Why do provitamins-A do not cause Vitamin-A toxicity?

Why do provitamins-A do not cause Vitamin-A toxicity?

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Why do beta-carotene and other provitamins like alpha-carotene not cause vitamin-A toxicity but rather carotenosis (Orange skin) whereas retinal, retinol, and retinoic acid cause vitamin A toxicity with dosage as low as 4000 IU?

Since, you didn't state whether you were referring to a concentrate or not, i'm assuming the following forms of Vitamin A were obtained via pill or topical suspension - except for the Carotenoid.

α-carotene and β-carotene are (primary) precursors to Vitamin A. Likewise with, Retinal, Retinol but not with Retinoic Acid (irreversibly metabolized/end point) however, i'm assuming that these first generation Retinoids are produced via ex situ (a facility) metabolism and hence, they do not contain the carotenoid component that cause yellowing of the skin due to the absence of lipid soluble orange/yellow pigments (Xanthaemia). Albeit, the color of the aforementioned FG retinoids when in a concentrated solid state are all yellow still due to molecular structure - explained in midsection.

For example:
Retinal: Otherwise known as Retinaldehyde, is ingested via meat (as a single/complete molecule) or produced by ingestion of carotenoid containing food-stuff (e.g. carots). The pigment causing the color are, Carotenes. Carotene is a component of the Carotenoid molecule; α-carotene and β-carotene.
Alternatively, Retinal can be produced from the metabolism of β-cryptoxanthin, a Xanthophyll containing compound. Xanthophyll and Carotene are similar in terms of molecular structure, however, a Xanthophyll molecule contains Hydroxyl groups and hence, Oxygen atoms - Carotenes are hydrocarbons.

On that note, hypervitaminosis A can be caused by an over ingestion of α-carotene and β-carotene sources e.g. Carrots, due to the process of metabolism; over an extended period of time.

Retinyl ester <=> Retinol <=> Retinal => Retinoic acid

What causes Xanthemia in this context?

α-carotene and β-carotene, are absorbed via (passive) diffusion within the gastrointestinal tract. From there, they are metabolized (not fully/partially) at the the mucousal layer of the intestine for the substance to be transported into the liver. Next, the metabolite is diffused into the peripheral tissues by the blood plasma. This is were the "issue" is: Excretion. Carotenoids are excreted via bowel movements (gastrointestinal secretions), Urination, through the secretion of sebum and by sweating.

If very high levels of Carotenoids are being ingested, the pigment tends to show itself when a "build up" occurs, in the sweet glands of our dermis and more noticeably, in areas of which there are a large amount of sweat glands e.g. nasolabial folds.

The orange color is defined is due to the classification of what Carotenoids are. All carotenoids are tetraterpenoids: essentially being tetraterpenes that have been modified by chemical transformations such as oxidation or cyclization. Furtherly, tetraterpenoids are made up 40 carbon atoms and contain 8 isoprene molecules. α-carotene and β-carotene, are bicylcic tetraterpenoids. This molecular classification may have an affect on the amount of energy that the molecule can absorb, and more formally, the colour. Albeit, the greatest majority of reasoning in regards to the orange color, is in favor of the long conjugated chain'ed structure of the molecule.

Carotenoids absorb light in the blue-green and violet region and reflect the longer yellow, red, and orange wavelengths; these pigments also dispose excess energy out of the cell.


Retinal and Retinal are preformed retinoids and are not obtained by means of carotenoid metabolism so, they won't contain the the yellow/orange dark pigment that is found within some plant-based food (Carotene).

Retinoic Acid, is a retinoid although it's function is as a cell signalling molecule. The difference between it and the other retinoids is the functional group present of the tail of the carbon-carbon backbone

Theoretically, speaking, and due to retinoids having a shorter/less extended conjugated system with less unsaturated (multiple) bonds in the molecules it will have shifted the absorption to shorter wavelengths (The two carotene precursors have 11 conjugated bonds and the latter retinoids contain 5).

Furtherly, I don't think that the carboxyl group attached to the Retinoic acid molecule could be classed as an Auxochrome although the remainder of the retinoic acids carbon-carbon chain is still the molecules Chromophore - likewise with the other retinoids. For example, this would mean that there is possibility that the retinoic acid molecule will be more inclined to absorb shorter wavelengths and hence, less orange/yellow. This is relevant as, you will often find retinoic acid in topical preparations that are used to treat certain dermatological conditions.

I don't think that there is a 100% correct answer for this question as there is no evidence to prove that it would be true in this particular case.

So, you are susceptible to toxicity at lower levels in regards to retinol, retinal and retinoic acid because, of the fact that they are metabolites/concentrates and you need ingest less in order to get to the same point of toxicity. Carotenoids are "raw" in contrast to the preformed retinoids and require breakdown. Look at the image below to get an idea of how much the molecular mass will have reduced when the carotenoid is metabolized into a useful form of Vitamin A.

Another example would be, you needing to eat more daffodil bulbs to get the required dose of Galantamine hydrobromide (used in Alzheimer's disease treatment) - that's a bit different though, to be fair.

Multivitamins Containing No Vitamin A or E

Vitamins are nutrients that are involved in many essential functions in your body. The National Institutes of Health MedlinePlus reports you need 13 vitamins to grow and develop normally. Taking a daily multivitamin supplement is a way to ensure you are getting the recommended amount of each vitamin. However, overconsuming some vitamins, including vitamin A and vitamin E, may cause toxicity. Consult your health-care provider about multivitamin supplements and whether you need to consume multivitamins without vitamin A or vitamin E.


For decades the ‘natural’ health industry has been touting thousands of vitamin supplements. The truth is that most vitamins in supplements are made or processed with petroleum derivatives or hydrogenated sugars [1-5]. Even though they are often called natural, most non-food vitamins are isolated substances which are crystalline in structure [1]. Vitamins naturally in food are not crystalline and never isolated. Vitamins found in any real food are chemically and structurally different from those commonly found in ‘natural vitamin’ formulas. Since they are different, naturopaths should consider non-food vitamins as vitamin analogues (imitations) and not actually vitamins.

The standards of naturopathy agreed to in 1947 (at the Golden Jubilee Congress) included the statements, “Naturopathy does not make use of synthetic or inorganic vitamins…Naturopathy makes use of the healing properties of…natural foods, organic vitamins” [5]. Even back in the 1940s, professionals interested in natural health recognized the value of food, over non-food, vitamins. Also, it should be mentioned that naturopathic definition of organic back then was similar to the official US government definition today–why does this need to be stated? Because one pseudo-naturopath once told this researcher that a particular brand of synthetic vitamins contained “organic vitamins”, because a sales representative had told him so. Sadly, that sales representative either intentionally gave out false information or gave out misleading information–misleading because by its ‘scientific’ definition, the term ‘organic’ can mean that it is a carbon containing substance, hence by that definition all petroleum derivatives (hydro-carbons) are organic. But false, because those type of vitamins are not organic from the true naturopathic, or even the U.S. government’s, perspective.

Officially, according to mainstream science, “Vitamins are organic substances that are essential in small amounts for the health, growth, reproduction, and maintenance of one or more animal species, which must be included in the diet since they cannot be synthesized at all or in sufficient quantity in the body. Each vitamin performs a specific function hence one cannot replace another. Vitamins originate primarily in plant tissues” [6]. Isolated non-food ‘vitamins’ (often called ‘natural’ or USP or pharmaceutical grade) are not naturally “included in the diet”, do not necessarily “originate primarily in plant tissues”, and cannot fully replace all natural vitamin activities. As a natural health professional, you should be able to read and interpret, even misleading supplement labels. For those who are unsure, hopefully this article will provide sufficient information to determine if vitamin tablets are food or imitations.

What is Your Vitamin Really?

Most vitamins in supplements are petroleum extracts, coal tar derivatives, and chemically processed sugar (plus sometimes industrially processed fish oils), with other acids and industrial chemicals (such as formaldehyde) used to process them [1-5]. Synthetic vitamins were originally developed because they cost less [7]. Assuming the non-food product does not contain fish oils, most synthetic, petroleum-derived, supplements will call their products ‘vegetarian’, not because they are from plants, but because they are not from animals. Most vitamins in vitamin supplements made from food are in foods such as acerola cherries, broccoli, cabbage, carrots, lemons, limes, nutritional yeast, oranges, and rice bran (some companies also use animal products).

Table 1. Composition of Food and Non-Food Vitamins [1-10]

Coal tar derivatives, hydrochloric acid acetonitrole with ammonia

Phytin hydrolyzed with calcium hydroxide and sulfuric acid

* Note: Although some companies use liver extracts as a source for vitamins A and/or D, and at least one company has a herring oil product supplying some vitamin E, no company this researcher is aware of whose products are made out of 100% food use animal products in any of their multiple vitamins. Some companies also use brewer’s yeast which is inferior to nutritional yeast in many ways (including the fact that it has not had the cell wall enzymatically processed to reduce possible sensitivities).

Read The Label to See the Chemical Differences!

