk for poor vitamin A status is actually the essential mineral zinc. Zinc's important here for three reasons. One, zinc, like protein, is needed to synthesize retinol binding protein and is also needed for vitamin A to actually bind to the protein. Two, zinc is needed for the conversion of the storage form of vitamin A, retinol pulmitate, into retinol, which allows it to be transported from the liver to other tissues by retinol binding protein. And three, zinc is used by alcohol dehydrogenase enzymes to convert retinol to retinol. Remember that retinol is the form crucial for vision. As such, zinc deficiency may increase one's risk for vitamin A deficiency or poor vitamin A status.
Speaker 1:Moderate vitamin A deficiency, as defined by the National Academy of Medicine and the World Health Organization, is serum retinol. So retinol is the retinoid being looked at here. Retinol concentrations lower than 20 micrograms per deciliter. This is equivalent to 0.7 micro moles per liter, depending on the exact way measurements are being reported. Severe deficiency, as defined by the National Academy of Medicine, would be a serum retinol concentration lower than 10 micrograms per deciliter or 0.35 micro moles per liter. Of course, these thresholds are set because of the deficiency syndrome symptoms that manifest at levels below these. Some professionals and health groups they do suggest that serum concentrations of retinol above 30 micrograms per deciliter or 1.05 micro moles per liter are better reflective of adequate vitamin A status and not someone who is at great risk for deficiency syndrome symptoms.
Speaker 1:However, vitamin A is one of the few different micronutrients whose tissue and blood levels are what we call homeostatically controlled. What is meant by that is that the body has mechanisms in place that help to maintain the serum concentration of vitamin A within a stable range, regardless of short term intake. When we have a very high vitamin A intake, the body will actually store more of it because it has a good capacity to do so, but it will also absorb less of it, which I'll mention, when we get to the actual intake. When vitamin A intake is low, the body will release stored vitamin A into the bloodstream and this allows for a consistent and optimal levels of vitamin A in the body, especially in blood. Because of this, serum levels of vitamin A are really only related to stored vitamin A when stores, mostly liver stores, get very low. Unless vitamin A stored in the liver is very low, serum vitamin A is not a great indicator of vitamin A status. Serum vitamin A is best used when assessing status of vitamin A at the population level, typically for research, and although it's currently recommended by the World Health Organization, serum concentrations generally aren't recommended to be used by themselves in most cases For individuals getting routine blood work, using serum retinol as a biomarker again is not the best indicator of status unless a real deficiency is present, but it is the most accessible biomarker right now with practical implications.
Speaker 1:It does correlate with the severity of something like xerophilia when you get to severe deficiency. Most retinol circulating in the blood is bound to retinol-binding protein. Again, that's what transports retinol from tissue to tissue. So retinol-binding protein is measuring serum retinol by proxy. There are two general types of retinol-binding protein in the blood that is, retinol-binding protein that's actually bound to retinol and the protein that's not bound to retinol. About 85% of retinol-binding protein in the blood is binding to and transporting retinol.
