The Vitamin D Newsletter December 2008
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Vitamin A Toxicity
Dr. Cannell: I am angry that you sent the paper written by sixteen prominent nutrition experts warning about the dangers of cod liver oil and vitamin A without providing a way for me to read the entire paper for free. Medical papers should be open access, not pay-per-view. Carole, New York
What you mean is, why didn't the Vitamin D Council pay to publish in an open access journal so you would not have to pay to read it? Because we don't have enough money in our account, that's why.
We published a paper on influenza in an open access journal earlier this year but it cost the Vitamin D Council $1,800.00! Open access is not free; someone pays, if not you, then we do. However, it's nice to be able to read the entire paper for free—the goal many of us have for all scientific papers.
Our second influenza paper is free and is relevant to the coming cold and flu season. It has an unbelievable quote from a 1919 Public Health Service physician who was trying to prove how influenza was transmitted, using volunteers from the Navy. Remember, 300,000 Americans had just died from influenza. Would you volunteer like they did? Why didn't any of the volunteers get sick? Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J. 2008 Feb 25;5:29.
In fact, the Vitamin D Council's second influenza paper is the most downloaded paper in the last 12 months, as well as in the past 30 days, in Virology Journal, although it has only been out only 9 months.
It seems as if someone, somewhere, is rethinking the idea that vaccinating everyone for everything may not be the best approach. The number of vaccines pointing at our children continue to increase, virtually every year.
Others have also written to ask why they can't read the abstract of the vitamin A toxicity paper. Editorials seldom have abstracts. Here is a link to the publisher where you will find the full citation of our paper: Cod Liver Oil, Vitamin A Toxicity, Frequent Respiratory Infections, and the Vitamin D Deficiency Epidemic—unfortunately, the publisher will charge you $20.00 to view the full paper. However, before you pay, read the excerpts below (in italics).
Proper Vitamin D–Vitamin A Ratio
Dr. Cannell: Can you quote from the paper, telling us why so many experts condemned cod liver oil? Robert, California
I don't know if copyright laws allow the author to do that, but I will take the chance. The crux of the problem is that a form of vitamin A, retinoic acid, weakly activates the vitamin D response element on the gene and perhaps blocks vitamin D's more robust activation. In fact, the authors of a 1993 study state "there is a profound inhibition of vitamin D-activated...gene expression by retinoic acid." MacDonald PN, et al. Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene. Mol Cell Biol. 1993 Sep;13(9):5907–17. Thompson PD, et al. Heterodimeric DNA binding by the vitamin D receptor and retinoid X receptors is enhanced by 1,25-dihydroxyvitamin D3 and inhibited by 9-cis-retinoic acid. Evidence for allosteric receptor interactions. J Biol Chem. 1998 Apr 3;273(14):8483–91.
The key is having the proper ratio of vitamin D to vitamin A in your body. To obtain this proper D/A ratio, you must make a choice. (1) Either obtain the D/A ratio Nature intended—that is, the ratio the human genome evolved on—or (2) assume one knows better and intervene in a closed system, bypass the controls in the intestine, and inject active A directly into your blood by taking vitamin A or cod liver oil. Vitamin A production is tightly controlled in the body, the source (substrate) being carotenoids from vegetables in your intestine. The body uses these carotenoid substrates to make exactly the right amount of retinol for your body. That is, it is a closed, tightly regulated, system, one designed to perfection by Nature. When you take vitamin A as retinol, such as in cod liver oil, you intervene in this closed system and bypass the controls. Proceed at your peril.
Vitamin D is also a closed, controlled system and I don't recommend intervening in that system either. Vitamin D cholecalciferol is a substrate like carotenoids, it is not the active substance. Taking vitamin A as retinol is like taking activated vitamin D (calcitriol). Doing so bypasses controls and I have never recommended anyone take activated vitamin D except patients with renal failure under the care of a nephrologist. As long as your vitamin D (cholecalciferol) dose is not excessive, you are not intervening in a closed system, you are simply providing the vitamin D substrate. The body, if and when it has enough vitamin D substrate, will use what it needs and dispose of, or store, the rest.