Although many doctors have been taught that food and non-food vitamins have the same chemical composition, this is simply untrue for most vitamins. As shown in table 2, the chemical forms of food and synthetic nutrients are normally different. Health professionals need to understand that since there is no mandated definition of the term ‘natural’ just seeing that term on a label does not mean that the supplement contains only natural food substances. One of the best ways to tell whether or not a vitamin supplement contains natural vitamins as found in food is to know the chemical differences between food and non-food vitamins (sometimes called USP vitamins). Because they are not normally in the same chemical form as vitamins found in foods, non-food vitamins should be considered by natural health professionals as vitamin analogues (artificial imitations), and not actually as true vitamins for humans.

Table 2. Chemical Form of Food and Non-Food Vitamins [1-10]

Ascorbic acid most mineral ascorbates (i.e. sodium

Vitamin E acetate Mixed tocopherols all-rac-alpha-tocopherol d-l–alpha-tocopherol d-alpha-tocopherol (isolated) dl-alpha-tocopheryl acetate all acetate forms

Vitamin K3 menadione phytonadione naphthoquinone dihydro-vitamin K1

* Note: This list is not complete and new analogues are being developed all the time. Also the term “(isolated)” means that if the word “food” is not near the name of the substance, it is probably an isolate (normally crystalline in structure) and is not the same as the true vitamin found in food.

Read the label of any supplement to see if the product is truly 100% food. If even one USP vitamin analogue is listed, then the entire product is probably not food (normally it will be less than 5% food). Vitamin analogues are cheap (or not so cheap) imitations of vitamins found in foods.

Beware of any supplement label that says that its vitamins are vegetarian and contain no yeast. This researcher is unaware of any frequently used vegetarian non-yeast way to produce vitamin D or many of the B vitamins, therefore, if a label states that the product “contains no yeast” then in pretty much all cases, this demonstrates that the product is synthetic or contains items so isolated that they should not be considered to be food.

Saccharomyces cerevisiae (the primary yeast used in baking and brewing) is beneficial to humans and can help combat various infections [11], including according to the German E monograph Candida albicans. In the text, Medical Mycology John Rippon (Ph.D., Mycology, University of Chicago) wrote, “There are over 500 known species of yeast, all distinctly different. And although the so-called bad yeasts do exist, the controversy in the natural foods industry regarding yeast related to health problems which is causing many health-conscious people to eliminate all yeast products from their diet is ridiculous. It should also be noted, that W. Crook, M.D., perhaps the nation’s best known expert on Candida albicans, wrote, “yeasty foods don’t encourage candida growth…Eating a yeast-containing food does not make candida organisms multiply” [12]. Some people, however, are allergic to the cell-wall of yeast [12] and concerned supplement companies which have nutrient-containing yeast normally have had the cell-wall enzymatically processed to reduce even this unlikely occurrence.

Food Vitamins are Superior to Non-Food Vitamins

Although many mainstream health professionals believe, “The body cannot tell whether a vitamin in the bloodstream came from an organically grown cantaloupe or from a chemist’s laboratory” [13], this belief is quite misleading for several reasons. First it seems to assume that the process of getting the amount of the vitamin into the bloodstream is the same (which is frequently not the case [3-10]). Secondly, scientists understand that particle size is an important factor in nutrient absorption even though particle size is not detected by chemical assessment. Thirdly, scientists also understand that, “The food factors that influence the absorption of nutrients relate not only to the nature of the nutrients themselves, but also their interaction with each other and with the nonabsorbable components of food” [14]. Fourthly, “the physiochemical form of a nutrient is a major factor in bioavailability” (and food and non-food vitamins are not normally in the same form) [15]. Fifthly, most non-food vitamins are crystalline in structure [1].

Published scientific research has concluded, “natural vitamins are nutritionally superior to synthetic ones” [8].

Food vitamins are in the physiochemical forms which the body recognizes, generally are not crystalline in structure, contain food factors that affect bioavailability, and appear to have smaller particle sizes (see illustrations in table 3). This does not mean that non-food vitamins do not have any value (they clearly do), but it is important to understand that natural food complex vitamins have actually been shown to be better than isolated, non-food, vitamins (see table 4).

Look at Electronic Photos to See the Structural Differences

Electronic photos demonstrate that isolated USP vitamins have a crystalline appearance compared to vitamins in foods which have more of a rounded appearance (see table 3).

Table 3. Physical and Structural Differences

Thiamine Hydrochloride

Electronic Photographs

Even before these types of pictures were available, the late Dr. Royal Lee knew that food vitamin C was superior to ascorbic acid. “Dr. Lee felt it was not honest to use the name ‘vitamin C’ for ascorbic acid. That term ‘should be reserved for the vitamin C COMPLEX’” [16]. Why then, according to the ingredients listed in a recent catalog, would a supplement company that Dr. Lee originally founded currently include ascorbic acid, inorganic mineral salts, and/or other isolated nutrients in the majority of its products? Dr. Lee, like the late Dr. Bernard Jensen [17], was also opposed to the use of other isolated, synthetic, nutrients [16].

Dr Lee specifically wrote, “In fact, the Food & Drug laws seem to be suspended where synthetic imitations of good foods are concerned, and actually perverted to prosecute makers and sellers of real products…The synthetic product is always a simple chemical substance, while the natural is a complex mixture of related and similar materials…Pure natural Vitamin E was found three times as potent as pure synthetic Vitamin E. Of course the poisonous nature of the synthetic Vitamin D…is well established. WHY DO NOT THE PEOPLE AND MEDICAL MEN KNOW THESE FACTS? Is it because the commercial promoters of cheap imitation food and drug products spend enough money to stop the leaking out of information?” [18].

Table 4. Comparison of Certain Biological Effects of Food and Non-Food Vitamins

Food VitaminCompared to USP/’Natural’/Non-Food Vitamins
Vitamin A More complete, as scientists teach that vitamin A is not an isolate [19]
Vitamin B Complex More effective in maintaining good health and liver function [20,21]
Vitamin B-9 More utilizable above 266mcg (Recommended Daily Intake is 400mcg) [22]
Vitamin C Over 15.6 times antioxidant effect [23]
Vitamin D Over 10 times the antirachitic effect [24]
Vitamin E Up to 4.0 times the free radical scavenging strength [25]
Vitamin H Up to 100 times more biotin effect [1]
Vitamin K Safer for children [26]

The difference is more than quantitative.

Let’s take vitamin C for an example. Even if one were to take 3.2 times as much of the so-called natural, non-food, ascorbic acid than food vitamin C, although the antioxidant effects might be similar in vitro, the ascorbic acid still will not contain DHAA [1], nor will it ever have negative oxidative reductive potential (ORP). An in vitro study performed at this researcher’s lab with a digital ORP meter demonstrated that a citrus food vitamin C has negative ORP, but that ascorbic acid had positive ORP [27].

It takes negative ORP to clean up oxidative damage [28], and since ascorbic acid has positive ORP (as well as positive redox potential [1]), it can never replace food vitamin C no matter what the quantity! Furthermore, foods which are high in vitamin C tend to have high Oxygen Radical Absorbance Capacity (ORAC, another test which measures the ability of foods and other compounds to subdue oxygen free radicals [23]). A US government study which compared the in vivo effects of a high vitamin C food (containing 80 mg of vitamin C) compared to about 15.6 times as much isolated ascorbic acid (1250 mg) found that the vitamin C-containing food produced the greatest increase in blood antioxidant levels (it is believed that bioflavonoids and other food factors are responsible) [23].

Furthermore, it is even possible isolated ascorbic acid only has in vitro and no in vivoantioxidant effects: “it has not been possible to show conclusively that higher than anti-scorbic intake of vitamin C has antioxidant clinical benefit” [29]. Why should people take supplemental synthetic ascorbic acid when it is NOT been proven to have antioxidant effects in humans?

“Cross sectional and longitudinal studies show that the occurrence of cardiovascular disease and cancer is inversely related to vitamin C intake…the protective effects seen in these studies are attributable to fruit and vegetable intake…In general, beneficial effects of supplemental vitamin C have been noted in small studies, while large well controlled studies have failed to show benefit” [29]. The other quantitative is that in humans, “Plasma is completely saturated in doses of 400 mg and higher daily producing a steady-state plasma concentration of 80 mM…Tissues, however, saturate before plasma” [29]. De-emphasizing vitamin C containing foods by attempting to consume higher quantities of isolated ascorbic acid simply will not have the effects on plasma vitamin C levels, ORP, ORAC, or other health aspects that many consumers of isolated ascorbic acid hope it will [3,27,29].

No matter how much isolated ascorbic acid one takes orally

  • It will never saturate plasma and/or tissue vitamin C levels significantly more than can be obtained by consuming sufficient vitamin C containing foods.
  • It will never have negative ORP, thus can never ‘clean-up’ oxidative damage like food vitamin C can.
  • It will never have the free radical fighting capacity of food vitamin C.
  • It will never contain DHAA (the other ‘half’ of vitamin C) or the promoting food factors.
  • It will never have the same effect on health issues, such as aging and cardiovascular disease as high vitamin C foods can.
  • It will not ever be utilized the way food vitamin C is.
  • It will always be a synthetic.