Speaker 1:There are several factors that can influence readings of retinol-binding protein, for instance. Like I had mentioned earlier, the protein and zinc malnutrition would actually depress the synthesis of retinol-binding protein. Retinol-binding protein is also what we call a negative acute phase reactant, meaning that it and the serum retinol concentrations actually go down in the presence of inflammation or infection. Because of this measuring, it doesn't have much use in identifying a vitamin A deficiency when an individual has an infection or they're sick. In a lot of cases, there are several factors that can influence readings of retinol-binding protein. For example, like I had mentioned before, that protein and zinc malnutrition would depress the synthesis of retinol-binding protein. Retinol-binding protein is also what we call a negative acute phase reactant, meaning that it and the serum retinol concentrations actually go down in the presence of inflammation or infection. Because of this measuring, it doesn't have much use in identifying vitamin A deficiency when individuals have a severe infection, and you could account for a false identification of a vitamin A deficiency by simultaneously measuring positive acute phase reactants like C-reactive protein, which goes up in the presence of inflammation or infection. Infection or illness itself can cause substantial loss of vitamin A through urine because retinol-binding protein is not able to be reabsorbed as well under these conditions and that may increase the risk of deficiency in people who don't have adequate stored vitamin A. Obesity would also affect concentrations of retinol-binding protein because proportionally higher amounts of retinol-binding protein are secreted into the bloodstream, possibly by adipose tissue in the form of the protein that's not actually bound to vitamin A. In that way, retinol-binding protein measurements in somebody who is quite obese might come back looking adequate and give what you'd call a false negative. So to summarize some of these points, serum retinol is related to vitamin A stores only when liver stores are very low. When one has adequate liver stores, serum retinol is tightly controlled by the body and does not relate to liver stores very much. Serum retinol-binding protein is closely related to serum retinol because most retinol-binding protein in the blood is bound to retinol, with the important distinction that serum retinol and retinol-binding protein are not one-to-one because retinol-binding protein may not be entirely saturated with retinol all the time.
Speaker 1:There are different dose response tests that can be administered as an indirect way to determine liver reserves of vitamin A. Breast milk retinol concentrations can be a good biochemical indicator of vitamin A status in a breastfeeding mother. It also would give an indirect information as to the vitamin A status of an infant. Breast milk is typically another one of those measurements used to determine vitamin A status at the population level and not so much at the individual level. There also actually exist functional tests of vitamin A deficiency.
Speaker 1:Remember earlier I had mentioned that abnormal dark adaptation that is, switching from cone to rod vision when you move from a well lit space to a dimly lit space or dark space. That's one of the earliest signs of a vitamin A deficiency. There are a few different tests that can measure the eye's darkness adaptation response, one of which is more complicated and it's really only used in clinical or experimental conditions because of the precision of the equipment that you would need. The other is called rapid dark adaptation testing and this measures dark adaptation when switching from cone to rod vision. That, remember, should take about under 10 minutes to actually occur. This test is more practical than the former, but it still requires a trained technician to actually give the test, so it's not exactly something that you can do at home.
Speaker 1:There are several other ways to look at vitamin A status, mostly used in experimental settings as of right now, that are beyond the scope of this particular episode. Being vitamin A status in an individual in a way that is widely accessible and practical right now is not perfect and it is an ongoing effort. It does go without saying. But I still need to say that you need to leave it up to your doctor to best determine how it's tested in you, the individual, if you feel that testing or evaluation of vitamin A status is needed.
Speaker 1:Now, moving into requirements, dietary reference intakes for vitamin A are developed by the Food and Nutrition Board of the National Academy of Medicine, and those were last revised for vitamin A in 2001. These guidelines were set for people living in the United States For vitamin A. These come in the form of the estimated average requirement, also called the ear, the recommended dietary allowance, also called the RDA, and the tolerable upper intake limit, also called UL, the upper limit. As most people know it, if you recall from episode one of this podcast where I had outlined and defined terms like this, the ear is defined as the average daily nutrient intake levels estimated to meet the requirements of 50% of healthy individuals in whatever group you're actually looking at. The RDA is defined as the average daily nutrient intake levels estimated to meet the requirements of 97% to 98% of healthy individuals in a group. It's important to be able to recognize and differentiate between these two terms because they mean different things and they're used for different purposes. The ear is usually used to assess the nutrient intake of groups because it represents the average requirement for that particular group, and that is 50% of healthy people in a group. On the other hand, the RDA is used to help individuals like you and I plan their dietary intake, as its purpose is to cover the needs of all healthy individuals in a group.
