Quote from tim on December 12, 2019, 5:44 pm

I don't have the link but from recollection there was a study showing D levels where correlated with mortality in an elderly scottish population, some think that some northern europeans may have adapted to low D levels and those with the genetic adaptation live longer.

There was a study showing carotenoids in the diet interfere with healing from rickets I mentioned in one of my posts.

VA interfering with VDRs probably explains why D studies based on D serum levels give mixed results but yeah all sorts of things could interfere with VDRs, it makes sense that pathogens would go for them since D is crucial for immunity.

Quote from hillcountry on December 15, 2019, 2:28 am

Photochem Photobiol. 2017    PMID:28130778

Photo-co-carcinogenesis of Topically Applied Retinyl Palmitate in SKH-1 Hairless Mice.

Division of Biochemical Toxicology, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.

Division of Bioinformatics and Biostatistics, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.

Office of Scientific Coordination, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.

Jefferson Laboratories, Toxicologic Pathology Associates, Inc., Jefferson, Arkansas.

Cosmetic products that contain retinyl palmitate are popular as antiaging skin treatments; however, recent studies suggest a risk for enhanced skin tumor development with topical retinyl palmitate applications and exposure to solar ultraviolet radiation (UVR). In this study, we investigated the potential of retinyl palmitate to enhance UVR-induced photo-co-carcinogenesis.

Compared to the control cream groups, mice exposed to SSL and administered the retinyl palmitate creams demonstrated earlier onsets of skin tumors and had increased incidences and multiplicities of squamous cell skin neoplasms.

This article is a U.S. Government work and is in the public domain in the USA.

comment: that's the first time I've seen the "public domain" disclaimer at the end of a paper. 

Quote from hillcountry on December 15, 2019, 3:59 am

Arch Osteoporos. 2019       PMID:31254130  

Restricting vitamin A intake increases bone formation in Zambian children with high liver stores of vitamin.

Department of Nutritional Sciences, University of Wisconsin-Madison

Cornell University, Ithaca, NY, USA.

National Food and Nutrition Commission of Zambia,

Tropical Diseases Research Center, Ndola, Zambia.

Osteoporosis Clinical Research Program, University of Wisconsin-Madison, Madison, WI, USA.

 

This analysis was performed in Zambian children who had a high prevalence of hypervitaminosis A, defined as > 1.0 μmol retinol/g liver. Bone parameters included markers of bone formation (P1NP), bone resorption (CTX), parathyroid hormone, calcium, vitamin A, and vitamin D. Low dietary vitamin A intake increased P1NP.

Vitamin A (VA) interacts with bone health, but mechanisms require clarification.

In countries where multiple interventions exist to eradicate VA deficiency, some groups are consuming excessive VA. Bone metabolism and inflammatory parameters were measured in Zambian children who had high prevalence of hypervitaminosis A determined by ¹³C-retinol isotope dilution.

comment: Kind of makes ya wonder if these "interventions" are mass-experiments. Useful for Osteoporosis Clinical Research perhaps? Or, maybe there's so many interventions that nobody's keeping track of the consequent interactions they have on some children (until long after the fact of damage done?). And how long has this been going on, with how many children affected? Is this a sign of push-back on the part of Zambian authorities? Wonder how many kids in Zambia are walking around with Hypervitaminosis A as a result of "interventions". The statement "mechanisms require clarification" is eerie, given that we know they already know what's needed to know about osteoporosis. At least I think we do, from all the papers we've seen on that subject regarding VA's involvement in it. I think the University of Wisconsin knows this too, as the second PubMed paper from the year 2000 and copied below demonstrates quite clearly. 

Children (n = 143), 5 to 7 years, were recruited into a placebo-controlled biofortified orange maize feeding study for 90 days. Bone turnover (P1NP and CTX) and inflammatory (C-reactive protein (CRP) and alpha-1-acid glycoprotein) biomarkers were measured in fasting blood samples before and/or after intervention with the following: (1) VA at the recommended dietary allowance (400 μg retinol activity equivalents/day (as retinyl palmitate)), (2) maize enhanced with the provitamin A carotenoid β-carotene (2.86 mg/day), or (3) a placebo. Parathyroid hormone, calcium, and 25(OH)-vitamin D were measured at end line.

