Vitamin A (retinol) Is Not Toxic To The Liver In High Doses

Amazoniac

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I just read that the chronic toxic dose was only 4,000 IU.

At a dose like this, you expect the majority to be stored safely in the liver as retinol esters. However, the liver will become saturated someday. When the storage capacity is exceeded than it may become a problem.

The tissue retinoic acid concentrations are dependent on the blood retinol concentrations. High retinoic acid levels increase transcription of hundreds of genes involved in cell growth. Topical retinoic acid can double the skin turnover rate, and high chronic fish oil consumption in The Nordic Countries is associated with osteoporosis consequent of increased alkaline phosphatase transcription. But this could be potentiated by the relatively low vitamin D photosynthesized in the Northern latitudes.

If you want to know exactly what happens to the cell with increased retinol, you have to look at an mRNA microarray study. This is where they extract all of the mRNA and characterize it; match it to the proteins they transcribe.

Shouldn't be an issue if your liver isn't saturated.

You might expect skin changes with even one high dose. If you exceed the storage rate of the liver, you would expect the blood level to rise. But your liver would then pull-out retinol from the bloodstream (HDL) and store it, so the increase would be short-lived. I think the only real problem is by totally saturating the liver, and this would take time. But there is certainly no way to know how much retinol esters are already stored in the liver before supplementation. A person on a hardcore paleoatkins diet might already be ~70% saturated.
A person can eat more than 50000IU from diet in a week, which exceeds that value, and from retinol alone. Perhaps greater amounts given at once allows a better regulation of its metabolism compared to chronic smaller daily doses. Regardless of clear toxicity, ingesting more than what's needed must demand extra stabilization since they're all unsaturated and vulnerable to damage, especially if they're not being put to good use. Can you view my thoughts as Lego and assemble them in a way that I can think properly and then take a picture and post on your instagram with the title "Work-in-progress" if you have any further comments?

Ps.: I used to use retinoic acid creams and I can tell up to this day the places that I used more of it, since the region still has a faster turn over. It's crazy how lingering the effects are.
 
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Amazoniac

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The acute and chronic toxic effects of vitamin A

"Research on vitamin A toxicity has been carried out primarily in animals, and most studies have been short-term and have focused on acute effects (11-13). Many studies used intramuscular or venous injections of various forms of vitamin A (14, 15), which cannot be extrapolated to physiologic conditions because injections bypass gastrointestinal effects."

"Case reports of vitamin A toxicity have shown serum retinol concentrations within normal limits (22-24), which suggests that serum retinol is not a good measure of vitamin A status during toxicity."

"esterification process may exist to prevent large increases in retinol and retinoic acid, both of which are known to be potentially toxic forms of vitamin A. Myhre et al (27) performed a meta-analysis, from which they concluded that the ingestion of large amounts of vitamin A as liver or oil-based supplements caused an increase in retinol, retinoic acid, and related retinoids, but not as great an increase as that resulting from the ingestion of comparable doses in water-miscible and emulsified forms. A postprandial increase in serum retinol concentration may be blunted when vitamin A is ingested with either food or ample dietary fat, whereas a significant amount of free (unesterified) retinol may circulate when vitamin A is consumed without dietary fatty acids, which leads to excessive production of retinoic acid (28)."
@Zeus

"Van Vliet et al (38) compared the metabolism of vitamin A from liver paste with that of a retinyl palmitate in oil supplement and measured the formation of retinoic acid and its metabolites in women (n = 35). Vitamin A was provided as 3000, 7500, or 15 000 RE. Blood was collected 2–24 h after supplementation. As in previous studies, serum retinol concentrations were unaffected by treatment. Increases in 2 isomers of retinoic acid and of 4-oxoretinoic acid were observed, and large individual differences were noted*. However, unlike the study of Buss et al, which used higher vitamin A doses, the study of van Vliet et al found no significant difference between the supplement and liver paste."

*Ray Peat Email Exchanges - Ray Peat Forum Wiki
Bonsai trimmer said:
The toxic effects of extremely big doses, such as 500,000 to a million i.u., seem to be from either oxidative processes (rancidity) that are prevented by adequate vitamin E, or by antithyroid effects. I found that when my need for vitamin A began to decrease I tended to accumulate carotene in my calluses; that happens when the thyroid function is lower, reducing the need for vitamin A. Since you are eating foods with carotene, the calluses on your palms or soles should serve as an indicator of when your tissues are saturated with vitamin A. About 100 i.u. of vitamin E would help to keep the vitamin A from being wasted by oxidation, and possibly could reduce your requirement for it.

