Low Toxin Diet Grant Genereux's Theory Of Vitamin A Toxicity

[Amazoniac]

I still think there is some kind of cofactor that may be missing for people with apparent vitamin A overload. I mean @Amazoniac banged on about how it can be difficult to supplement nutrients alone because they all work together in some way. I still think food retinol isn't likely to be toxic and that sunlight and thyroid are factors.

This is worse when the body is weak because the need for regeneration is increased and at such point various nutrients probably were compromised and a generalized depleted state is likely. As soon as you add one missing piece, it's consumed immediately, requiring other missing nutrients along that aren't present. It's more guaranteed to have them in conjuction, otherwise it rarely works and often creates some gross distortions.

You can lower everything in the diet to prevent the distortions, but you can also increase everything else that's required for the accumulated nutrient to work again. The suggestion to restrict table salt is a similar example.

 

[Amazoniac]

I am still waiting for evidence that β-carotene can also inhibit the thyroid (@Amazoniac).

For some reason I didn't receive this notification. I already replied on the other thread, but if you doubt that excess carotenes are capable of suppressing the metabolism further when the body is weak, ask a friend that has symptoms of hypopboydism to consume a lot of carotenes for a week. But ask him to rotate the sources to not blame the effect on some plant toxin. Keep monitoring what happens throughout the process as the yellow coloration intensifies.

 

[Mito]

I'm not trying to excessively fearmonger, I just had to point this out because many people on this forum concentrate on the presumed antithyroid activity of β-carotene while retinol is given a free pass.

Ray has spoken about the thyroid suppressive effects of vitamin A (retinol).

CALLER: What would be a good dose of Vitamin A on average for a 50 year old adult woman?

RAY PEAT: That's hard to say because being an unsaturated oily material, it can interfere with thyroid function, so the amount you need corresponds exactly to the level of thyroid activity you have. A low thyroid person can get symptoms of Vitamin A poisoning from just a very small amount like 5000 units.

CALLER: Okay. If I were to take vitamin A internally to help with other issues? How much is a safe dose ? (I have liver issues, I have a problem with my esophagus and several other problems). So, vitamin A would be helpful, but how much would be a safe dose taken internally?

RAY PEAT: It depends on the status of your thyroid exactly, because the thyroid hormone and vitamin A are carried on the same protein in the blood. And if you take too much vitamin A, it can act as an antagonist to thyroid; it acts like polyunsaturated fat in competing against the thyroid hormone, and can also block the production of adrenal and ovarian steroids, if you get too much. But 10.000 IU a day if your thyroid is ok.

 

[Terma]

If you seriously think your issues are due to retinoic acid, there are other things to experiment with other than eating shi-tty beef all day (this is a supplement to this post by Amazoniac):
Antidepressant Effects of Abscisic Acid Mediated by the Downregulation of Corticotrophin-Releasing Hormone Gene Expression in Rats
(wheatgrass, sweet potatoes, maple syrup, etc.; actual mg's unknown)
ABA itself is also an immune and cancer modulator. Conceivably, it could even be a substance with negative effects for some conditions.

If you're feeling adventurous or you have nothing to lose:
Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application
(disulfiram, citral, even tryptophan metabolites)
Not only does RA lower from RALDH inhibition, but retinaldehyde can directly and indirectly antagonize some RA effects (they achieve results by simply injecting retinaldehyde, e.g. "Our previous studies indicate that Rald directly binds the PPARγ-RXR complex and inhibits the activation of a transfected PPAR response element (PPRE) after agonist stimulation with rosiglitazone"):
Retinaldehyde represses adipogenesis and diet-induced obesity
Retinaldehyde Dehydrogenase 1 Deficiency Inhibits PPARγ-Mediated Bone Loss and Marrow Adiposity

There was also weak evidence of link between cAMP and RALDH, but needs more research:
Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans

For this I have no concrete suggestions, but a potential means of controlling RA effects is CRABP2/FABP5 partitioning:
Dual transcriptional activities underlie opposing effects of retinoic acid on cell survival
This would be promising, but I don't know how. That said, PPAR activation is not always benign either, as you can see from the article above this (where in fact RA merely aggravates the pathology primarily driven by PPARgamma, though this is subject to other interpretation), but in most cases it's nowhere near that scary and people are looking to upregulate it.