Let’s take vitamin E as another example—the body has a specific liver transport for the type of vitamin E found in food [10]—it does not have this for the synthetic vitamin E forms (nor for the ‘new’ vitamin E analogues that are frequently marketed)—thus no amount of synthetic vitamin E can truly equal food vitamin E—the human body actually tries to rid itself of synthetic vitamin E as quickly as possible [30]. As another example, it should be understood that certain forms of vitamin analogues of B-6 [19], D [10], and biotin [1] have been shown to have almost no vitamin activity.

Fractionated, synthetic, vitamins do not replace all the natural function of food vitamins in the body. This is due to the fact that they are normally chemically and structurally different (they also do not have the naturally occurring food factors which are needed by the body) from vitamins found in foods (or vitamin supplements made up entirely of foods).

Food Vitamins and Non-Food Vitamin Analogues

Vitamin A/Betacarotene: Vitamin A naturally exists in foods, but not as a single compound. Vitamin A primarily exists in the form of retinyl esters, and not retinol and beta carotene is always in the presence of mixed carotenoids with chlorophyll [10]. Vitamin A acetate is from methanol, it is a retinol which is crystalline in structure [1]. Vitamin A palmitate can be fish oil [1] or synthetically derived [2] but once isolated it bears little resemblance to food and can be crystalline in structure [1,2]. Synthetic betacarotene is “prepared from condensing aldehyde (from acetone) with acetylene” [2] “not much natural beta-carotene is available due to the high costs of production” [2].

“Beta-carotene has been found to have antioxidant effect in vitro…Whether beta-carotene has significant antioxidant effect in vivo is unclear” [32]. Carrots, a food high in betacarotene, do have high antioxidant ability [32,33]. Natural betacarotene, as found in foods, is composed of both all-trans and 9-cis isomers, while synthetic betacarotene is all-trans isomers [34]. Carrots, yellow and green leafy vegetables, and turmeric contain natural betacarotene along with multiple carotenoids. Natural betacarotene was found to significantly decrease serum conjugated diene levels for children exposed to high levels of irradiation, though it is not known if synthetic betacarotene would provide similar benefits [34].

Regarding isolated betacarotene, “The data presented provide convincing evidence of the harmful properties of this compound if given alone to smokers, or to individuals exposed to environmental carcinogens, as a micronutrient supplement” [35]. “The three beta-carotene intervention trials: the Beta Carotene and Retinol Efficacy Trial (CARET), Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and Physician’s Health Study (PHS) have all pointed to a lack of effect of synthetic beta-carotene in decreasing cardiovascular disease or cancer risk in well-nourished populations. The potential contribution of beta-carotene supplementation to increased risk of lung cancer in smokers has been raised as a significant concern. The safety of synthetic beta-carotene supplements and the role of isomeric forms of beta-carotene (synthetic all-trans versus “natural” cis-trans isomeric mixtures)… have become topics of debate in the scientific and medical communities” [36]. Now, although the consumption of both synthetic betacarotene and food betacarotene raise serum vitamin A levels about the same, this obscures the fact that synthetic betacarotene tends to mainly increase serums all-trans betacarotene, while food betacarotene increases other forms as well [37].

It is possible that synthetic betacarotene can negatively affect vitamin E’s antioxidant ability as a clinical study found, “These results support earlier findings for the protective effect of a-tocopherol against LDL oxidation, and suggest that beta-carotene participates as a prooxidant in the oxidative degradation of LDL under these conditions. Since high levels of alpha-tocopherol did not mitigate the prooxidative effect of beta-carotene, these result indicate that increased LDL beta-carotene may cancel the protective qualities of alpha-tocopherol” [38]. In a consumer-directed publication, Stephen Sinatra (M.D.) observes, “Research has shown that high doses of synthetic beta-carotene—the kind found in many popular brands—may actually increase your risk for lung cancer. Because at high levels it can become prooxidative—exactly the opposite of what you want…I’ve seen harmful effects (such as serious vision loss) in people who have taken up to 80,000 IU of beta-carotene per day. The bottom line is: Less is more when it comes to beta-carotene. To be safe I recommend between 12,500 and 25,000 IU of beta-carotene per day from food sources such as carrots” [39].

In my opinion, betacarotene in carrots, however, is safer than even Dr. Sinatra suggests (there is about 12,000 i.u. of betacarotene in one raw carrot). The reason for this is because betacarotene in carrots is attached to lipoproteins which appear to aid in preventing toxicity. Isolated USP betacarotene, even if it allegedly comes from “natural” sources, simply does not have the attached lipoproteins or other potentially protective substances as found in foods like carrots.

While isolated synthesized vitamin A and polar bear livers have posed toxicity issues, this is simply not considered to be the case of any other food that is supplying vitamin A/beta-carotene [40,41]. Foods containing vitamin A and/or beta carotene are superior [8].

Vitamin B-1, Thiamin: Vitamin B-1 exists in food in the forms of thiamin pyrophosphate, thiamin monophosphate, and thiamin [10]. The non-food thiamin mononitrate is a coal tar derivative [4], never naturally found in the body [10], and is a crystalline isolate [1] (the same is true for thiamin hydrochloride and other chloride forms). Synthetic forms are often used in “food fortification” (where processing removes the naturally occurring thiamin) as they are cheaper and, in that context more stable. However, they are inferior to naturally occurring thiamin forms [8,42]. “The nutritive value of straight-run white flour…has been found to be inferior to that of wholemeal flour, even when the defects of the former in protein, minerals and vitamin B1 have been corrected” [42].

Vitamin B-2, Riboflavin: Naturally exists as riboflavin and various co-enzyme forms in food [10]. In non-foods it is most often synthetically made with 2N acetic acid, is a single form isolate, and is crystalline in structure [1]. Some synthetic riboflavin analogues have weak vitaminic activity [43]. Some natural variations, especially in coenzyme forms, occur in plants (including fungal) species [44]. Various studies suggests that food riboflavin are superior to non-food forms [8,41].

Vitamin ‘B-3’, Niacinamide: Primarily exists in foods in forms other than niacin [10]. “Niacin is a generic term…the two coenzymes that are the metabolically active forms of niacin (are)…nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP)…Only small amounts of free forms of niacin occur in nature. Most of the niacin in food is present as a component of NAD and NADP…nicotinamide is more soluble in water, alcohol, and ether than nicotinic acid…many analogues of niacin have been synthesized, some of which have antivitamin activity ” [10]. Niacinamide (also called nicotinamide) is considered to have less potential side-effects than niacin [10] it also does not seem to cause gastrointestinal upset or hepatotoxicity that the synthetic time-released niacin can cause [45]. Processing losses for this vitamin are mainly due to water leaching [46]. Isolated, non-food, niacinamide is normally from 3-cyanopyridine and can form crystals [1]. This non-food ‘niacin’ is synthesized from acetaldehyde through several chemical reactions often involving formalydehyde and ammonia [2,47]. Beef, legumes, cereal grains, yeast, and fish are significant natural food sources of vitamin B3 [45].

Vitamin ‘B-5’, Pantothenate: Naturally exists in foods as pantothenate [10]. “Pantothenate, usually in the form of CoA, performs multiple roles in cellular metabolism, being central to energy-yielding oxidation of glycolytic products and other metabolites through the mitochondrial tricarboxylic acid cycle…Synthesis of fatty-acids and membrane phospholipids, including regulatory sphingolipids requires pantothenate, and synthesis of the amino acids leucine, arginine, and methionine requires a pantothenate requiring step. CoA is required for synthesis of isoprenoid derivatives, such as cholesterol, steroid hormones, dolichol, vitamin A, vitamin D, and heme A” [10]. “It also appears to be involved in the regulation of gene expression and signal transduction…may have antioxidant and radioprotective properties…It has putative anti-inflammatory, wound healing and antiviral activities…may be helpful in the management of some with rheumatoid arthritis…shown to accelerate wound healing” [32]. “Synthetic D-pantothenate…is available as a calcium or sodium salt” [10], and is sold in forms such as sodium D-pantothenate or calcium D-pantothenate or sometime just listed as pantothenic acid [32]. Other synthetic “multivitamin preparations commonly contain its…alcohol derivative, panthenol” [10]. “Dexopanthenol is a synthetic form which is not found naturally” [32]. USP pantothenic acid is made by condensing isobutyraldehyde with formaldehyde [2]. “Pantothenic acid consists of pantoic acid in amide linkage to beta-alanine”, but vitamin B-5 is not found that way in nature [48]. Vitamin B-5 is found in food as pantothenate forms foods do not naturally contain pantothenic acid [48]. The vegetarian foods which are highest in natural pantothenate are nutritional yeast, brown rice, peanuts, and broccoli [10,32,48]. Specifically, Saccharomyces cerevisiae is one of the best natural sources of food pantothenate [10,32]. Calcium pantothenate is a synthetic enantiomer [10] and is a calcium salt [1] and is crystalline [2].