Speaker 1:The RDA is what we're going to focus on right now, because that's the general daily goal that has been set to ensure that nearly all of the US population is achieving adequate hepatic levels of vitamin A in the body. By hepatic I mean liver stores. This would translate to that serum retinol level of 20 micrograms per deciliter, or 0.7 micro moles per liter, or slightly higher, as I mentioned earlier. Some argue that that level should be set higher, but the consensus is that the current RDA for vitamin A does support normal reproductive function, immune function, vision, gene expression and so on. As I had mentioned earlier, some argue that that level or threshold of vitamin A should be set higher, but the consensus is that the current RDA for vitamin A does support normal reproductive function, immune function, vision, gene expression and so on.
Speaker 1:The RDAs for vitamin A used to be given in international units. You used to see this reflected on a food or supplement label, as I use. However, international units, although still used by some pharmaceutical applications of vitamin A, were determined to not properly reflect the differences in biological activity of preformed vitamin A and pro vitamin A carotenoids. Meaning that storage forms of vitamin A, like retinal pulmitate that you would be getting from animal tissue-based foods and beta-carotene from plant food, would both convert into active retinol, but they would do so at different rates, so they would have different vitamin A activity. As such, food and supplement labeling for vitamin A is no longer only expressed in international units, but is now given as retinal activity equivalents. You'll see that abbreviated as RAE and you will see that reflected on a label as micrograms of RAE. Again, this helps to account for the different biological activity of preformed vitamin A and pro vitamin A from food and supplements. This change on labels was recommended in 2016 by the FDA, but was only fully implemented within the last two years. Here, one microgram of retinal activity equivalents means that you are getting one microgram of retinol, so one microgram of active vitamin A.
Speaker 1:The National Academy of Medicine has set the RDA of vitamin A at the following values. This is the recommended average daily intake for vitamin A. From birth to six months of age, 400 micrograms of retinal activity equivalents are needed for both males and females. For those that are 7 to 12 months of age, 500 micrograms of retinal activity equivalents are needed for both males and females. For those that are 1 to 3 years of age, 300 micrograms of retinal activity equivalents are needed for both males and females. For those who are 4 to 8 years of age, 400 micrograms of retinal activity equivalents are needed for males and females. For people 9 to 13 years of age, 600 micrograms of retinal activity equivalents are needed for males and females. When going above 13 years of age, values change for males and females because of developmental changes and pubertal differences. From 14 to 18 years of age, males require 900 micrograms of retinal activity equivalents. 14 to 18 year old females require 700 micrograms of retinal activity equivalents. Because 14 to 18 year old females are considered to be in age where reproduction is possible, 750 micrograms of RAEs, as we'll call them now, are needed for females in this age range who become pregnant, and 1200 micrograms RAE for the same group as needed if breastfeeding For males who are 19 years onward, 900 micrograms of RAEs are needed. So that remains consistent with the last group. Females 19 years old and up who are pregnant require at least 770 micrograms of RAEs and if breastfeeding require 1300 micrograms of RAEs. And remember that's as an average daily intake.
Speaker 1:Now here is where things get seemingly tricky. But if you are trying to gauge or track how many micrograms of retinal activity equivalents from food or supplements that you're getting, I promise you it's not as tricky once you hear it more than once. And if coming from a supplement, if that supplement is labeled correctly, the conversions should be properly done and laid out for you. One microgram of retinal pulmitate from food or supplements gives you one microgram of retinol, so that's one microgram retinal activity equivalents. However, beta carotene which, remember from the beginning of this episode, is the most abundant food source of Provitamin A, is different. It takes two micrograms of beta carotene, provided in supplement form specifically for the body to convert into one microgram of active retinol, which means that the retinol activity equivalent ratio of beta carotene from a supplement is 2 to 1. Now, when getting into beta carotene from food, it takes 12 micrograms of beta carotene to provide one microgram of active retinol for the body, giving beta carotene from food a retinal activity equivalent ratio of 12 to 1.