RA is slave to so many other processes that it's ridiculous to demonize it. In my opinion Retinol or RA only aggravates select existing immune and gut issues, and deficiencies. In non-inflammatory contexts it can do the opposite and dampen the immune system, and RA overall effects are intimately tied to TGF-B signaling, which have overlapping roles, so analysis breaks down in isolation. It's better if I don't try to explain it myself again; here is a study that goes in the right direction:
Modulation of T Cell and Innate Immune Responses by Retinoic Acid
(http://www.jimmunol.org/content/jimmunol/192/7/2953/F1.large.jpg?width=800&height=600&carousel=1)

They generalize a little much, because some models of conditions showed benefits from RA rather than aggravation, so "autoimmune" and "inflammatory" should be interpreted as specialized and even organ-specific and depends on the cytokines.

 

[Travis]

For some reason I didn't receive this notification. I already replied on the other thread, but if you doubt that excess carotenes are capable of suppressing the metabolism further when the body is weak, ask a friend that has symptoms of hypopboydism to consume a lot of carotenes for a week. But ask him to rotate the sources to not blame the effect on some plant toxin. Keep monitoring what happens throughout the process as the yellow coloration intensifies.

So basically 'there's absolutely no evidence for this, but it must be true anyway!'

Would you expect retinol should be avoided then with increased diligence in hypothyroidism because it's starts inhibiting thyroid peroxidase transcription at about 100·nM in porcine thyroid cells?

 

[Amazoniac]

So basically 'there's absolutely no evidence for this, but it must be true anyway!'

Would you expect retinol should be avoided then with increased diligence in hypothyroidism because it's starts inhibiting thyroid peroxidase transcription at about 100·nM in porcine thyroid cells?

So basically if it isn't written somewhere, it's all in their heads, right?

 

[InChristAlone]

I'm not trying to excessively fearmonger, I just had to point this out because many people on this forum concentrate on the presumed antithyroid activity of β-carotene while retinol is given a free pass. [?] I can not find one study indicating that β-carotene has antithyroid effects of any kind, yet retinol shows a direct dose-dependent inhibition on iodine uptake in the nanomolar range. Retinol also reduces expression of thyroid peroxidase and inhibits thyroxine synthesis.

The study below reports circulating retinol concentrations in 16,058 humans expressed as means of percentiles.

Ballew, Carol. "Serum retinol distributions in residents of the United States: third National Health and Nutrition Examination Survey, 1988–1994." The American journal of clinical nutrition (2001)​

The range of circulating retinol in males between the 1 and 99 percentiles—nearly all Americans—is between .87–3.42 μM. I think we can all agree that this is a surprisingly-narrow range, and is approximately the width of the red line below. The interpersonal variance in vitamin D, sex steroids, and growth hormone concentrations are all much larger than this; the range of retinoic acid is even tighter.

View attachment 10080

The liver is so efficient at sequestering retinol from the serum that large fluctuations are not observed until it becomes saturated and spills-over. Nonetheless, excessive retinol is correlated with osteoporosis within this narrow threefold range in the Nordic countries—yet this was on account of extreme intakes. Milk had been heavily-fortified with vitamin A in Sweden and Norway in the 1990's, and fish liver oil is somewhat popular there.

Autopsy data reveal widely-variable liver concentrations:

Huque, T. "A survey of human liver reserves of retinol in London." British Journal of Nutrition (1982)

'Median retinol stores (Table 5) were highest in individuals who had met sudden, accidental death.' ―Huque

View attachment 10081
​

Retinol can be stored in the liver, yet pre-retinol can exist as inactive dimers of β-carotene nearly everywhere in the body. Carotenes are cleaved into retinol as needed, and serve as antioxidants before that point.