RESULTS:

Bone formation, as measured by P1NP, increased (P < 0.0001) in the placebo group who consumed low preformed VA during the intervention. Bone resorption, measured by CTX, was not affected. P1NP and CTX were negatively associated with inflammation, most strongly with CRP. Serum calcium did not differ among groups and was low (7.29 ± 0.87 μg/dL). Serum 25(OH) D did not differ among groups (54.5 ± 15 nmol/L), with 91% < 75 nmol/L and 38% < 50 nmol/L.

CONCLUSIONS:

Reduction of dietary preformed VA in Zambian children for 4 months improved bone formation. Chronic consumption of preformed VA caused hypervitaminosis A and may impair bone formation. In children, this could be associated with failure to accrue optimal peak bone mass.

comment: is this the state of modern science? Is nothing ever proven? What's with the "may impair" and "could be associated with" verbiage? Check out what the University of Wisconsin's Institute of Aging had to say about this 19 years ago. Maybe their departments don't read each other's work? Maybe somebody retired and no longer teaches? What's up?

 

Nutr Rev.        2000          PMID:10860393

Hypervitaminosis A and bone.

Institute on Aging, University of Wisconsin, Madison 

Animal, human, and in vitro data all indicate that excess vitamin A stimulates bone resorption and inhibits bone formation. This combination would be expected to produce bone loss and to contribute to osteoporosis development and may occur with relatively low vitamin A intake. It is possible that unappreciated hypervitaminosis A contributes to osteoporosis pathogenesis.

comment: there they go with the "it is possible" verbiage again, as if they somehow need to negate what they've already said. I wonder if they'll ever change that last bit to read: It is possible that unappreciated sub-clinical VA-toxicity contributes to osteoporosis pathogenesis. Is there some hint in the statement that they're going to need to redefine hypervitaminosis A levels one of these days? Will their African data come into play at that point? As if we don't have enough osteoporosis data already in North America. I keep wondering how much of modern research is just a form of  make-work programs. Or maybe there's just some kind of institutional Alzheimer's at work, so they keep digging holes and filling them back in, over and over as years roll on.

Here's another one from 2015 that indicates consensus on hypervitaminosis a and osteoporosis. It sounds like they're also not quite sure where the cut-off should be, when they reference "increased levels" and epidemiological research.

Front Endocrinol (Lausanne). 2015    PMID:25814978

Retinoid receptors in bone and their role in bone remodeling.

Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

Department of Physiology and Biophysics, University of Arkansas for Medical Sciences , Little Rock, AR , USA.

Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden ; Department of Molecular Periodontology, Umeå University , Umeå , Sweden.

Vitamin A (retinol) is a necessary and important constituent of the body which is provided by food intake of retinyl esters and carotenoids. Vitamin A is known best for being important for vision, but in addition to the eye, vitamin A is necessary in numerous other organs in the body, including the skeleton. Vitamin A is converted to an active compound, all-trans-retinoic acid (ATRA), which is responsible for most of its biological actions. ATRA binds to intracellular nuclear receptors called retinoic acid receptors (RARα, RARβ, RARγ). RARs and closely related retinoid X receptors (RXRα, RXRβ, RXRγ) form heterodimers which bind to DNA and function as ligand-activated transcription factors. It has been known for many years that hypervitaminosis A promotes skeleton fragility by increasing osteoclast formation and decreasing cortical bone mass.

Some epidemiological studies have suggested that increased intake of vitamin A and increased serum levels of retinoids may decrease bone mineral density and increase fracture rate, but the literature on this is not conclusive. [comment: they don't actually say it, but here they must be talking about increased intake and serum levels that are not quantitatively hypervitaminotic. I wonder what the process of deciding that the literature is conclusive looks like. Wood-paneled, smoke-filled rooms at exclusive clubs?] The current review summarizes how vitamin A is taken up by the intestine, metabolized, stored in the liver, and processed to ATRA. ATRA's effects on formation and activity of osteoclasts and osteoblasts are outlined, and a summary of clinical data pertaining to vitamin A and bone is presented.

comment: the National Cancer Institute is in agreement as well, going back to 2009 at least.

Consult Pharm. 2009    PMID:19275452

Spontaneous fracture: multiple causes.