Vitamin B-6: Plants naturally primarily contain vitamin B6 in forms such as 5’0-(beta-D-glycopyransosyl) and other pyridoxines, not pyridoxal forms [10]. Pyridoxine hydrochloride is not naturally found in the body [10], is a crystalline isolate [1], and is generally made from petroleum and hydrochloric acid and processed with formaldehyde [4]. Pyridoxal-5-phosphate is made by combining phosphorus oxychloride and/or adenosine triphosphate with pyridoxal [1] it becomes a crystalline isolate [1] and bears almost no resemblance to food vitamin B6. At least one synthetic vitamin B-6 analogue has been found to inhibit natural vitamin B-6 action [49]. A study of healthy elderly individuals found about 1/3 had marginal vitamin B-6 deficiency [32].

Vitamin ‘B-9’, Folate: Folate was once known as vitamin B-9, as well as vitamin M. Initially food folate was given for people with a pregnancy-related anemia in the form of autolyzed yeast later a synthetic USP isolate was developed [10]. Pteroylglutamic acid (folic acid), the common pharmacological (USP) form of folate is not found significantly as such in the body [10]. “Folic acid is a synthetic folate form” [50]. Folic acid, such as in most supplements, is not found in food, folates are [15]. Insufficient folate can result in fatigue, depression, confusion, anemia, reduced immune function, loss of intestinal villi, and an increase in infections [11]. Folate deficiency is the most important determinant in high homocysteine levels [11], and supplemental folate is effective in reducing homocysteine [51,52]. “The highest concentrations of folate exist in yeast…and brocolli” [10]. Insufficient folate can result in fatigue, depression, confusion, anemia, reduced immune function, loss of intestinal villi, and an increase in infections [11]. “(C)onsumption of more than 266 mcg of synthetic folic acid (PGA) results in absorption of unreduced PGA, which may interfere with folate metabolism for a period of years” [10]. A 2004 paper from the British Medical Journal confirmed what many natural health professional have known all along: since folic acid is unnatural and the body cannot fully convert large amounts of it into usable folate, this artificial substance can be absorbed and may have unknown negative consequences in the human body [22]–folate supplementation obviously should be in food folate forms and not folic acid.

Vitamin B-12: The naturally active forms are methylcobalamin and deoxyadenosylcobalamin and are found in food [10]. Cyanocobalamin is not a naturally active form [10] it is an isolate which is crystalline in structure [1]. Initially natural food complex vitamin B12 was given for people with pernicious anemia in the form of raw liver, but due to cost considerations a synthetic USP isolate was developed [7]. According to Dr. Victor Herbert (and others) vitamin B-12 when ingested in its human-active form is non-toxic, yet Dr. Herbert (and others) have warned that “the efficacy and safety of the vitamin B12 analogues created by nutrient-nutrient interaction in vitamin-mineral supplements is unknown” [52]. Some synthetic vitamin B12 analogues seem to be antagonistic to vitamin B12 activity in the body [53,54]. Most synthetic B-12 is made through a fermentation process with the addition of cyanide [4].

Vitamin B-x, Vitamin B-8, Vitamin B factors like Choline: PABA was once called vitamin B-x, while inositol was once called vitamin B-8. They and choline are considered to be vitamin B co-factors.

In large doses, PABA is “indicated for Peyronie’s disease, scleroderma, morphea and linear scleroderma” [11]. The non-food version of PABA is made from coal tar [2]. In addition, there is a non-food potassium salt synthetic form, called aminobenzoate potassium [11]. PABA is found in foods such as kidney, liver, molasses, fungal foods, spinach, and whole grains [55].

The non-food version of inositol is made from phytin processed with sulfuric acid [2]. Inositol is a lipotrophic factor, as is also necessary for hair growth. While nutritional yeast is probably the best source of inositol, it is also found in fruits, lecithin, legumes, meats, milk, unrefined molasses, raisins, vegetables, and whole grains [55].

Choline bitartrate and choline chloride, the types most often encountered in allegedly “natural” vitamin supplements, are actually “commercial salts” [11]—they are synthetic forms. Ethylene is involved in the production of one or more of the synthetic forms [2].

Phosphatidyl-choline is the major delivery form of choline, and is naturally found in many foods such as beef liver, egg yolks, and soya [11]. Specially grown nutritional yeast appears to be the best food form for supplements.

Vitamin C: Vitamin C naturally occurs in fruits in two ascorbate forms with bioflavonoids [10]. Non-food, so-called ‘natural’ ascorbic acid is made by fermenting corn sugar into sorbitol, then hydrogenating it until it turns into sorbose, then acetone (commonly referred to as nail polish remover) is added to break the molecular bonds which creates isolated, crystalline, ascorbic acid. It does not contain both vitamin C forms (nor bioflavonoids), thus is too incomplete to properly be called vitamin C [2]. The patented ‘vitamin C’ compounds that are touted as less acidic than ascorbic acid also are not food (it is not possible to get a US patent on naturally occurring vitamins as found in food–anytime a health professional hears that some vitamin is patented, that should set off warning signals that it is not real food). An in vitro study found that food complex vitamin C has negative ORP (oxidative reductive potential) [27], yet the Merck Index shows that so-called ‘natural’ ascorbic acid has positive ORP [1] (negative ORP is much better as it helps ‘clean up’ oxidative damage whereas items with positive ORP do not) [56]. Food complex vitamin C is also 10x less acidic than ascorbic acid.

Some of the many functions that vitamin C is involved in include collagen formation, carnitine biosynthesis, neurotransmitter synthesis, enhancement of iron absorption, immunocompetence, antioxidant defense, possible anticarcenogenic effects, protection of folate and vitamin E from oxidation, and cholesterol catabolism [1].

One study found that food complex vitamin C had 492 micro moles per gram T.E. (Trolox equivalents) of hydrophilic ORAC (oxygen radical absorbance capacity) [57]—ORAC is essentially a measurement of the ability to quench free radicals (antioxidant ability)—while blueberries (one of the highest ORAC sources [23]) only had 195 micro moles per gram T.E. [57]—thus food complex vitamin C has 2.52 times the ORAC ability of blueberries. Vitamin C containing food has over 15.6 times the ORAC of isolated ascorbic acid [23] (food complex vitamin C is even higher). Actually, there are doubts that isolated ascorbic acid has any significant antioxidant effects in humans [29]. Food vitamin C is clearly superior for any interested in ORAC.

Although food vitamin C is superior to isolated ascorbic acid [8], at least one mainstream researcher has written, “The bioavailability of vitamin C in food and ‘natural form’ supplements is not significantly different from that of pure synthetic AA” [10] this is simply not true. As “proof” that particular author cites two papers. The first citation is a study that concludes since serum ascorbic acid levels were at similar levels after various vitamin C containing foods and synthetic ascorbic acid were consumed, that the bioavailability is similar [58]. The conclusions reached seem to ignore that fact that it may be possible that DHAA or other food constituents associated with natural vitamin C may have positive effects other than raising serum ascorbate levels. The second citation is a study that probably should not have been cited as it never compared vitamin C as complexed in food versus synthetic ascorbic acid (it compared synthetic ascorbic acid to Ester-C which is a commercial blend of synthetic ascorbic acid and select metabolites as well as to synthetic ascorbic acid mixed with some bioflavonoids) [59]. Hence, those who claim that there is no difference really do not have strong scientific proof for there contrary opinion.

More recent scientific investigations (cited previously. i.e. 8,23,27,57) have demonstrated that food vitamin C is superior to isolated ascorbic acid.

Vitamin D: The history of synthetic vitamin D is a shocking one. “The first vitamin isolated was a photoproduct from the irradiation of the fungal sterol ergosterol. This vitamin was known as D1…vitamin D obtained from irradiation of ergosterol had little antirachitic activity” [60]–in other words, the first synthetic vitamin D did not act the same as natural vitamin D. “At the time of its identification, it was assumed that the vitamin D made in the skin during exposure to sunlight was vitamin D2”, but it was later learned that human skin produced something called vitamin D3 [60]. It was first believed that provitamin D3 was directly converted to vitamin D3, but that was incorrect. The skin actually contains a substance commonly called provitamin D3 after exposure to sunlight previtamin D3 is produced and it begins to isomerize into vitamin D2 in a process which is temperature dependent, with isomerized vitamin D3 being jettisoned from the plasma membrane into extracellular space. Vitamin D2 was used to fortify milk in the US and Canada for about forty years until it was learned that D3 was the substance which had better antirachitic activity, so D3 has been used for the past twenty-five years [60]. But vitamin D has many benefits which are unrelated to rickets: B and T lymphocytes have been shown to have receptors for vitamin D similar to those found in the intestines, vitamin D seems to affect phagocytosis, and may even have some antiproliferation effect for tumor cells [60]. It has not been proven that any single USP isolated form of vitamin D has all the benefits as natural occurring forms of vitamin D. (Also, since the vitamin D was not particularly stable, manufacturers used to put in 1.5 to 2 times as much of synthetic vitamin D as they claimed on the product labels. This led to neonatal problems and hypercalcemia. [60].) One older report found that “natural vitamin D is about 100 times more potent in protecting chickens and children from rickets than…irradiated ergosterol” [61], USP vitamin D2.