I am still waiting for evidence that β-carotene can also inhibit the thyroid (@Amazoniac).

I would expect retinol to be an issue in Nordic countries. Very low UV for most of the year. Look at the Masai, they thrive on whole raw milk, and they will drink blood! They live outside in full sunlight year round, very tall and hardy people. Unless you are overloaded with supplements, liver, oxidized cod liver oil, I refuse to believe the VA is the issue. More likely lifestyle (low UV, blue light past sunset), stress, and lack of cofactors.

 

[Travis]

I would expect retinol to be an issue in Nordic countries. Very low UV for most of the year. Look at the Masai, they thrive on whole raw milk, and they will drink blood! They live outside in full sunlight year round, very tall and hardy people. Unless you are overloaded with supplements, liver, oxidized cod liver oil, I refuse to believe the VA is the issue. More likely lifestyle (low UV, blue light past sunset), stress, and lack of cofactors.

Eating liver can also do it, but just not any liver. If you look at the autopsy data, you can get an idea of how much liver retinol can vary. I do wonder what the second-biggest overload risk is, besides supplements, and I was thinking it could be eggs.

 

[Travis]

So basically if it isn't written somewhere, it's all in their heads, right?

Well a person could claim just about anything is thyrotoxic, but why would they do such a thing without evidence?

 

[Travis]

If you're feeling adventurous or you have nothing to lose:
Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application
(disulfiram, citral, even tryptophan metabolites)
Not only does RA lower from RALDH inhibition, but retinaldehyde can directly and indirectly antagonize some RA effects (they achieve results by simply injecting retinaldehyde, e.g. "Our previous studies indicate that Rald directly binds the PPARγ-RXR complex and inhibits the activation of a transfected PPAR response element (PPRE) after agonist stimulation with rosiglitazone"):
Retinaldehyde represses adipogenesis and diet-induced obesity
Retinaldehyde Dehydrogenase 1 Deficiency Inhibits PPARγ-Mediated Bone Loss and Marrow Adiposity

That study on retinol's direct thyroid inhibition, linked above, had used TGF-β and had even mentioned its' similarity to retinol in effect. It is also interesting that you mention disulfiram, as I am very interested in this drug because it increases plasma 5-hydroxytryptophol.

So far as I know, there is only one high-affinity ligand of PPARγ: Prostaglandin J₂ is formed spontaneously from the dehyrdration of prostaglandin D₂.

prostaglandin D₂ ⟶ prostaglandin J₂ + H₂O​

Since this is a nonenzymatic event, concentrations of prostaglandin J₂ are always proportional to those of prostaglandin D₂.

 

[Terma]

That study on retinol's direct thyroid inhibition, linked above, had used TGF-β and had even mentioned its' similarity to retinol in effect. It is also interesting that you mention disulfiram, as I am very interested in this drug because it increases plasma 5-hydroxytryptophol.

So far as I know, there is only one high-affinity ligand of PPARγ: Prostaglandin J₂ is formed spontaneously from the dehyrdration of prostaglandin D₂.

prostaglandin D₂ ⟶ prostaglandin J₂ + H₂O​

Since this is a nonenzymatic event, concentrations of prostaglandin J₂ are always proportional to those of prostaglandin D₂.

I read the good parts of that study, quite informative actually. I loosely interpreted it as RA reallocating resources from metabolism toward specific growth, but that could be wrong.

To me, very often RA superficially appeared like a stress hormone (hard to reconcile with what Peat writes), but I think it's more like an broad enabler or amplifier with a "defensive" predisposition (set of target genes).

But it only scratches the surface of the RA<->TGF-B interaction, which is so tissue-dependent and more complex than I've been able to follow, I wouldn't know where to begin linking studies. They both trigger, complement and counter each other at every turn, with differences between TGF-B1 and B2. At least in some tissues, RA is protective against the pro-fibrotic effects of TGF-B, and seems kinder. I'm more scared of TGF-B.