"Hepatic storage of vitamin A will continue until a pathologic liver condition develops (20, 57)."

"The existence of stellate cells in other organs, such as the kidneys and the lung, suggests that they may be fully capable of and adapted to storing vitamin A as retinyl esters (5, 58-60)."
"Some studies suggest that extrahepatic vitamin A stores, such as those in the kidneys, rise during vitamin A deficiency (72), possibly as a reserve for the production of retinoic acid that is required for growth and cellular differentiation."

"Historically, vitamin A toxicity has been associated with bone alterations of various types in many species (89-93), although variable tolerance exists between species (20). Human skeletal remains and reports of toxicity in Arctic people, whose intake of preformed vitamin A has traditionally been high, confirmed bone involvement (17, 18, 94). Clinical observations, such as hypercalcemia and elevated alkaline phosphatase, in persons with vitamin A toxicity clearly suggested that vitamin A affects bone."

"it [appears] that a single large dose of preformed vitamin A may not be as beneficial as a long-term food-based strategy or low-dose vitamin A supplements given for a longer period of time. Research in rats suggests that sustained chylomicron delivery may be the most important means by which vitamin A is delivered to mammary tissue (126). Moreover, the large doses of vitamin A may be toxic or teratogenic (or both), and, therefore, the timing of the dose is critical."

@Enchantingthatrefusestotag
 

DaveFoster

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@haidut Why do you put tocopherols in the palmitate version of Retinil; wouldn't the MCT oil be good enough even for topical absorption?
 
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haidut

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@haidut Why do you put tocopherols in the palmitate version of Retinil; wouldn't the MCT oil be good enough even for topical absorption?

To prevent oxidation. Most products with retinyl palmitate have some vitamin E (usually as tocopheryl acetate) to keep the product from oxidizing. It was @Amazoniac who provided some very good references on adding vitamin E to the A for stability and maybe he can chime here and re-post those references.
 

DaveFoster

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To prevent oxidation. Most products with retinyl palmitate have some vitamin E (usually as tocopheryl acetate) to keep the product from oxidizing. It was @Amazoniac who provided some very good references on adding vitamin E to the A for stability and maybe he can chime here and re-post those references.
I see, that makes sense. Thanks for the info, and :hattip to Amazoniac.
 

Momado965

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As a follow up on my previous post, this study looks at toxicity of retinol acetate in doses exceeding 300,000 IU per day taken for months and in combination with a SERM (tamoxifen) which itself is quite estrogenic and as such is a proven liver burden.

Plasma retinol levels and side effects following high-dose retinyl acetate in breast cancer patients. - PubMed - NCBI

Do you think vitamin A 'toxicity' stems from studies done using B carotene? Also, I hve taken up to 250,000 iu a day with only benefits similar to yours and Nick's.
 

Motif

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@haidut
As a follow up on my previous post, this study looks at toxicity of retinol acetate in doses exceeding 300,000 IU per day taken for months and in combination with a SERM (tamoxifen) which itself is quite estrogenic and as such is a proven liver burden.

Plasma retinol levels and side effects following high-dose retinyl acetate in breast cancer patients. - PubMed - NCBI



What would you recommend for dermatitis and Seborrhoic eczema?

In my case it gets triggered from histamine.
 
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@haidut




What would you recommend for dermatitis and Seborrhoic eczema?

In my case it gets triggered from histamine.

Well, have you tried any of the safer antihistamines or a natural alternative like theanine? Low thyroid function is commonly involved in all of these skin conditions, so thyroid supplement or progesterone may help.
 

Mito

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Here is a pop-up chart,† just found, that confirms my beliefs regarding the relationship between liver and blood levels. High doses may be perfectly fine for some time, but there may come a point—depending on the dose—that the volumetric capacity of the liver is exceeded. At this point, the same dose would be expected to have a much more dramatic effect on blood retinol levels than had previously.
Does that pop-up chart suggest a serum Vitamin A level that a person may not want to exceed? It appears that liver retinol begins to increase significantly when the serum level exceeds about 50 μg/dL?
 