Speaker 1:So why is there a difference between supplemental and food-sourced beta carotene? The difference is attributed to a few things, one being the form of beta carotene. Beta carotene comes in two generally different chemical configurations, known as cis and trans configurations. The body seems to more efficiently absorb and convert the trans form of beta carotene to retinal Subtl. Beta carotene tends to have proportionally higher amounts of this type of beta carotene compared to food sources.
Speaker 1:Another factor in potency of supplement-first food beta carotene is the food matrix itself. The presence or lack of other nutrients like fiber, fats etc. Can affect its absorption from food. Also, other carotenoids present in food might actually compete for absorption. Beta carotene might also be encapsulated in plant structures. If taken in from food, that might make it difficult for the body to liberate and absorb. Cooking methods also alter the bioavailability of beta carotene from foods, such that most forms of cooking will result in a higher bioavailability in this case.
Speaker 1:Other relevant pro-vitamin A compounds in food are alpha carotene and beta cryptozanthin. These have less vitamin A activity compared to beta carotene and it's been determined that we would need to take in approximately 24 micrograms of either of these two carotenoids to yield 1 microgram of retinol, giving them a retinol activity equivalent ratio of 24 to 1. So to summarize that 1 microgram of retinol activity equivalence is equal to 1 microgram of retinol, 2 micrograms of supplemental beta carotene, 12 micrograms of dietary beta carotene from food and 24 micrograms of dietary alpha carotene or beta cryptozanthin. Regarding these very specific ratios of retinol activity for the pro-vitamin A carotenoids, it's really important to note that those ratios are not static across individuals or even different kinds of foods. Retinol equivalency ratios reported in humans have ranged from 4 to 28 to 1, so absorption and bioavailability of specific foods change from food to food and individual to individual. For instance, past research has shown that beta carotene from spinach was not as useful for yielding active retinol as beta carotene from carrots, with 21 micrograms of beta carotene needed from the spinach to yield 1 microgram of active retinol, compared to 15 micrograms of beta carotene needed from carrots. Another study showed that pureed spinach decreased the amount of beta carotene needed substantially to 10 micrograms needed to yield 1 microgram of active retinol. The retinol equivalence ratio of sweet potatoes was 13 to 1 in that same study.
Speaker 1:When a carotenoids from food sources. Those are anywhere from 5 to 65% bioavailable, and that means that 5 to 65% of the pro-vitamin A carotenoids you eat will wind up in systemic circulation after first past metabolism. On top of that, conversion rates of carotenoids from food to retinol can be anywhere from 10 to 90%, so that's a very wide range. How much pro-vitamin A converts into retinol depends on the pro-vitamin A compound and the form it's found in the food it's coming from and individuals conversion capacity to retinol and also someone's vitamin A needs, as a higher need for vitamin A would result in better absorption of preformed or pro-vitamin A, along with proportionally more conversion to retinol from pro-vitamin A sources, compared to someone who had adequate stores of vitamin A.
Speaker 1:Beta-carotene and other relevant pro-vitamin A carotenoids can be pretty readily noticed in plant foods because of their orange-red color that they give off. Plant foods with relatively high amounts of vitamin A include pumpkin. Canned pumpkin is a good option. For instance. Sweet potatoes, carrots, cantaloupe and butternut squash are all high in pro-vitamin A carotenoids, although not as high in carotenoids as the foods I just mentioned. Many green vegetables like spinach, broccoli and kale contain relevant amounts of beta carotene, but its orange-red color is overshadowed by the green color of chlorophyll in those plants.