New vitamin D analogues are still being developed: some which may have greater affects on calcium utilization [62], some even may be helpful for breast cancer [63]–but these really may be pharmacological, and not naturopathic, applications since these analogues are not food. In view of the historical errors in the supplementation with forms of vitamin D, it is reasonable to conclude that additional benefits of natural source vitamin D may be discovered, further distinguishing it from synthetic isolates.

Vitamin D is not an isolate, it exists as a combination of substances (including vitamin D3), with promoting metabolites [10]. Non-food vitamin analogues D1, D2, D3, and D4 are isolates without the promoting metabolites. USP D1 does not have appreciable antirachitic effects [10], is crystalline, and is made with benzene [1]. USP D2 is considered a synthetic form and is made by bombarding ergosterol with electrons [1] and is “recovered by solvent extraction” [2]. USP D3 and D4 are both made through irradiating animal fat [1,10,31] or through irradiating “the spinal cords and brains of cattle” [2]. Scientists are even developing a ‘new’ form of vitamin D (which is admitted to be an analogue) which is supposed to be helpful for osteoporosis [64]—natural vitamins cannot be invented! The fact that some drugs are chemically similar to vitamin D as found in foods, does not make them true vitamins. Food vitamin D has been reported to have at least 10 times the antirachitic effects than one or more isolated USP forms [65].

Vitamin E: Natural vitamin E “as found in foods is [d]-alpha tocopherol, whereas chemical synthesis produces a mixture of eight epimers” [66] (natural vitamin E has recently been renamed to be called RRR-alpha-tocopherol whereas the synthetic has now been renamed to all-rac-alpha-tocopherol, though supplement labels rarely make this clear on supplement labels d-alpha-tocopherol is generally ‘natural’, whereas dl-alpha-tocopherol is synthetic [25]). Natural RRR-alpha-tocopherol has 1.7 – 4.0 times the free radical scavenging strength of the other tocopherols, RRR-alpha tocopherol has 3 times the biological activity of the alpha-tocotrienol form, and synthetic vitamin E simply does not have the same biologic activity of natural vitamin E (some synthetic forms have only 2% of the biological activity of RRR-alpha-tocopherol) [25]. The biologic activity of vitamin E is based on its ability to reverse specific vitamin E-deficiency symptoms [25], therefore it is a scientific fact that, overall, synthetic vitamin E has less ability to correct vitamin E deficiencies than food vitamin E. There is an interesting reason for this, which is that the body regulates plasma vitamin E through a specific liver alpha-tocopherol transfer protein, whereas it has no such protein for other vitamin E forms [25]. Or in other words, the liver produces a protein to handle vitamin E found in food, but not for the synthetic forms. The body retains natural vitamin E 2.7 times better than synthetic forms [30].

Even mainstream researchers teach, “Vitamin E is the exception to the paradigm that synthetic and natural vitamins are the equivalent because their molecular structures are identical…Synthetic vitamin E is produced by commercially coupling trimethylhydroquinone (TMHQ) with isophytol. This chemical reaction produces a difficult-to-separate mixture of eight isomers” [67] (vitamin E, of course, is not the only exception–all nutrients are better if they are Food). Isolated natural vitamin E has been found to have twice the bioavailability as synthetic vitamin E [68]. The form of vitamin E found in Foodhas been found to be 2.7 times better retained in the body than a synthetic form [26]—this appears to be because the body attempts to rid itself of synthetic forms as quickly as possible [26]. Food vitamin E, as found in specially grown rice, has been proven to have 12 micro moles per gram T.E. of lipophilic ORAC (oxygen radical absorbance capacity) [57]—ORAC is essentially a measurement of the ability to quench free radicals (antioxidant ability). It is interesting to note that so-called “natural” forms (like succinate) do not even work like Foodvitamin EEven the PDR notes, “d-Alpha-Tocopherol succinate itself has no antioxidant activity” [32], so why would anyone want that for their vitamin E supplement?

Both chemical form and source of vitamin E may play a role as “chemically synthesized alpha-tocopherol is not identical to the naturally occurring form” [25]. Thus those who claim that a synthetic vitamin, even when it is in the same “chemical form” (it is never in the same actual form due to the presence of food constituents), is as good as one in a natural, food form, are simply overlooking the scientific facts about vitamins.

Vitamin E is necessary for the optimal development and maintenance of the nervous system as well as skeletal muscle [67]. Vitamin E deficiency can lead to certain anemias, nutritional muscular dystrophy, reproductive problems, and hyperlipidemia [66]. Vitamin E has been shown to reduce the risk of various cancers, coronary heart disease, cataract formation, and even air pollution [25,67]. It also is believed it may slow the aging process and decrease exercise-induced oxidative stress [25,67]. Artificial fats seem to increase the need for vitamin E [69]. Vitamin E content is highest in vegetable oils, also relatively high in avocados (4.31 i.u. each) [70] and rice bran [71].

Natural vitamin E as found in foods is [d]-alpha tocopherol (also called RRR-alpha tocopherol) and is never found as an isolate [10]. The so-called ‘natural’ forms are most frequently in supplements as isolates, a way they are never found in nature.

Vitamin ‘H’, Biotin: The only active form found in nature is d-(+) biotin and is usually protein bound [10]. Non-food biotin is normally an isolated, synthesized, crystalline form that is not protein bound [1]. Biotin l-sulfoxide is a lessor used isolated and/or non-food form, involves pimelic acid, is an isolate, and has less than 1% of the vitamin H activity of food biotin [1].

Vitamin K: Vitamin K naturally is found in plants as phylloquinone [10]. Non-food vitamin K3 menadione is now recognized as dangerous and is a synthetic naphthoquinone derivative (naphthalene is a coal tar derivative) [1]. USP K1, though also called phylloquinone, is an isolate normally synthesized with p-allylic-nickel [1]. There is another form of vitamin K inadvertently formed during the hydrogenation of oils called dihydro-vitamin K1 [72] however since the consumption of hydrogenated oils appears to be dangerous [73], it does not seem that this form would be indicated for most humans. Dark leafy vegetables, as well as cabbage [74], appear to be the primary food source of vitamin K [75].

Types of Available Vitamins

There are really only two types of vitamins sold: food vitamins and non-food vitamins. Food vitamins will normally state something like “100% Food” on the label. Sometimes the label will also state “No USP nutrients” or “No synthetic nutrients”.

Non-food vitamins, however are somewhat less obvious. First of all, no non-food vitamin this researcher has seen says “100% food” on the label and none of them state ‘No USP or synthetic nutrients”—thus if none of these expressions are present, it is normally safe to conclude that the vitamins are not from food. If a label states that the product contains USP vitamins or ‘pharmaceutical grade’ nutrients, then it should be obvious to all naturopathic practitioners that the product is not food. Also, if a multi-vitamin or a B-complex formula states something to the effect that it “contains no yeast” that is basically a guarantee that it contains synthetic nutrients.

However, just because a company uses the term ‘natural’ or ‘all natural’ as a description of its vitamins does not make them, in fact, natural—this is because the US Government has no definition of natural! Also, just because a company may have a reputation for having natural products, this does not mean its vitamins are not synthetic—carefully check the label for proof that the product is truly 100% food.

Some companies seem to confuse the issue by using the term ‘food-based’ on their supplement labels. ‘Food-based’ vitamins are almost always USP vitamins mixed with a small amount of food. This mixing does not change the chemical form of the vitamin, so it is still a vitamin analogue and not a food vitamin (this differs from food, as true food vitamins are not simple mixture).

Some other companies (that do not use the term ‘food-based’) mix foods with the vitamin analogue and seem to imply that the vitamin is a food. For example, if a label states something like Vitamin C (Vitamin C, acerola) then it is also normally a synthetic mixed with a food. If the product were a food, it would normally state that the vitamin C was in food or from acerola and not use the term ‘vitamin C’ twice in a row on the label (many companies mix ascorbic acid with acerola).

Many companies use the term ‘yeast-free’ on their synthetic vitamin labels, apparently implying that yeast should not be used in vitamins. There are a couple of problems with this. The first is that several non-food isolated vitamins are produced by yeast, before they are industrially processed and isolated, thus it is unlikely that any multiple vitamin formula has not been partially made up of yeast, yeast extracts, or yeast by-products [1,2]. The second problem is that nutritional yeast is not the same as brewer’s yeast, which is essentially a waste by-product.

Most vitamins sold are not food–they are synthetically processed petroleum and/or hydrogenated sugar extracts–even if they say “natural” on the label. They are not in the same chemical form or structural form as real vitamins are in foods thus they are not natural for the human body. True natural food vitamins are superior to synthetic ones [8,16,41]. Food vitamins are functionally superior to non-food vitamins as they tend to be preferentially absorbed and/or retained by the body. Isolated, non-food vitamins, even when not chemically different are only fractionated nutrients.