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Spontaneous fractures occur in seemingly normal bone with no apparent blunt-force trauma. Spontaneous fracture occurs primarily in two distinct groups of patients: the very active young and the elderly. Researchers and clinicians have used several terms interchangeably for spontaneous fracture, including pathologic fracture, fragility fracture, compression fracture, or fatigue or insufficiency fracture. Among the most common causes of spontaneous fracture are osteoporosis (calcium deficiency and corticosteroid-induced), malignancy, overexposure to vitamin A, periprosthetic weakening, Brucellosis, cerebral palsy (especially in children), and osteodystrophy because of chronic renal failure. Preliminary research observations indicate that spontaneous fracture may be a rare adverse outcome associated with bisphosphonates.

Comment: and check out what the University of Wisconsin had to say in 2006. Let's repeat what their report said in 2019 at the top of this thread: "Chronic consumption of preformed VA caused hypervitaminosis A and may impair bone formation. In children, this could be associated with failure to accrue optimal peak bone mass".

Am J Clin Nutr. 2006      PMID:16469975

The acute and chronic toxic effects of vitamin A.

Department of Nutritional Sciences, University of Wisconsin-Madison

The acute and chronic effects of vitamin A toxicity are well documented in the literature. Emerging evidence suggests that subtoxicity without clinical signs of toxicity may be a growing concern, because intake from preformed sources of vitamin A often exceeds the recommended dietary allowances (RDA) for adults, especially in developed countries. Osteoporosis and hip fracture are associated with preformed vitamin A intakes that are only twice the current RDA.

Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are nonsensitive indicators in this range of liver vitamin A reserves.

The metabolism in well-nourished persons of preformed vitamin A, provided by either liver or supplements, has been studied by several research groups. To control vitamin A deficiency, large therapeutic doses are administered in developing countries to women and children, who often are undernourished. Nevertheless, little attention has been given to the short-term kinetics (ie, after absorption but before storage) of a large dose of vitamin A or to the short- and long-term effects of such a dose given to lactating women on serum and breast-milk concentrations of retinol and its metabolites. Moreover, appropriate dosing regimens have not been systematically evaluated to ascertain the quantitative improvement in vitamin A status of the women and children who receive these supplements. The known acute and chronic effects of vitamin A toxicity have been reported previously. However, further research is needed to ascertain the areas of the world in which subclinical toxicity exists and to evaluate its effects on overall health and well-being.

Comment: so in 2006, they're wagging their finger at what's going on in Africa. 

Quote from tim on December 15, 2019, 5:37 am

Good studies, thanks for posting.

Quote from Jenny on December 15, 2019, 6:23 am

@hillcountry thanks for those. It’s just incredible how this has not been pieced together sooner. Several years ago in the UK a well known nutritional therapist & a well known scientist tried to get a paper published about vitamin A toxicity after moderate intake. Despite both having numerous publications to their names they could not get it published ‘for love nor money’. Makes me think there is some force blocking negative opinions about vitamin A & perhaps people use tentative language to get their work published. 

Quote from hillcountry on December 16, 2019, 4:31 am

It's a pleasure to have enough time to do some digging. Here's one that shows certain folks are getting a bit worried.

 

Ann N Y Acad Sci.        2019 Jun         PMID:30265402

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Special Issue:

Risk of Excessive Intake of Vitamins and Minerals

ORIGINAL ARTICLE

Overlapping vitamin A interventions in the United States, Guatemala, Zambia, and South Africa: case studies.

https://nyaspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/nyas.13965

 

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin.

National Food and Nutrition Commission, Lusaka, Zambia.

HarvestPlus, Washington, DC.

Burden of Disease Research Unit, South African Medical Research Council, Cape Town, South Africa.

Division of Human Nutrition, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.

Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.

Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa.

Abstract

Vitamin A (VA) deficiency is a serious public health problem, especially in preschool children who are at risk of increased mortality. In order to address this problem, the World Health Organization recommends periodic high-dose supplementation to children 6-59 months of age in areas of highest risk. Originally, supplementation was meant as a short-term solution until more sustainable interventions could be adopted. Currently, many countries are fortifying commercialized common staple and snack foods with retinyl palmitate.

However, in some countries, overlapping programs may lead to excessive intakes.