Travis

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Does that pop-up chart suggest a serum Vitamin A level that a person may not want to exceed? It appears that liver retinol begins to increase significantly when the serum level exceeds about 50 μg/dL?

The article below has a data chart reporting circulating retinol concentrations of 16,058 Americans, arranged into percentiles:


Ninety percent of all Americans have concentrations varying by less than a threefold difference; this is much tighter range than is found with circulating vitamin D, E, and K levels because there are so many negative-feedback loops. Most vitamins cannot actively regulate their own concentration because they have no conjugate nuclear receptors, and the only other vitamin I am 100% certain that does is vitamin D—the the other classic 'vitamin–hormone.' The protein having the highest transcriptional response through the vitamin D receptor is the enzyme that hydroxylates it for the last time—transforming it into the most water-soluble congener, and hence the most readily excreted. And yet, the circulating values of calcitriol are found to range between percentiles with roughly twice the magnitude of retinol. Retinoic acid is of course much more active, and this form falls into an even more narrow range. Retinol can perhaps be seen as more analogous to the mono- and di-hydroxylated vitamin D precursors having larger ranges than calcitriol, making the juxtaposition between the first (retinol) and second (cholecalciferol) most-regulated vitamins even more extreme.
 
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LeeLemonoil

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It might not be so fine for mitochondria after all:

https://www.sciencedirect.com/science/article/pii/S0304416505002096

Retinol induces permeability transition and cytochrome c release from rat liver mitochondria

Abstract
Biological actions of retinoids on modulation of cellular gene expression by nuclear receptors are widely known. Recently, extra-nuclear effects of retinoids have been proposed, but remain to be better elucidated. Considering that retinoids induce apoptosis in tumor cells by an unknown mechanism, and that mitochondria play a key role in controlling apoptosis via cytochrome c (cyt c) release, we exposed rat liver mitochondria to 3–40 μM of retinol (vitamin A), and observed that retinol causes mitochondrial permeability transition (MPT) and cyt c release, in a concentration-dependent pattern. Increased superoxide anion generation and lipoperoxidation were also observed. Cyclosporin A or trolox co-administration reverted all parameters tested. In view of these findings, we conclude that retinol induces mitochondria oxidative damage, leading to MPT and cyt c release by opening of the permeability transition pore, thus suggesting a putative mechanism of apoptosis activation by retinol.
 

BigChad

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@Travis @Amazoniac

Im wondering why you say vitamin D3 is the third most dangerous after vitamin a or iron, i would think that would be copper, manganese, iodine, selenium etc.

Anyway i see A and D ratios commonly posted of 5:1. What would happen if you took A to D in a 1:2 ratio, so 5000IU D3 for every 2500iu A? Wouldn't this speed up the metabolism more and be better than more A and less D? D seems to promote thyroid hormone function while A is an antagonist, it seems like more D than A would be better for metabolism?
 

Frankdee20

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I feel great on Vitamin D3, and only get my A from Calve's Liver. I have not supplemented A for any period of time to know if it helps. I am low on Testosterone frequently, and have elevated Triglycerides, indicating Thyroid or Poor Liver function. My Thyroid numbers are always great though, so I cannot be that. I have high cholesterol frequently, not insanely high, so maybe I need more A to convert to steroids.
 

BigChad

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I feel great on Vitamin D3, and only get my A from Calve's Liver. I have not supplemented A for any period of time to know if it helps. I am low on Testosterone frequently, and have elevated Triglycerides, indicating Thyroid or Poor Liver function. My Thyroid numbers are always great though, so I cannot be that. I have high cholesterol frequently, not insanely high, so maybe I need more A to convert to steroids.

have you tried tudca or jarrows bile acids product
 

RPDiciple

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I have suddenly started to get dry flaky skon on my scalp and face around nose and eyebrows. It seems like to much vitamin A can cause this as well? Im taking thyroid as well. So can it be from to much or to little? I have taken a good amount of vitamin A as well
 

ddjd

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I have suddenly started to get dry flaky skon on my scalp and face around nose and eyebrows. It seems like to much vitamin A can cause this as well? Im taking thyroid as well. So can it be from to much or to little? I have taken a good amount of vitamin A as well
Try b6p5p. Swanson do a good product very cheap. Stops the dry skin issue for me
 

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