Speaker 1:Now, interestingly enough, a few different studies in lower-income countries did find that the bioavailability of beta carotene and conversion of beta carotene to retinol is actually higher in orange fruits compared to vegetables. This is most likely because in ripe fruits, more beta carotene is situated inside of what are called chromoplasts. This is where a plant produces and stores pigments like beta carotene, and there tends to be proportionally higher amounts of chromoplasts in the fruit part of a plant compared to other parts of the plant when the fruit is ripe. Specifically, beta carotene is thought to be more readily liberated from chromoplasts of a plant matrix compared to chloroplasts where pigments are also found. That liberation is thought to be made easier by the presence of dietary lipids or fats. Like I had mentioned earlier, dietary fat is needed to efficiently absorb beta carotene and other sources of provitamin A. In humans, 3 to 5 grams of fat per meal at a minimum has been given by some as a recommendation. And staying on the topics of fat, some research and animals suggest that a higher intake of omega-3 fatty acids actually results in a higher conversion rate of provitamin A carotenoids to active forms of vitamin A. No telling yet if this is the case in humans as far as I can tell, but it's salient advice that one be sure they get ample dietary omega-3 fatty acids in their diet regardless.
Speaker 1:Now, moving to preformed vitamin A. The best example of preformed vitamin A is retinal palmitate as the principal form in animal tissues and many supplements. Anywhere between 70 to 90% is actually absorbed and stored in healthy individuals who ingest ample dietary fats and oils. Since we are primarily talking about animal food sources, it would make sense that dietary fat is accompanying intake much of the time, as fat content of animal products is also a storage site of vitamin A, because the liver is the primary storage site of vitamin A, again accounting for anywhere from 50 to 90% of whole body vitamin A. So it makes sense that animal liver, especially beef liver, is one of the highest dietary sources of preformed vitamin A, boasting over 6,000 micrograms of vitamin A per every three ounces, and that's about seven times the RDA set for an adult male. Remember from earlier also that cod liver oil has been used for centuries for night blindness because of its vitamin A content. Cod liver oil contains roughly 1,300 micrograms of preformed vitamin A per teaspoon. Adipose tissue and other fats, like milk, fat membranes also store vitamin A. As such, whole milk, whole fat milk or 2% milk are good sources of vitamin A. Vitamin A is usually fortified in 2% milk due to the removal of its content with the fat during processing. One egg yolk also contains around 80 micrograms of vitamin A.
Speaker 1:Regarding supplements, the most frequently used forms of preformed vitamin A are retinal pulmitate and retinal acetate. In practice, the application would determine the use of retinal pulmitate or retinal acetate, but for typical ingestion as a dietary supplement, both are reliable sources of preformed vitamin A. Beta carotene is also a common source of vitamin A in supplements and you will typically find a combination of one of those preformed types of vitamin A and beta carotene in supplements, like a multivitamin, for instance. National Academy of Medicine does not suggest supplementing with beta carotene alone unless specifically to prevent deficiency, and I tend to agree with that sentiment. If it's found in a multivitamin or supplement you're taking for another purpose, that's fine because it can add value in that preparation, especially for ensuring you get enough enough daily vitamin A without getting too much. But I really don't see much reason to purchase a beta carotene standalone supplement. I mean you can. You can easily get enough beta carotene from food. Using vitamin A supplements can be fine and it's good that we choose food sources of vitamin A that provide us with ample amounts of the vitamin, but we still we do still need to be careful with our intake, especially in parts of the world where vitamin A is more abundant or accessible.
Speaker 1:Along with RDAs, the National Academy of Medicine has set tolerable upper intake limits for vitamin A. This is defined as the maximum daily intake unlikely to cause adverse health effects. The upper limit for preformed vitamin A is set at the following values 600 micrograms is the upper limit set for males and females from birth to three years of age. The upper limit set for children for eight years of age is 900 micrograms. 1700 micrograms is the upper limit set for males and females 9 to 13 years of age. 2800 micrograms is the upper limit for males and females 14 to 18 years old. For those 19 years and older, 3000 micrograms is the set upper limit, and that is equivalent to 10,000 international units. These upper limits apply only to preformed vitamin A from animal sources and supplements whose vitamin A comes entirely from retinol or ester forms, like retinol palmitate. At the time of establishing the upper limit, which was 2021, the lowest amount of chronic vitamin A ingestion found by the National Institute of Medicine to cause liver toxicity was actually 14,000 micrograms a day. So by using an uncertainty factor of approximately five, that's how they arrived at the upper limit of 3,000 micrograms a day, just to ensure safety. Since then, research has found slightly lower doses, taken consistently, to be tied to chronic toxicity, as I'll explain shortly.