Our review uses case studies in the United States, Guatemala, Zambia, and South Africa to illustrate the potential for excessive intakes in some groups. For example, direct liver analysis from 27 U.S. adult cadavers revealed 33% prevalence of hypervitaminosis A (defined as ≥1 μmol/g liver).

In 133 Zambian children, 59% were diagnosed with hypervitaminosis A using a retinol isotope dilution, and 16% had ≥5% total serum VA as retinyl esters, a measure of intoxication.

In 40 South African children who frequently consumed liver, 72.5% had ≥5% total serum VA as retinyl esters. All four countries have mandatory fortified foods and a high percentage of supplement users or targeted supplementation to preschool children.

The long-term impact of simultaneous implementation of VAS and fortification on VA status in the same target groups is currently unknown. Minimal human data exist on actual liver VA concentrations compared with serum biomarkers that are accessible and could be used in population surveys to monitor the impact of multiple overlapping interventions.

 

Comment: “Minimal human data exist …” - is that crazy or what? How many autopsies are performed each year? Isn’t this data super-relevant? Shouldn’t it have been nailed-down 50 years ago? This is a 15-page report in 2019. Unbelievable.

Fortification of commercialized common foods dates back almost a century.

In 1925, VA was added to vegetable-derived margarine to make it more nutritionally equivalent to animal-derived butter.

In the 1940s, this became mandatory by some governments.

In order to be a good candidate for fortification, the food needs to be widely consumed among the target groups and manufactured in a manageable number of facilities for appropriate monitoring. Issues associated with VA fortification include fortificant stability and quality control.

Comment: Those dates were surprises to me. I thought it all went down in the 1970’s. Recall the Wolbach-Howe paper - title copied below? How much did they really know about Retinol back then? They had to be extracting it from something, right? Industrialization of food, i.e. hydrogenation of vegetable oils, must have been in full swing. Did they advertise “Vitamin A” or some other designation on the margarine labels? Did that give the new-fangled substances some market-credibility? I read they had to get a yellow-color into the original unpalatable gray-colored end-product; no idea if retinol contributes to that, or if it was just food-coloring, but the big question is how did they go from supposedly proving VA-deficiency in the Wolbach-Howe study in 1925 to inserting retinoids into margarine in 1925? Was there any necessary connection between these two things? Who was making the decisions to supplement the new margarine product? Did they need proof that it was a good thing, or did they just go ahead and do it? Did the Wolbach-Howe study give some legitimacy to “fortifying” the margarine? Or, are they separate events, connected only by coincidence?

TISSUE CHANGES FOLLOWING DEPRIVATION OF FATSOLUBLE A VITAMIN.

BY S. BURT WOLBACH, M.D., AND PERCY R. HOWE, M.D. From the Department of Pathology, Harvard University Medical School, and the Forsyth Dental Infirmary, Boston. Received for publication, September 4, 1925

 

More excerpts from the full NY Academy of Sciences pdf

(here comes some of the bombshell stuff - some a repeat from the abstract)

Our review uses case studies in the United States, Guatemala, Zambia, and South Africa to illustrate the potential for excessive intakes in some groups. For example, direct liver analysis from 27 U.S. adult cadavers revealed 33% prevalence of hypervitaminosis A (defined as >1 micromol/g liver).

In 133 Zambian children, 59% were diagnosed with hypervitaminosis A using a retinol isotope dilution, and 16% had >5% total serum VA as retinyl esters, a measure of intoxication. In 40 South African children who frequently consumed liver, 72.5% had >5% total serum VA as retinyl esters. All four countries have mandatory fortified foods and a high percentage of supplement users or targeted supplementation to preschool children.

In each of these countries, either biological or survey data indicate that some groups are receiving too much VA. The purpose of our review is to inform the readers, including nutritional scientists, dietitians, policy makers, and program support staff, of the risk of hypervitaminosis A due to overlapping programs and the importance of evaluating these programs to determine where changes may need to be made in the delivery systems or target areas.

In the United States, the 2013–2014 National Health and Nutrition Examination Survey (NHANES) found that the mean daily intake for VA was about 600 microgram RAE for children and 640 microgram RAE for adults. These estimates do not include VA from supplements and prescribed medicines.

Males tended to have higher intakes than females in all age groups.

The child estimate is well above the Recommended Daily Allowance (RDA) for children below 9 years of age (300–400 microgram RAE).