Studies cited throughout this paper suggest that the bioavailability of food vitamins is better than that of most isolated USP vitamins, that they may have better effects on maintaining aspects of human health beyond traditional vitamin deficiency syndromes, and at least some seem to be preferentially retained by the human body. It is not always clear if these advantages are due to the physiochemical form of the vitamin, with the other food constituents that are naturally found with them, or some combination. Regardless, it seems logical to conclude that for purposes of maintaining normal health, natural vitamins are superior to synthetic ones [8,16,41]. Unlike some synthetic vitamins, no natural vitamin has been found to not perform all of its natural functions.

The truth is that only foods, or supplements composed of 100% foods, can be counted on as not containing non-food vitamin analogues. Natural health advocates are supposed to build health on foods or nutrients contained in foods. That was the standard set for the profession in 1947—that standard—that commitment to real naturopathy should remain for natural health professionals today.


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Anti-Peat Grant Genereux's Theory Of Vitamin A Toxicity

I'm pretty sure Genereaux and Smith are the only ones who will argue that vitamin A is unequivocally bad. Everyone that is still commenting in this thread has settled for the interpretation of a disturbed relationship with vitamin A in developed countries.

Genereaux lists three ways:
1. Accutane, et al
2. More brightly colored plant foods, year round
3. Fortification of non-fat milk and bread products.

Smith has added another:
4. Glyphosate interferes with vitamin A breakdown (and does other stuff like chelate minerals, block glycine)

In 2018 a study was published that looks at how vancomyocin alters vitamin A metabolism in the gut, so:
5. Antibiotics

Adding on to #3, there is also the matter of context. Getting vitamin A in liver, butter, and eggs appears to be not nearly as problematic. The saturated fat is important, but as Smith says in the video I posted, there are other co-factors in those foods that keep RA from getting crazy with the RXR receptors. Dietary guidelines have been moving the population away from butter and eggs for decades, and so for many people their largest intake of vitamin A comes from non-fat milk, bread, and plants -- all of which have no fat to emulsify the A. (Ironically, all of this information comes from Genereaux and Smith, but I'm not sure they can be credited for developing this understanding. They see the world in black and white -- they deny that vitamin A has a proper context -- and that's why it's an addendum here.)

So the question for the rest of us is why does limiting A appear to help some people?

If you want to prove Genereaux and Smith wrong about the essentiality of vitamin A, that's a different deal. I think their case using scientific studies against essentiality is much stronger than a handful of observations in uncontrolled environments. More importantly, a victory will be fruitless. Let's say you prove it's essential. Then what? Just forget about the whole thing? It's short-sighted.

I'd rather deepen our understanding of vitamin A metabolism because it will help us know the proper role of vitamin A and how to troubleshoot more health issues. Arguing about essentiality is not going to accomplish that. Let's move beyond that, just like we moved beyond that in iron management.

Vitamin E

Fat-soluble vitamin E can also threaten your health if you take too much. Normally, vitamin E plays a beneficial role in cardiovascular health by helping to regulate blood clot formation. However, too much vitamin E can excessively thin your blood, increasing the risk of internal bleeding. Taking high doses of vitamin E supplements might increase the risk of death from cardiovascular disease, but the Linus Pauling Institute explains that studies into the risks of vitamin E have yielded conflicting results. To avoid the possibility of side effects, don't consume more than 1,500 IU of vitamin E daily, recommends the Institute of Medicine.

Some B12 Vitamins contain Cyanide

So, since the body can break down cyanocobalamin, what’s the big deal?

The big deal is in order for the conversion to take place, the cyanide bond must be released.

Of course, cyanide is toxic.

Now if you read about Vitamin B17 (laetrile), you’ll find that cyanide is the basis of banning that particular “vitamin”, despite the fact that we eat cyanide-containing foods every day such as broccoli and cauliflower.

This synthetic form of Vitamin B12 has had the cyanide essentially added as a by-product of charcoal filtering. The FDA has deemed the cyanide by-product as “insignificant.”

So apparently, according to the FDA, some cyanide is fine for human ingestion. Well, many of you who know me, know that I don’t buy into anything the FDA says I did a bit of investigating of my own.

Let’s see: Cyanide in foods and in Vitamin B12 are okay, while cyanide in Vitamin B17 is not okay. Why this double standard and is there a difference?

There is a big difference! And it is all about the bonding.

It is well known that cobalamin has a high affinity to cyanide and bonds with it. In fact, a means of counteracting cyanide poisoning is with the use of hydroxocobalamin. However, cobalamin in the case of Vitamin B12, cannot bind to the cyanide molecule because it is already bound.

Though the amounts of cyanide are small and thought to be “harmless” when this is added to the already smalls amounts we are exposed to every day via road salt, automobile exhausts, and even in table salt (used as a stabilizer), adding more cyanide to already elevated levels can potentially be harmful. This is not the case regarding cyanide-containing foods.

Sadly the FDA is banning the wrong substance!

There is an option, to take Vitamin B12 in the form of methylcobalamin, the active form of Vitamin B12, instead.

Methylcobalamin is an active form of cyanocobalamin. It is this form that is necessary for the synthesis of the amino acid, methionine from homocysteine. Methionine is important for the DNA methylation essential for normal human development as well as development or inhibition of carcinogenesis (prevention of cancer.)

Interestingly, Proper functioning DNA methylation is being linked with longevity.

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is a board-certified Chiropractic Physician and Life Coach who also holds a Bachelor of Science degree in Human Biology, and a minor in Medical Research. She is a life-long athlete who after curing herself 100% naturally from MS and anxiety, became an avid nutrition health researcher/promoter.

She has been featured in many Health magazines and has been a guest on radio talk shows in the USA, Canada, United Kingdom, and Australia. She is the author of Health Freedom Revolution: Exposing the Lies, Deceit and Greed of the Medical Profession, Founder of Online Holistic Health, and a contributing writer for other popular informative health website/blogs.

She is the host of Holistic Health Radio – where she discusses how she recovered her health as well as other hot health topics, and she is also co-founder of Crazy Meets Common Sense! – The Podcast that Makes Sense Out of the Crazy, to Help You Live a More Healthy, Fulfilling and Empowering Life!

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Too Much Vitamin C

Taking megadoses of vitamin C is fairly common — especially during cold and flu season. Although vitamin C is a water-soluble vitamin and excess is excreted in urine, very large doses can result in unabsorbed vitamin in the intestinal tract. Possible side effects of this residual vitamin C include headache, along with nausea, diarrhea, stomach cramps and heartburn. The daily recommendation for vitamin C from food and supplements is 75 mg for women and 90 mg for men. Taking more than 2,000 mg per day — the upper tolerable limit — could lead to undesirable effects.

Assessment of Magnesium Status

At present, there is no simple, rapid and accurate laboratory test to indicate the total body magnesium status. The most commonly used method for assessing magnesium status is the serum magnesium concentration. Other methods available for assessing magnesium status are listed in Table 4 .

Table 4

Tests used in assessing magnesium status

Serum Magnesium Concentration
 Total magnesium
 Ultrafiltrable magnesium
 Ionised magnesium
Intracellular Magnesium content
 Red cells
 Mononuclear blood cells
 Skeletal muscle
Physiological tests
 Metabolic balance studies
� h urinary excretion of magnesium
 Magnesium loading test
Intracellular free magnesium ion concentration
𠀿luorescent dye
 Nuclear magnetic resonance spectroscopy
 Magnesium balance
 Isotope studies
 Hair or tooth magnesium
𠀿unctional assays

Serum total magnesium can be measured by a variety of techniques. 4 , 17 Serum is preferable to plasma as the anticoagulant could be contaminated with magnesium or affect the assay. For instance, citrate binds not only calcium but also magnesium and affects fluorometric and colorimetric procedures. Haemolysis, bilirubin, lipaemia, high phosphate concentration and delay in separating serum can affect the measurement. 18 In adults serum magnesium concentration is not influenced by sex or age except in the very elderly where it may be slightly higher. 18 Serum magnesium concentration increases after a short period of maximal exercise but decreases after endurance exercises. 18 It is lower during the third trimester of pregnancy and is higher in subjects on a vegetarian diet. 18 , 19 Intra-individual variation in serum magnesium ranges between 3.4% and 4.7%. 20

The total serum magnesium concentration is not the best method to evaluate magnesium status as changes in serum protein concentrations may affect the total concentration without necessarily affecting the ionised fraction or total body magnesium status. The correlation between serum total magnesium and total body magnesium status is poor. 4 , 21

Measurement of ultrafiltrable magnesium may be more meaningful than the total magnesium as it is likely to reflect ionised magnesium concentration, but methods are not available for routine use.