Some people try disulfiram as a nootropic. I was too much of a *****.

I thought I saw some other major ligands for PPARgamma, but I'd have to look for it again.

 

[Diokine]

is it possible that |3 - ¢arotene could influence the redox state of tissue, and that this redox state could render said tissue less reactive towards the status tantalizingly offered by thyroid?

Asking for a friend

 

[InChristAlone]

Eating liver can also do it, but just not any liver. If you look at the autopsy data, you can get an idea of how much liver retinol can vary. I do wonder what the second-biggest overload risk is, besides supplements, and I was thinking it could be eggs.

Yes it could be eggs. I was eating 3-4 eggs a day along with my 3 tablespoons of butter and raw milk when I had that chapped lips thing going on. I always try to start eating eggs again and I just can't no matter how many good things I read about them. I was going through so many pasture raised eggs back then I just can't. Now the yolk in haagen dazs is all I need.

 

[Amazoniac]

Well a person could claim just about anything is thyrotoxic, but why would they do such a thing without evidence?

Thyroid toxicity has been a concern of yours based on your interpretation. I already mentioned many times that carotene is safer than retinol without a doubt.
The issue is that vitamin A is needed for thyroid function and vice and versa. At the same time that the body can have plenty of carotene around, it can't make use of it. Regardless of the cause, it starts accumulating and the consequence is evident here: someone's body was shutting down from its excess. Do you think that insisting on more and more carotene in such cases wouldn't make them worse? Raj had many similar cases. If reducing dietary carotene provides relief, it's clear that it can have a detrimental effect under those a circa of the stances.

 

[Amazoniac]

is it possible that |3 - ¢arotene could influence the redox state of tissue, and that this redox state could render said tissue less reactive towards the status tantalizingly offered by thyroid?

Asking for a friend

There are some publications on potential problems with carotenes but I'm not too confident that the same occurs in humanoids. However indeed some sort of unwanted desensitization or inactivation from the excess may not be too fetching at the far.

- The toxicity of antioxidants and their metabolites
- Beta-carotene affects oxidative stress-related DNA damage in lung epithelial cells and in ferret lung
- Antioxidant/Pro-oxidant Actions of Carotenoids
- Why Do We Expect Carotenoids to be Antioxidants in vivo?
- Prooxidant and antioxidant reaction mechanisms of carotene and radical interactions with vitamins E and C
- Prooxidant Actions of Carotenoids in Biologic Systems
- Antioxidant and Prooxidant Properties of Carotenoids
- Cytotoxic and genotoxic effects of |3 - ¢arotene breakdown products on primary rat hepatocytes
- Procarcinogenic and Anticarcinogenic Effects of β-Carotene
- Naturally-occurring eccentric cleavage products of provitamin A β-carotene function as antagonists of retinoic acid receptors (shared elsewhere)

 

[Travis]

Regardless of the cause, it starts accumulating and the consequence is evident here: someone's body was shutting down from its excess.

As I said before, I think you are confounding a consequence with a cause. The association between carotenemia and hypothyroidism can logically be explained by them both existing in the presence of excessive retinol:

Retinol has been shown to inhibit iodine thyroid uptake and thyroxine output in nanomolar concentrations: Retinoic acid, a more active congener, reliably lowers the conversion of β-carotene into retinol via carotone monooxygenase expression. Both of these effects have been experimentally proven, and I have seen no evidence that β-carotene is anything more than an easily-visualized biomarker of hypervitaminosis A and retinol-induced hypothyroidism..

 

[postman]

In the case of the Mikhaila Peterson, she said she had a severe reaction to a meal of "miso soup with tofu, with edamame beans, covered in soy sauce". Not all of those are said to have VA in them, but edamame for example has ~300 IU per 100 grams. But again, the hypothesis here is super-sensitivity to VA after being on a low VA diet — so its enough IMO to say that this meal could have some small amount of VA.