Thus the goal is to provide all the vitamin A and vitamin D substrate the body would have obtained in a natural state, so the body can regulate both systems naturally. This is best done by eating colorful vegetables and by exposing your naked skin to equatorial sun every day. Since most of us can't do the later, and won't do the former, we have to take the same amount of vitamin D substrate we would have obtained living 100,000 years ago—and may want to take beta-carotene substrate in a multivitamin. As far as I know, low doses of beta-carotene (1,000–2,000 IU per day) will not do too much harm. The best way to get vitamin D substrate, as far as I can tell, is to take at least 5,000 IU of vitamin D3 per day in the winter and stop all vitamin D in the summer and sunbathe. Alternatively, use a tanning bed when the sun is too low on the horizon to sunbathe. Remember, when you are outside, if your shadow is longer than you are, you are not making any vitamin D.
Excerpts from our paper
The italicized passages below are from our paper and are the heart of the reasoning used to issue the warning about vitamin A and cod liver oil. They are the advice of the 16 experts who co-authored the paper with me, not just mine alone:
"Although activated vitamin D and vitamin A signal through common cofactors, they compete for each others function. Retinoic acid antagonizes the action of vitamin D and its active metabolite. In humans, even the vitamin A in a single serving of liver impairs vitamin D's rapid intestinal calcium response. In a dietary intake study, Oh, et al, found that a high retinol intake completely thwarted vitamin D's otherwise protective effect on distal colorectal adenoma, and they found a clear relationship between vitamin D and vitamin A intakes, as the women in the highest quintile of vitamin D intake also ingested around 10,000 IU/d of retinol." Rohde CM, Deluca HF. All-trans retinoic acid antagonizes the action of calciferol and its active metabolite, 1,25-dihydroxycholecalciferol, in rats. J Nutr. 2005;135(7):1647–1652. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001;16(10):1899–1905. Oh K, Willett WC, Wu K, Fuchs CS, Giovannucci EL. Calcium and vitamin D intakes in relation to risk of distal colorectal adenoma in women. Am J Epidemiol. 2007;165(10):1178–1186.
"Furthermore, the consumption of preformed retinol even in amounts consumed by many Americans in both multivitamins and cod liver oil may cause bone toxicity in individuals with inadequate vitamin D status. Women in the highest quintile of total vitamin A intake have a 1.5-times elevated risk of hip fracture." Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47–54.
"Indeed, a recent Cochrane Review found that vitamin A supplements increased total mortality rate by 16%, perhaps through antagonism of vitamin D." Bjelakovic G, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2008 Apr 16;(2):CD007176.
"Another recent Cochrane meta-analysis concluded that although vitamin A significantly reduced the incidence of acute lower respiratory tract infections in children with low intake of retinol, as occurs in the Third World, it appears to increase the risk and/or worsen the clinical course in children in developed countries." Chen H, Zhuo Q, Yuan W, Wang J, Wu T. Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age. Cochrane Database Syst Rev 2008.
"As early as 1933, Alfred Hess, who discovered that sunlight both prevented and cured rickets Hess A. The Prevention and Cure of Rickets By Sunlight. [PDF download] American Journal of Public Health, 1921. warned about vitamin A consumption, concluding, ...as to a requirement of thousands of units of vitamin A daily, the unquestionable answer is that this constitutes therapeutic absurdity, which, happily, will prove to be only a passing fad (p 662)." Hess AF, Lewis JM, Barenberg LH. Does our dietary require vitamin A supplement? JAMA. 1933;101:657–663.
"Unfortunately, Hess's prophecy of a passing fad proved premature and Americans continue consuming multivitamins and/or cod liver oil containing small amounts of vitamin D but undesirable quantities of vitamin A. For example, multivitamins, until recently, had small amounts of vitamin D (200 to 400 IU) but high amounts of preformed retinol (5,000 to 10,000 IU). This pales in comparison to a tablespoon of modern cod liver oil, most of which contains sub-physiological amounts of vitamin D (400 to 1200 IU) but supra-physiological amounts of completely preformed retinol (5,000 to 15,000 IU or, in some cases, 30,000 IU)." Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83(2):191–201.