Speaker 1:Currently, there is no limit set for pro vitamin A carotenoids like beta carotene. Due to the body's tight regulatory control and checks and balance system it has over vitamin A status, your body can tune up and down its rate of conversion of pro vitamin A carotenoids. Therefore, high intakes of fruit and vegetables usually are not going to be a cause of vitamin A toxicity. Of course, there is enzyme activity that can be affected by genes which can be subject to mutations, causing differences between people in their ability to use beta carotene, but I believe going too deep into a topic like that is really outside the scope of this episode.
Speaker 1:Although beta carotene does not have an official upper limit set for its intake, that does not mean that high doses, usually through supplementation, are not contraindicated at times, and I'll touch on that shortly here. Recall that many dietary supplements, such as multivitamins do not provide all of their vitamin A in retinol or its ester forms. Many times beta carotene is included in that. So when checking to see if you are routinely taking in excess vitamin A, you can account for the fact that beta carotene content does not contribute to the tolerable upper intake limit. Notice that I said routine excessive intake, as occasionally or infrequently going above the upper limit, isn't likely to cause harm in most instances. Also, if sick or infected, depending on the illness, your primary medical doctor might instruct you to take vitamin A that exceeds the upper limit for reasons that are warranted under those circumstances.
Speaker 1:If you recall from earlier, when we talked about deficiency, vitamin A repletion protocols used in people in lower income countries far exceed the RDA and upper limit set as American guidelines At times when certain disease manifests. The World Health Organization's protocol for vitamin A repletion can include giving doses as high as 60,000 micrograms, again equating to 200,000 international units of vitamin A. That is, 20 times the upper limit set in the United States. However, that is for very specific purposes in deficient populations, and doses are given once every couple of months, usually, or two consecutive days, and then waiting a few weeks to months for another dose, depending on the severity of the disease. However, that is for very specific purposes in deficient populations, and doses are given once every couple of months or two consecutive days, then waiting a few weeks or months to dose again, depending on the severity of the deficiency.
Speaker 1:Our ability to store so much vitamin A in our liver, as well as adipose tissue as retinal esters, mitigates intoxicating effects of taking in a lot of vitamin A at a single time. As such, vitamin A can be administered in relatively large doses, so long as those doses are infrequent and there is a supervised and established reason behind the large doses. Frequent high intake, especially through supplements or fortified foods, can actually accumulate to the point of causing harm. Acute vitamin A toxicity, which is relatively rare, is referred to as acute hypervitaminosis A. This can occur within days to weeks of ingesting too much preformed vitamin A and is typically associated with high dose exposure over a short period of time, typically over 100 times the RDA. Signs and symptoms include severe headache, blurred vision, nausea, dizziness, aching muscles, ataxia, which is, coordination problems. Basically, severe cases of hypervitaminosis A cause an increase in cerebral spinal fluid pressure, which can lead to coma and possibly be fatal. Chronic hypervitaminosis A is more tied to routine use of vitamin A that is usually more than 10 times the RDA. Usually doing that for up to and over a month can lead to issues in healthy people who have sufficient vitamin A stores. Those symptoms include dry, itchy skin, loss of appetite, weight loss, bone and joint pain and possibly liver damage. Chronic toxicity is more common than acute toxicity because it takes time to get to the point where symptoms manifest and they can sneak up on you if you aren't paying attention to vitamin A intake. That isn't insanely high, but still might be quite high.