In the last few years, ion selective electrodes for magnesium have been developed and several commercial analysers are now available for the measurement of ionised magnesium concentration. 3 , 4 Measurement of ionised magnesium has been found to be useful in several clinical situations. 3 , 4 However, results from different instruments do not agree as the electrodes are not entirely selective for ionised magnesium concentration and a correction is applied based on the ionised calcium concentration. 4

Red cell magnesium concentration can be determined easily but does not seem to correlate well with total body magnesium status or with other measures of magnesium status. 22 The magnesium content of mononuclear cells may be a better predictor of skeletal and cardiac muscle magnesium content. However, this method is technically more difficult and intraindividual variation is high at about 12�%. 23 As muscle contains nearly 30% of the total body magnesium it is an appropriate tissue for the assessment of magnesium status and studies in patients undergoing heart surgery showed that skeletal muscle magnesium was a better predictor of heart magnesium than lymphocyte or serum magnesium concentration. 24 However, this is an invasive and expensive procedure requiring special expertise.

In the steady state, a 24-hour urine excretion of magnesium reflects intestinal absorption and is also of value in determining whether magnesium wasting is occurring by the renal route. In the presence of hypomagnesaemia, magnesium excretion > 1 mmol/day is suggestive of renal magnesium wasting. On the other hand, magnesium excretion < 0.5 mmol/day is suggestive of magnesium deficiency. 10

The magnesium tolerance test has been used for many years and it appears to be an accurate means of assessing magnesium status. In this test, the percentage of magnesium retained after parenteral administration of magnesium is determined. The percentage of magnesium retained is increased in magnesium deficiency and is inversely correlated with the concentration of magnesium in bone. 25 In a study of 23 healthy subjects, 13 hypomagnesaemic patients and 24 normomagnesaemic patients at high risk of magnesium deficiency, the percentage retention was 14ଔ% (mean ± SEM) in normals, 85ଓ% in hypomagnesaemic patients and 51କ% in patients at risk of developing magnesium deficiency. These data suggest that this test is a very sensitive method to detect magnesium deficiency. 9 , 11 The test, however, depends on normal renal function and is of limited value in patients with renal magnesium loss.

Intracellular free magnesium concentration can be determined using fluorescent probes such as fura-2 or by nuclear magnetic resonance (NMR). 4 Magnesium balance studies and studies using isotopes of magnesium are mainly used in research. Hair and tooth have also been used to assess magnesium status. Activation of enzymes such as creatine kinase and alkaline phosphatase by magnesium has also been examined as a measure of magnesium status. In experimental studies, however, it was not shown to be as good as serum or red cell magnesium concentration. 26

In summary, no single method is satisfactory to assess magnesium status. The simplest, most useful and readily available tests are the measurement of serum total magnesium and the magnesium tolerance test. 3 , 4 Ionised magnesium measurement may become more readily available with the development of reliable analysers.

Heart defects and Alagille syndrome

Approximately 90 percent of children with Alagille syndrome have a heart defect at birth. The severity of the heart defect can range from a simple murmur causing no problems to a major structural heart defect. Most Alagille-related heart defects involve the pulmonary arteries, which carry blood from the right side of the heart to the lungs. The most common defect is peripheral pulmonary stenosis. Other potential structural cardiac defects include:

  • Tetralogy of Fallot (12 percent of cases)
  • Ventricular septal defects (VSD)
  • Atrial septal defects (ASD)
  • Aortic stenosis
  • Coarctation of the aorta

The more severe congenital heart defects may require treatment, including surgical intervention. If your child has Alagille-associated heart problems, his or her doctor will talk with you about treatment options.


The classic symptoms of pellagra are diarrhea, dermatitis, dementia, and death ("the four Ds"). [4] A more comprehensive list of symptoms includes:

J. Frostig and Tom Spies —according to Cleary and Cleary [5] described more specific psychological symptoms of pellagra as:

  • Psychosensory disturbances (impressions as being painful, annoying bright lights, odors intolerance causing nausea and vomiting, dizziness after sudden movements),
  • Psychomotor disturbances (restlessness, tense and a desire to quarrel, increased preparedness for motor action), as well as
  • Emotional disturbances [5][6]

Independently of clinical symptoms, blood level of tryptophan or urinary metabolites such as 2-pyridone/N-methylniacinamide ratio <2 or NAD/NADP ratio in red blood cells can diagnose pellagra. The diagnosis is confirmed by rapid improvements in symptoms after doses of niacin (250–500 mg/day) or niacin enriched food. [7]

Pellagra can develop according to several mechanisms, classically as a result of niacin (vitamin B3) deficiency, which results in decreased nicotinamide adenine dinucleotide (NAD). Since NAD and its phosphorylated NADP form are cofactors required in many body processes, the pathological impact of pellagra is broad and results in death if not treated.

The first mechanism is simple dietary lack of niacin. Second, it may result from deficiency of tryptophan, [3] an essential amino acid found in meat, poultry, fish, eggs, and peanuts [8] that the body uses to make niacin. Third, it may be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of niacin or nicotinic acid to nicotinamide mononucleotide (NMN) causing pellagra like symptoms to occur. [9]

Some conditions can prevent the absorption of dietary niacin or tryptophan and lead to pellagra. Inflammation of the jejunum or ileum can prevent nutrient absorption, leading to pellagra, and this can in turn be caused by Crohn's disease. [10] Gastroenterostomy can also cause pellagra. [10] Chronic alcoholism can also cause poor absorption which combines with a diet already low in niacin and tryptophan to produce pellagra. [10] Hartnup disease is a genetic disorder that reduces tryptophan absorption, leading to pellagra.

Alterations in protein metabolism may also produce pellagra-like symptoms. An example is carcinoid syndrome, a disease in which neuroendocrine tumors along the GI tract use tryptophan as the source for serotonin production, which limits the available tryptophan for niacin synthesis. In normal patients, only one percent of dietary tryptophan is converted to serotonin however, in patients with carcinoid syndrome, this value may increase to 70%. Carcinoid syndrome thus may produce niacin deficiency and clinical manifestations of pellagra. Anti-tuberculosis medication tends to bind to vitamin B6 and reduce niacin synthesis, since B6 (pyridoxine) is a required cofactor in the tryptophan-to-niacin reaction.

Several therapeutic drugs can provoke pellagra. These include the antibiotics isoniazid, which decreases available B6 by binding to it and making it inactive, so it cannot be used in niacin synthesis, [11] and chloramphenicol the anti-cancer agent fluorouracil and the immunosuppressant mercaptopurine. [10]

If untreated, pellagra can kill within four or five years. [3] Treatment is with nicotinamide, which has the same vitamin function as niacin and a similar chemical structure, but has lower toxicity. The frequency and amount of nicotinamide administered depends on the degree to which the condition has progressed. [12]

Pellagra can be common in people who obtain most of their food energy from corn, notably rural South America, where maize is a staple food. If maize is not nixtamalized, it is a poor source of tryptophan, as well as niacin. Nixtamalization corrects the niacin deficiency, and is a common practice in Native American cultures that grow corn, but most especially in Mexico and the countries of Central America. Following the corn cycle, the symptoms usually appear during spring, increase in the summer due to greater sun exposure, and return the following spring. Indeed, pellagra was once endemic in the poorer states of the U.S. South, such as Mississippi and Alabama, where its cyclical appearance in the spring after meat-heavy winter diets led to it being known as "spring sickness" (particularly when it appeared among more vulnerable children), as well as among the residents of jails and orphanages as studied by Dr. Joseph Goldberger. [13]

Pellagra is common in Africa, Indonesia, and China. In affluent societies, a majority of patients with clinical pellagra are poor, homeless, alcohol-dependent, or psychiatric patients who refuse food. [14] Pellagra was common among prisoners of Soviet labor camps (the Gulag). In addition, pellagra, as a micronutrient deficiency disease, frequently affects populations of refugees and other displaced people due to their unique, long-term residential circumstances and dependence on food aid. Refugees typically rely on limited sources of niacin provided to them, such as groundnuts the instability in the nutritional content and distribution of food aid can be the cause of pellagra in displaced populations. In the 2000s, there were outbreaks in countries such as Angola, Zimbabwe and Nepal. [15] [16] [17] In Angola specifically, recent reports show a similar incidence of pellagra since 2002 with clinical pellagra in 0.3% of women and 0.2% of children and niacin deficiency in 29.4% of women and 6% of children related to high untreated corn consumption. [17]

In other countries such as the Netherlands and Denmark, even with sufficient intake of niacin, cases have been reported. In this case deficiency might happen not just because of poverty or malnutrition but secondary to alcoholism, drug interaction (psychotropic, cytostatic, tuberculostatic or analgesics), HIV, vitamin B2 and B6 deficiency, or malabsorption syndromes such as Hartnup disease and carcinoid. [17] [18] [19] [20] [21]

Native American cultivators who first domesticated corn (maize) prepared it by nixtamalization, in which the grain is treated with a solution of alkali such as lime. Nixtamalization makes the niacin nutritionally available and prevents pellagra. [22] When maize was cultivated worldwide, and eaten as a staple without nixtamalization, pellagra became common.