"Clinical lore holds that Vitamin A is an anti-infective. We suggest that lore exists because of old cod liver oil studies. Semba reviewed early literature on vitamin A, usually given as cod or halibut liver oil, as a successful anti-infective. For reasons that are not entirely clear, fish liver oils of the time contained much higher amounts of vitamin D then does modern cod liver oil, perhaps because modern processing removes the vitamin D during distillation and then replace it at lower doses. Furthermore, a meta-analysis concluded that vitamin A, when given alone, increases the incidence of respiratory tract infections. If vitamin A increases the risk of respiratory infections, its high content in modern cod liver oils will only mask the full benefit of adequate vitamin D nutrition." Semba RD. Vitamin A as "anti-infective" therapy, 1920–1940. J Nutr 1999;129:783–791. Grotto I, Mimouni M, Gdalevich M, Mimouni D. Vitamin A supplementation and childhood morbidity from diarrhea and respiratory infections: a meta-analysis. J Pediatr 2003;142:297–304.
"As the prevalence of vitamin A deficiency in the United States is apparently much lower than the prevalence of subclinical vitamin A toxicity, we cannot recommend cod liver oil for either adults or children. (We exclude fish body oil from our warning, as it contains no vitamin A or vitamin D but is a very important source of omega-3 fatty acids.) For example, in a recent assessment of serum retinyl esters in a group of obese individuals, four percent had levels >10% of total retinol which usually indicates hypervitaminosis A. Instead, a diet rich in carrots, sweet potatoes, cantaloupe, and other orange fruits and vegetables will supply all the carotenoids the body needs to make retinol without the potential for hypervitaminosis A, especially when additional preformed retinol already exists in dairy products, eggs, and fortified cereal. We wish our diet were as rich in vitamin D. With the exception of infants on formula or toddlers drinking large amounts of milk or fortified juice, adequate amounts of vitamin D are virtually impossible to obtain from diet." Hathcock JN, Hattan DG, Jenkins MY, McDonald JT, Sundaresan PR, Wilkening VL. Evaluation of vitamin A toxicity. Am J Clin Nutr. 1990;52:183–202. Mills JP, Furr HC, Tanumihardjo SA. Retinol to retinol binding protein (RBP) is low in obese adults due to elevated apo-RBP. Exp Bio Med. In press. Tanumihardjo SA. Food-based approaches for ensuring adequate vitamin A nutrition. Comp Rev Food Sci Food Safety. In press.
Long story short, don't take cod liver oil or vitamin A as a retinol.
Vitamin A harmful for liver?
Dr. Cannell: A friend of mine told me vitamin A hurt his liver. Is that possible? Jason, New York
Not only is it possible, it may be common. When patients present to their doctor with abnormal liver function tests or overt liver disease—and many hundreds of thousands do every year—how many physicians inquire about vitamin A or cod liver oil supplements? The authors below found 41 cases and warned that "chronic vitamin A consumption might represent an appreciable cause of chronic liver disease." Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology. 1991 Jun;100(6):1701–9.
But if you think these 41 cases are the only ones reported, think again. A PubMed search reveals nearly 100 reports on vitamin A-induced liver disease.
If you know anyone taking cod liver oil or vitamin A, advise them to stop and have a "liver panel" blood test. It may be that abnormal liver function tests are the most sensitive indicator of vitamin A toxicity. I don't know how long it takes for toxic amounts of vitamin A to clear from the liver.
Cod Liver Oil During Pregnancy
Dr. Cannell: I took cod liver oil during my pregnancy and everything went fine except a little high blood pressure but that would have been worse except for the omega-3 oils in cod liver oil. Why don't you read about cod liver oil on the Weston Price Foundation's website. Joanne, Pennsylvanis
In one study, women who took cod liver oil during pregnancy were 5 times more likely to develop hypertension during their pregnancy. The authors attempted to control for intakes of vitamins A and D but the cod liver oil the women took contained about 10,000 IU of vitamin A and only 800 IU of vitamin D. By the way, the paper reports that the vitamin A content of Icelandic cod liver oil was reduced five fold in 2006, from 8,000 to 1,200 IU per 10 cc, mainly due to the literature showing vitamin A causes birth defects. Olafsdottir AS, et al. Relationship between high consumption of marine fatty acids in early pregnancy and hypertensive disorders in pregnancy. BJOG. 2006 Mar;113(3):301–9.