The carnivore diet per se does include eggs and organ meat so most of the benefits people are geting on a carnivore diet has nothing to do with vitamin A. In Jordan's case it might be different though, he's even more restrictive, I don't think he eats organ meats. Those who only eat muscle meat and receive greater benefit, that could definitely have something to do with vitamin A.

 

[Travis]

• Josephs, Hugh. "Hypervitaminosis A and carotenemia." American Journal of Diseases of Children (1944)

'As has been said above, knowledge of hypervitaminosis A is confined to the effects in animals, particularly in rats and mice, which are especially sensitive to the toxic effects of overt symptoms; the hair, especially about the head, becomes unkempt and falls out and the skin becomes greasy and has a peculiar odor suggestive of hydrous wool fat. Later the eyes become sore, there is a bloody secretion from the nose and diarrhea develops. These symptoms along with the extreme loss of weight and frequent loss of use of the posterior extremities provide a superficial resemblance to vitamin A deficiency. An almost constant feature is the development of multiple spontaneous fractures of the bones of the extremities. Some investigators reported exophthalmos, the cause of which is unknown; others stated specifically that they had never seen this result. [...] Histologically two features stand out, rarefaction of the bones with extreme thinning of the cortex and increased deposition of fat in the reticuloendothelial cells, especially in the Kupffer cells of the liver and in the spleen.' ―Hugh J.

'When vitamin A in large but nontoxic daily doses was given to rats, guinea pigs or rabbits, a rise in cholesterol and in total lipids of the serum occurred. This rise was only temporary, however, and tended to disappear after a time, even while the large doses of vitamin A were being given. The same effect was observed in human beings but not in dogs. In rats previous deficiency intensified and prolonged the response, and a similar reaction was seen after pneumonia in infants receiving vitamin A. Apart from this lipid reaction, the effect of vitamin A on physiologic processes has been little studied. No effect was observed on the formation of blood in animals. The serum calcium and phosphorus were not affected, though there was an increase in excretion of calcium, which was attributed to "décalcification" of the bones. The basal metabolic rate was decreased.' ―Hugh J.

'In contrast to the harmful results of overdosage with vitamin A, toxic effects have not been seen in animals after ingestion of excessive amounts of carotene; the animals have not lost weight or died and have not shown any of the outward manifestations of hypervitaminosis.' ―Hugh J.

'Carotenemia has been considered completely harmless, its only symptom being the development of the characteristic yellow color of the skin which generally disappears as soon as the responsible conditions have been corrected.' ―Hugh J.

 

[Amazoniac]

As I said before, I think you are confounding a consequence with a cause. The association between carotenemia and hypothyroidism can logically be explained by them both existing in the presence of excessive retinol:

Retinol has been shown to inhibit iodine thyroid uptake and thyroxine output in nanomolar concentrations: Retinoic acid, a more active congener, reliably lowers the conversion of β-carotene into retinol via carotone monooxygenase expression. Both of these effects have been experimentally proven, and I have seen no evidence that β-carotene is anything more than an easily-visualized biomarker of hypervitaminosis A and retinol-induced hypothyroidism..

But the suppression of metabolism and appearance of carotenemia can happen without a change in dietary vitamin A intake. In the case of that guy, it was solved with B12, some are solved with extra thyroid hormone. A mere deficiency of these cause vitamin A to accumulate, so it should be a consequence. Either way, how can you expect that more carotenes won't be troubling? Even though it's a regulated process, the disposal of excess is slow, and given people's experiences, it must not be completely harmless.

 

[Travis]

But the suppression of metabolism and appearance of carotenemia can happen without a change in dietary vitamin A intake.

Liver retinol accumulates with age, and so does serum retinol. This is plainly demonstrated by the London autopsy data and the NHANES survey.

Either way, how can you expect that more carotenes won't be troubling?

In the case of the thyroid, I don't think it would be harmful because I have seen no evidence for this. As far as I can tell, this had all started from the misinterpretation of carotenemia's relationship with hypothyroidism.