Speaker 1:There is evidence that some populations may be more susceptible to toxicity at lower doses, and those populations include the elderly. A few prospective cohort studies and so I mean but as observational studies these were published in the early 2000s suggested that long-term intake of retinol or retinol derivatives not far over the RDA were associated with reduced bone mineral density as well as an increased risk for fracture in older adults. Even a 2014 published meta-analyses of prospective studies looking at people over 40 years old found that people with the highest intake of retinol were at increased risk of hip fracture. However, other studies then came out and showed that this risk only existed in women with high retinol intake, but who also had very low vitamin D intake. Overall, it's not fully known whether high retinol intake is truly causal or contributory to fracture in adults, but, in an abundance of caution, and less instructed by one's medical doctor, older adults should try not to routinely exceed the RDA a preformed vitamin A intake for long periods of time. No increased risk of hip fracture has been observed amongst people with high beta carotene intake in these same studies that I'm mentioning.
Speaker 1:As I had mentioned earlier, it's not only low intake of retinoids that contribute to birth defects. High intakes of retinoids can be tereogenic, which means that they can contribute to developmental abnormalities and fetal malformations. In this case, high intakes of preformed retinoids, but not beta carotene, used during pregnancy increases the risk of malformations to the skull, eyes, lungs and heart of a developing child. This risk is highest during early pregnancy. Experts recommend that people who are or might be pregnant, and even women who are breastfeeding, not take doses of vitamin A of more than 3,000 micrograms of retinol activity equivalents daily, which again is equivalent to 10,000 international units daily. As you will recall, that is the established daily upper limit of vitamin A intake for men and women over the age of 19 years old in the United States, so it's salient advice to follow if pregnant or nursing. No increase in the risk of birth defects has been observed at doses of preformed vitamin A under those levels.
Speaker 1:It's important to also mention here that the use of synthetic retinoids like isotretinoin or tretinoin, which have routinely been used to treat dermatological issues like severe acne, the form is usually given in oral format and the latter is usually given in a topical delivery format. Both are pharmaceutical prepared synthetic derivatives of retinoic acid. As retinoic acid is one of the more biologically active forms of vitamin A, it does come with it more of a toxicity risk, especially at high doses. Treatment with high doses of natural or synthetic retinoids overrides the body's own control mechanisms. Therefore, all dose retinoid therapies, all high dose retinoid therapies, are associated with potential side effects and toxicities. The use of these synthetic retinoids, especially isotretinoin, during pregnancy is known to cause birth defects, so it's usually contraindicated prior to and during pregnancy.
Speaker 1:Beta keratin, again, is not known to be terepigene or to cause any fetal abnormalities. The most common side effect of consuming too much beta keratin results in a generally harmless condition known as hypercarotonidermia. This is when the skin can develop a yellow-orange, jaune disc, like tint, to it due to the excessive intake of the orange pigment, and this can be reversed by simply discontinuing supplementation or lowering beta keratin intake. I think it's important here to segue into a circumstance where high beta keratin intake may cause some harm potentially. I'm referring specifically to lung cancer. I will preface this topic by saying that several systematic reviews and meta-analyses with different observational studies have shown that recommended dietary intake of retinoids and carotenoids from food are generally associated with lower risks of several different types of cancer.
Speaker 1:However, one particular study published in 1996, known as the beta keratin and retinol efficacy trial, which is carrot for short, suggested that high-dose preformed vitamin A and beta keratin should be avoided in people with, or at, or those at risk for, lung cancer. This study looked at 18,000 men and women who are heavy smokers or former heavy smokers, meaning that they were smoking one pack of cigarettes a day for up to 20 years, or two packs a day for 10 years, at least at some point in their life. There were also men in this study who had previous asbestos exposure. Thus they were also at higher risk for lung cancer. Half of the participants were given 7,500 micrograms of retinal activity equivalents from preformed vitamin A in the form of retinal palmitate and 30 milligrams of beta keratin. Together. Mind you, this is well over 13 times the upper limit set for retinal activity equivalents. That happened just a few years later. These supplements were meant to be taken in this study for about six years. However, the trial actually ended prematurely because there was an increased risk in lung cancer by 28% and an increased death from lung cancer by 46% in people taking the supplements.
