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

[Amazoniac]

- The Roles of Vitamin A in the Regulation of Carbohydrate, Lipid, and Protein Metabolism

"In comparison to rats, mice are more resistant to the development of VA deficiency. A normal growth curve is usually observed in weaning mice with sufficient hepatic VA storage, despite being sustained on a VA deficient diet [63,64]. In one study, a significant weight loss was achieved in mice fed on a VA deficient diet only when the VA storage was pre-depleted prior to weaning [63]. This suggests that mice might have special mechanisms to maintain VA homeostasis or they might use VA more efficiently. As a result, experimental conclusions obtained in mice cannot be directly extrapolated to rats or humans in terms of VA and its effect on growth and metabolism." @Yi at LDT

"In VA deficient rats, the liver glycogen content is abolished due to decreased glycogenesis from acetate, lactate, and glycerol, rather than directly from glucose [94,95]. The decreased glycogenesis can be recovered by the administration of glucocorticoid hormones [95]. Since VA deficient animals have lower adrenal steroid production, it is possible that VA deficiency partially affects glycogen metabolism via decreasing glucocorticoid hormone synthesis [95]. In hypervitaminotic A rats, the liver glycogen deposition in the fed state is almost the same or slightly lower than in rats fed on a chow diet [96,97]. However, the hepatic glycogenesis of hypervitaminotic A rats after fasted for 18 to 20 h is significantly higher than in rats fed chow diet [97]. This suggests that excessive VA intake for a short-term can prevent the hepatic glycogenolysis under the fasting condition. Additionally, excessive VA can also enhance the hepatic glycogenesis from glucose after refeeding in normal rats, but not in adrenalectomized rats [98]. This suggests that adrenal hormones are involved in the VA-regulated hepatic glycogen metabolism [98]."

"Very few studies looked at the effects of hypervitaminosis A on protein metabolism in animals. It is proposed in one study that 400 times the normal VA dose causes toxicity-induced weight loss and negative nitrogen balance [115]. However, the molecular mechanism by which the VA toxicity offsets the nitrogen balance in vivo is unknown."

"Dysregulation in the metabolism of either VA or lipids could negatively affect the metabolism of the other. On the one hand, long-term retinoid drug users and people who take excessive amounts of VA supplements exhibit symptoms of hypercholesterolemia, hypertriglyceridemia, and high serum low density lipoprotein levels [116,117,118]. On the other hand, patients with severe type V hyperlipoproteinemia-associated hypertriglyceridemia have an increased risk for developing hypervitaminosis A [119]. The mechanisms underlying these phenomena have been actively investigated in rodent models. Oral administration of large doses of retinol leads to the accumulation of lipid droplets in the rat liver [120]. Overdose of retinol or retinyl palmitate also causes the elevation of hepatic cholesterol, FA, and TG contents in different strains of rats [121,122,123]." @Blossom

"It has been shown that hypervitaminotic A rats have increased rates of hepatic FA oxidation and ketogenesis [123]. On the other hand, the hepatic TG synthesis rate is greatly enhanced in hypervitaminotic A rats. This is due to the increased incorporation rate of palmitate into TGs and the formation of glycerophosphate from glucose [122,123]. Interestingly, the rate of hepatic TG secretion is not changed in hypervitaminotic A rats [124]. These data suggest that VA increases hepatic lipid synthesis to an extent much greater than that it elevates hepatic lipid oxidation. The net result is the accumulation of lipids in the liver."

"Contrary to the hyperlipidemic effect of hypervitaminosis A, VA deficiency causes a partial hypolipidemic effect in rodents. In general, VA deficient rats have decreased hepatic phospholipid content and decreased serum levels of TG, cholesterol, and high density lipoprotein [60,125]. Interestingly, these rats manifest unaltered hepatic contents of TG and cholesterol [123,126,127,128]. Depending on the severity of VA deficiency in the animals, not all of the above-mentioned symptoms can be observed. The partial hypolipidemic effect of VA deficiency in rodents may be caused by a decreased FA synthesis activity in the liver and impaired cholesterol synthesis from mevalonate [125,128]. However, it is worth mentioning that the VA deficiency-induced body mass loss and food intake drop may also contribute to the hypolipidemic symptoms."

"RA treatments in mice increase hepatic FA oxidation, which has been reviewed in detail elsewhere [131]. Available data suggest that the dyslipidemia in VA deficient and hypervitaminotic A animals is a multicausal effect."

"[..]the capacity for oxidative phosphorylation is severely impaired in liver mitochondria of hypo- and hypervitaminotic A rats without affecting ATPase activity [137]. These data suggest that deficient or excessive VA status may increase basal energy metabolism in the liver."

"[..]retinoid receptors require preferential ligands to exert their full function[.]"