Pellagra was first described for its dermatological effect in Spain in 1735 by Gaspar Casal. He explained that the disease causes dermatitis in exposed skin areas such as hands, feet and neck and that the origin of the disease is poor diet and atmospheric influences. [23] His work published in 1762 by his friend Juan Sevillano was titled 'Historia Natural y Medicina del Principado de Asturias' or Natural and Medical History of the Principality of Asturias (1762). This led to the disease being known as "Asturian leprosy", and it is recognized as the first modern pathological description of a syndrome. [24] It was an endemic disease in northern Italy, where it was named, from Lombard, as "pell agra" (agra = holly-like or serum-like pell = skin) [25] by Francesco Frapolli of Milan. [26] With pellagra affecting over 100,000 people in Italy by the 1880s, debates raged as to how to classify the disease (as a form of scurvy, elephantiasis or as something new), and over its causation. In the 19th century Roussel started a campaign in France to restrict consumption of maize and eradicated the disease in France, but it remained endemic in many rural areas of Europe. [27] Because pellagra outbreaks occurred in regions where maize was a dominant food crop, the most convincing hypothesis during the late nineteenth century, as espoused by Cesare Lombroso, was that the maize either carried a toxic substance or was a carrier of disease. [28] Louis Sambon, an Anglo-Italian doctor working at the London School of Tropical Medicine, was convinced that pellagra was carried by an insect, along the lines of malaria. Later, the lack of pellagra outbreaks in Mesoamerica, where maize is a major food crop, led researchers to investigate processing techniques in that region.

Pellagra was studied mostly in Europe until the late 19th century when it became an epidemic especially in the southern United States. [29] [30] In the early 1900s, pellagra reached epidemic proportions in the American South. [30] Between 1906 and 1940 more than 3 million Americans were affected by pellagra with more than 100,000 deaths, yet the epidemic resolved itself right after dietary niacin fortification. [31] Pellagra deaths in South Carolina numbered 1,306 during the first ten months of 1915 100,000 Southerners were affected in 1916. At this time, the scientific community held that pellagra was probably caused by a germ or some unknown toxin in corn. [31] The Spartanburg Pellagra Hospital in Spartanburg, South Carolina, was the nation's first facility dedicated to discovering the cause of pellagra. It was established in 1914 with a special congressional appropriation to the U.S. Public Health Service (PHS) and set up primarily for research. In 1915, Joseph Goldberger, assigned to study pellagra by the Surgeon General of the United States, showed it was linked to diet by observing the outbreaks of pellagra in orphanages and mental hospitals. Goldberger noted that children between the ages of 6 and 12 (but not older or younger children at the orphanages) and patients at the mental hospitals (but not doctors or nurses) were the ones who seemed most susceptible to pellagra. [32] Goldberger theorized that a lack of meat, milk, eggs, and legumes made those particular populations susceptible to pellagra. By modifying the diet served in these institutions with "a marked increase in the fresh animal and the leguminous protein foods," Goldberger was able to show that pellagra could be prevented. [32] By 1926, Goldberger established that a diet that included these foods, or a small amount of brewer's yeast, [33] prevented pellagra.

Goldberger experimented on 11 prisoners (one was dismissed because of prostatitis). Before the experiment, the prisoners were eating the prison fare fed to all inmates at Rankin Prison Farm in Mississippi. [34] Goldberger started feeding them a restricted diet of grits, syrup, mush, biscuits, cabbage, sweet potatoes, rice, collards, and coffee with sugar (no milk). Healthy white male volunteers were selected as the typical skin lesions were easier to see in Caucasians and this population was felt to be those least susceptible to the disease, and thus provide the strongest evidence that the disease was caused by a nutritional deficiency. Subjects experienced mild, but typical cognitive and gastrointestinal symptoms, and within five months of this cereal-based diet, 6 of the 11 subjects broke out in the skin lesions that are necessary for a definitive diagnosis of pellagra. The lesions appeared first on the scrotum. [35] Goldberger was not given the opportunity to experimentally reverse the effects of diet-induced pellagra as the prisoners were released shortly after the diagnoses of pellagra were confirmed. [34] In the 1920s he connected pellagra to the corn-based diets of rural areas rather than infection as contemporary medical opinion would suggest. [36] [37] Goldberger believed that the root cause of pellagra amongst Southern farmers was limited diet resulting from poverty, and that social and land reform would cure epidemic pellagra. His reform efforts were not realized, but crop diversification in the Southern United States, and the accompanying improvement in diet, dramatically reduced the risk of pellagra. [38] Goldberger is remembered as the "unsung hero of American clinical epidemiology". [39] Though he identified that a missing nutritional element was responsible for pellagra, he did not discover the specific vitamin responsible.

In 1937, Conrad Elvehjem, a biochemistry professor at the University of Wisconsin-Madison, showed that the vitamin niacin cured pellagra (manifested as black tongue) in dogs. Later studies by Dr. Tom Spies, Marion Blankenhorn, and Clark Cooper established that niacin also cured pellagra in humans, for which Time Magazine dubbed them its 1938 Men of the Year in comprehensive science. [40]

Research conducted between 1900 and 1950 found the number of cases of women with pellagra was consistently double the number of cases of afflicted men. [41] This is thought to be due to the inhibitory effect of estrogen on the conversion of the amino acid tryptophan to niacin. [42] Some researchers of the time gave a few explanations regarding the difference. [43]

Gillman and Gillman related skeletal tissue and pellagra in their research in South African Blacks. They provide some of the best evidence for skeletal manifestations of pellagra and the reaction of bone in malnutrition. They claimed radiological studies of adult pellagrins demonstrated marked osteoporosis. A negative mineral balance in pellagrins was noted, which indicated active mobilization and excretion of endogenous mineral substances, and undoubtedly impacted the turnover of bone. Extensive dental caries were present in over half of pellagra patients. In most cases, caries were associated with "severe gingival retraction, sepsis, exposure of cementum, and loosening of teeth". [44]

Etymology Edit

The word pellagra is likely a coined scientific term based on Latin pellis ("skin") and the Greek suffix -agra, "seized by", as in podagra.

Alternatively, pellagra may be an Italian or, more precisely, Lombard coinage.

United States Edit

Pellagra was first reported in 1902 in the United States, and has "caused more deaths than any other nutrition-related disease in American history", reaching epidemic proportions in the American South during the early 1900s. [30] Poverty and consumption of corn were the most frequently observed risk factors, but the exact cause was not known, until groundbreaking work by Joseph Goldberger. [45] A 2017 National Bureau of Economic Research paper explored the role of cotton production in the emergence of disease one prominent theory is that "widespread cotton production displaced local production of niacin-rich foods and driven poor Southern farmers and mill workers to consume milled Midwestern corn, which was relatively cheap but also devoid of the niacin necessary to prevent pellagra." [30] The study provided evidence in favor of the theory: there were lower pellagra rates in areas where farmers had been forced to abandon cotton production (a highly profitable crop) in favor of food crops (less profitable crops) due to boll weevil infestation of cotton crops (which occurred randomly). [30]

The whole dried corn kernel contains a nutritious germ and a thin seed coat that provides some fiber. [46] There are two important considerations for using ground whole-grain corn.

  1. The germ contains oil that is exposed by grinding, thus whole-grain cornmeal and grits turn rancid quickly at room temperature and should be refrigerated.
  2. Whole-grain cornmeal and grits require extended cooking times as seen in the following cooking directions for whole-grain grits

"Place the grits in a pan and cover them with water. Allow the grits to settle a full minute, tilt the pan, and skim off and discard the chaff and hulls with a fine tea strainer. Cook the grits for 50 minutes if the grits were soaked overnight or else 90 minutes if not." [47]

Most of the niacin in mature cereal grains is present as niacytin, which is niacin bound up in a complex with hemicellulose which is nutritionally unavailable. In mature corn this may be up to 90% of the total niacin content. [48] The preparation method of nixtamalization using the whole dried corn kernel made this niacin nutritionally available and reduced the chance of developing pellagra. Niacytin is concentrated in the aleurone and germ layers which are removed by milling. The milling and degerming of corn in the preparation of cornmeal became feasible with the development of the Beall degerminator which was originally patented in 1901 and was used to separate the grit from the germ in corn processing. [49] However this process of degermination reduces the niacin content of the cornmeal.

Casimir Funk, who helped elucidate the role of thiamin in the etiology of beriberi, was an early investigator of the problem of pellagra. Funk suggested that a change in the method of milling corn was responsible for the outbreak of pellagra, [50] but no attention was paid to his article on this subject. [51]

Pellagra developed especially among the vulnerable populations in institutions such as orphanages and prisons, because of the monotonous and restricted diet. Soon pellagra began to occur in epidemic proportions in states south of the Potomac and Ohio rivers. The pellagra epidemic lasted for nearly four decades beginning in 1906. [51] It was estimated that there were 3 million cases, and 100,000 deaths due to pellagra during the epidemic. [45]