Most of the estimated RAEs are from preformed retinyl esters (REs) (60–80%)

In the U.S. NHANES 2009–2012, the usual intake of preformed VA exceeded the tolerable upper intake level (UL) for an estimated 21% of infants from 6 to 11 months and 16% of toddlers 12–23 months of age.

The UL [upper limit] for this age group is 600 microgram retinol equivalents.

The UL for VA is always in preformed retinol equivalents because dietary intake from provitamin A carotenoids is presumed to be safe.

A cross-sectional study in young U.S. women evaluated long-term VA intake and determined total body VA stores (141.5–3116 micromol) using retinol isotope dilution (RID) methods.

In these young adult women, VA intake exceeded the RDA of 700 microgram RAE, and intake was correlated with estimated total liver VA reserves.

Comment: How to interpret that? If there’s a spread of total VA-stores that large (the upper being over 20x the lower value), are they saying the lowest-level is also a result of exceeding the RDA? Are they saying that some of these women are taking in 20-times the RDA?

Fortification of foods in the United States is mostly voluntary except for some foods that have a standard of identity. For VA, only two foods are subject to mandatory VA fortification, that is, margarine and skimmed milks. VA has been added to milk since the 1940s. In 1978, this practice became mandatory because skim and lower fat milks were widely consumed.

It must be noted that nutrition labeling in the United States is based on DVs and not RDAs. Up until 2016, a huge discrepancy existed between the DV and the RDA for VA. The DV, which is used on Supplement and Nutrition Facts’ panels, was based on the 1960s RDA value of 1500 microgram retinol equivalents.

However, on July 26, 2016, the final rule was changed, and by July 2018 and 2019 for larger and smaller food manufacturers, respectively, the labels must be updated to the current RDA for adult males as 100% of the DV, that is, 900 microgram RAE.

Supplement usage in the United States is very common, with an estimated 71% of adults consuming dietary supplements of all kinds and 75% of those individuals taking a mulitvitamin. Supplements are usually preformed retinyl acetate or palmitate, but some supplements are now formulated with beta-carotene.

The prevalence of hypervitaminosis A is largely unknown in the United States. In part, this is due to lack of appropriate biomarkers to use at the population level. While serum retinol concentrations have utility in diagnosing frank VA deficiency, serum retinol concentrations are not useful for diagnosing hypervitaminosis A because of the homeostatic mechanisms that keep plasma retinol under control.

Comment: Lots more on methods of fortification in the other countries (sugar seems popular) and a blur of statistics. They’re definitely sounding the alarm in this report. I was surprised by the NHANES surveys and the number of children at risk. If the “mean” number they generated is above the RDA, then some large percentage of children are getting a monster-dose every day. I don’t see that hitting the headlines and that’s disturbing. Another thing that struck me, was that it appears (in a way) that the authors are saying that hypervitaminosis A is a chronic, hidden condition. I was under the impression from what the NIH has on their website, that it’s an acute condition brought on by eating 12-milligrams a day or more of VA over some period of time. It sounds like a lot of people must be walking around with hypervitaminosis A, if the liver-autopsies are any indication, but they must not be too symptomatic or something. Sometimes reading this stuff, a thought passes by that maybe there’s an element of meta-research going on that seeks to know how much people can handle. Remember the study that Josh posted where the guy was hypervitaminotic and they used a high-protein diet to bring his liver under control. I think it said he was not very symptomatic before finally presenting at a hospital.

 

Quote from tim on December 16, 2019, 5:28 am

Wow... that study. Skeptic silencer. Our little forum community here is the start of a huge wave of grassroots VA awareness in the future.

The UL for VA is always in preformed retinol equivalents because dietary intake from provitamin A carotenoids is presumed to be safe.

This statement in the study is a non sequitor, retinol activity equivalent is designed to include carotenoids and has nothing to do with them being assumed to be safe.

Quote from hillcountry on December 16, 2019, 7:30 am

tim, good catch!! Totally missed that. Your 'non sequitur' insight says something deeply critical about what can slip past us in these papers; how the people who write them can perpetuate myths, or create new ones, by such mistakes in their thought-processes. 

Quote from lil chick on December 16, 2019, 8:56 am

I'm so thankful for all the research that goes on here!!!