Dr. Cannell: I am six months pregnant and I took cod liver oil up until now. Will my baby be deformed? Jill, Oregon
While I don't know how much cod liver oil you took, or the brand, the chances are overwhelming that your baby will be just fine. Three well-conducted case controlled trials showed excessive vitamin A leads to birth defects. The first study, Teratogenicity of high vitamin A intake (PDF format) you can download for free, thanks to the NEJM. You can get the other two references from the downloaded paper if you are interested. But don't be alarmed Jill, the vast majority of women taking vitamin A had normal babies.
Also, when people tell me they take cod liver oil, I have no way of knowing what they actually taking—in terms of vitamin A and vitamin D—as different cod liver oil brands have such widely varying amounts of both vitamins.
Should I Supplement With Vitamin A?
Dr. Cannell: Are you saying no vitamin A at all or just not too much of a good thing? John, California
No extra vitamin A unless you have a bowel disease that impairs absorption of vegetables and transportation of carotenoids. The paper referenced at the end of this paragraph discusses how Americans are getting too much of a good thing. Vitamin A is like vitamin D, it has a U-shaped curve, too much or too little will harm you. Too much is the rule, not too little, in developed countries. Furthermore, it gives a mechanism by which excessive doses of vitamin A will impair brain development and, although I can't put my finger on the reference right now, at least one author has proposed that excessive vitamin A intake may worsen autism. The vitamin D theory of autism would predict just that. McCaffery PJ, Adams J, Maden M, Rosa-Molinar E. Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen. Eur J Neurosci. 2003 Aug;18(3):457–72.
Liver Consumption and Vitamin A Toxicity
Dr. Cannell: I am a nutritionist and a member of the Weston A. Price Foundation. You forget that humans no longer consume the liver of all animals and fish as we have throughout history. Second, our ability to convert the beta-carotene from plants into the required animal form of vitamin A has been shown to vary from poor to nonexistent. Joe, New Mexico
The idea that the human genome evolved eating liver is absurd. By the time humans could hunt large mammals, the genome had already evolved. Humans evolved eating a diet not dissimilar to the Great Apes: vegetables, fruit, roots, and some bugs. As far as us eating all kinds of liver, have you tried polar bear liver lately? Or sled dog liver? One serving can be fatal. There is evidence that later humans, when they learned to bring down large mammals, suffered vitamin A toxicity, probably from the liver they began consuming. Chronic consumption of chicken liver caused vitamin A toxicity in twin girls. Walker A, Zimmerman MR, Leakey RE. A possible case of hypervitaminosis A in Homo erectus. Nature. 1982 Mar 18;296(5854):248 50. Mahoney CP, Margolis MT, Knauss TA, Labbe RF. Chronic vitamin A intoxication in infants fed chicken liver. Pediatrics. 1980 May;65(5):893 7.
Secondly, the idea that the natural system (our intestinal system that converts carotenoids into vitamin A as we need it) Nature created to regulate vitamin A levels is malfunctioning in almost everyone is simply silly. The studies you are referring to are from developing countries where chronic malabsorption and diarrheal diseases are endemic. Just because an autistic child has "bowel problems," it does not mean he is vitamin A deficient. Also, how many case reports of vitamin A deficiency has anyone found in American vegetarians? Plenty of iron and B12 and vitamin D deficiencies in vegans, but virtually no vitamin A deficiency even though many vegetarians have no preformed vitamin A intake at all, only carotenoids.
I admired everyone I met at the Weston A. Price Foundation when I spoke there several years ago, mainly because of their commitment to healthy soil. However, when I brought up toxicity of cod liver oil, the atmosphere quickly turned from science to religion. Not only did I warn them about cod liver oil, the vitamin A researcher they flew in, Dr. Noel Solomon, also warned them about cod liver oil. No use. With every word either of us spoke, the flasks flashed as members of the audience took swigs of their cod liver oil.
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