Speaker 1:A study published two years prior to that gave male smokers 20 milligrams a day a beta keratin, 50 milligrams a day of vitamin E, or both of those together with a placebo. This study went on for five to eight years and, interestingly, the group taking the beta-carotene alone experienced their risk of lung cancer go up by 18%. These two studies raised the flag that large supplemental doses of beta-carotene, with or without preformed vitamin A as retinal palmitate, might have detrimental effects in current or former smokers and also people who had previously been exposed to asbestos. However, future studies, even those using beta-carotene alone in groups of people which lower percentages were smokers or former smokers, did not find similar results as the two earlier studies I just mentioned. Now, a 2003 Cochrane review that was revised in 2012 determined that beta-carotene or retinol supplementation did not increase the risk for lung cancer in those who were not current or former smokers. However, there does exist a small but significant risk of lung cancer in people who are current or former smokers, or who had former exposure to asbestos. Why is this the case? Well, there are a few prevailing theories, but the one that seems the most plausible is this Vitamin A and pro-vitamin A carotenoids are very sensitive to things like oxygen, light and heat.
Speaker 1:The lungs, of course, are rich in oxygen, but it's not oxygen alone here that may be the issue. It is well known that cigarette smoke is highly oxidative, meaning that its presence can aid in the production of compounds that, if they accumulate to a certain extent, can cause damage to cells and create what is essentially a pro-inflammatory environment. Now, a study conducted in 1996, published in the American Journal of Nutrition, showed that beta-carotene in human plasma did not degrade when exposed to air in a room. However, when exposed to cigarette smoke, the beta-carotene in human plasma, despite its location in lipid molecules, was destroyed. Studies conducted in the mid-1980s and mid-1990s show that beta-carotene can exhibit pro-oxygen activity, especially under conditions of high oxygen tension, like would be found in the lungs, but which would also be exacerbated by the presence of cigarette smoke. Therefore, beta-carotene or vitamin A, when given alone in high doses and in the lungs of smokers, can likely be oxidized to a pro-oxygen compound which, if that's the case, would act as a carcinogen and promote a favorable environment for something like lung cancer to develop. That is the leading theory for the time being. This would certainly lead into a larger discussion of nutrient-neutrion interactions in the body and the need for the presence of many compounds that work in complementary ways, especially in different redox reactions, to maintain a balance between pro and anti-inflammatory compounds in the body. But I will save that for an episode dedicated to general antioxidant intake, as I would need time to flesh that out. So, to end this part of the discussion, that was only a brief glance at some of the existing data on vitamin A and cancer risk. Intake of preformed or pro-vitamin A from food is usually associated with reduced cancer rates. However, high dose supplementation of preformed or pro-vitamin A by itself is not advisable in people with, or at risk of having, lung cancer.
Speaker 1:With the time I chose to allot for this particular episode, it was not possible to tackle every angle on vitamin A in a highly nuanced fashion.
Speaker 1:For instance, we only briefly touched on part of the role of vitamin A in immune function. To give every known function of, and accompanying studies on, vitamin A would take hours and hours and hours to go through, so I chose what pieces of information I thought be most salient for the objective of this episode. That objective was to relay the importance of vitamin A in bodily function as well as health and disease. It was also my hope to transfer enough information to you so that you can be informed about your intake and needs of this very special essential vitamin. If you want to learn more about specific nutrients, their functions, protocols for identifying nutrient status, attaining or sustaining nutrient status, then please subscribe to this show wherever it is you are listening. If you are not listening on YouTube, please go and subscribe there so I can continue to build this show and improve it as I go and dedicate more time to it. Thank you for listening and I do hope to see you again here soon.