"The skeletal muscle is the largest organ in the body, which plays a critical role in the regulation of energy metabolism [182]. However, very limited research has been performed to investigate the effects of VA on carbohydrate and protein metabolism in the skeletal muscle. In avian species, VA deficiency depletes the glycogen content in the pectoralis major muscle [183]. On the other hand, RA treatment of mouse myoblast C2C12 cells leads to increased glucose uptake, possibly through the activation of AMP-activated protein kinase [184]. In addition, VA deficient rats have lowered protein synthesis and increased proteolysis rates in the skeletal muscle [111,185]. This change in protein metabolism partly contributes to the body mass loss in VA deficient animals. Interestingly, acute VA toxicity accelerates myofibrillar protein breakdown without affecting the rate of protein synthesis, which may also lead to muscle wasting [186]. These data, though sparing, collectively demonstrate the involvement of VA in the regulation of glucose and protein metabolism in the skeletal muscle."​

- Vitamin A, endocrine tissues and hormones: interplay and interactions

- “Turnover” of Vitamin A

I've actually never been to our med library so far, so it will be a scary, exciting quest.

There might be a secret passage somewhere, make sure to move everything.

If you could direct me to a post of yours that outlines what kind of diet you support I will gladly read it. It has never been clear, as you mainly post studies or a long book from Kellogg 'the emasculator'. You seem to be a fan of diversity in diet to take in plenty of nutrients, but that seems out of reach for many people.

There is none. Our needs for nutrients don't usually vary as much as how each person manages to get them. It's difficult to tell what's best for a given guru.

As commented various times before, I find it preferable to eat according to cravings and supplement what the diet isn't providing enough instead of trying to trick senses and force-feed. Of course if you need too many supplements, there might be something wrong with the diet.

Before you comment that mice experiments cannot be extrapolated to humans, we need to work with what we have available. If no such experiment on human exists, it's better to base on one that involved other animals that has some simriarslaities with us than nothing.

 

[Amazoniac]

So, according to this study, vitamin E/K inhibit the enzyme which removes vitamin A...there was some other posts about how vitamin E could necessitate an increase in vitamin A consumption or help with hypervitaminosis, so that vitamin E could help to deplete Vitamin A stores. Am i misunderstanding this study?

Also another odd thing is that I have Gilbert's syndrome which involves a sluggish cytochrome P450 system. So in my case maybe vitamin A would give me temporary benefits...yet I don't experience these. Just something I noted.

The odservation was:

[39] Each vitamin has been shown to act as a competitive inhibitor of the hydrolase. This effect may explain the apparently impaired hepatic vitamin A mobilization by animals fed very high levels of vitamin E.​

- α-Tocopherol Influences Tissue Levels of Vitamin A and Its Esters

"Total vitamin A (retinol and retinyl esters) liver stores and plasma retinol are diminished during a-tocopherol deficiency (5-7), and are increased during a-tocopherol supplementation (8, 9). The most effective synthetic substitute for Dio-tocopherol known, the antioxidant DPPD (10), is incapable of reproducing these effects (11). Therefore, the antioxidant properties of kine-tocopherol are not considered responsible for affecting vitamin A liver storage."

"To assess hydrolysis of retinyl palmitate in vitro,[8] two-month-old Sprague-Dawley rats were used as a source of tissue homogenates and liver acetone powders. Addition of a-tocopherol to assays with liver acetone powders inhibited hydrolysis of retinyl palmitate in a concentration- dependent manner. a-Tocopheryl acetate appeared as potent as the unesterified vitamin E, but the more polar succinate was a less effective inhibitor of hydrolase activity. Phylloquinone (vitamin K,) was even more potent than a-tocopherol, though menadione (K3) was less effective. The effects of phylloquinone and a-tocopherol were additive and not synergistic."

[8] Vitamin A metabolism: α-Tocopherol modulates tissue retinol levels in vivo, and retinyl palmitate hydrolysis in vitro​

"In a subsequent paper by Napoli and Beck,[9] a more detailed characterization of the in vitro inhibition of retinyl ester hydrolysis by a-tocopherol and phylloquinone was reported. Acetone-extracted powders from rat small intestine were used, since most lipids were removed to minimize potential complication with the lipophilic test compounds. In this system, with an apparent Km of 44 uM for retinyl palmitate, 200 uM a-tocopherol inhibited 62 percent, whereas 50 uM phylloquinone inhibited 74 percent. The nature of inhibition was non-competitive, that is, the compounds inhibited the enzyme rather than competing with substrate for the active site. Since inhibition did not increase by increasing the incubation time, and no cofactors were added, it appears that metabolic alteration of a-tocopherol or phylloquinone is not required to cause inhibition."

[9] Alpha-tocopherol and phylloquinone as non-competitive inhibitors of retinyl ester hydrolysis​

"The work of Napoli et al.[8,9] further supports the earlier indications that vitamin E status can influence the concentrations of vitamin A and its esters in tissues. Moreover, it seems probable that a-tocopherol at physiological concentration is sufficiently effective as a noncompetitive inhibitor of retinyl ester hydrolase to modulate vitamin A stores. Though phylloquinone is even more inhibitory than vitamin E in vitro, the lower concentration of vitamin K in tissues” (~ 0.1 uM) argues against a physiological role for vitamin K in modulating retinol release from retinyl esters in vivo."​

Unfortunately they used colossal doses of vitamin E. According to this, the rat requirement is about 5 mg/kg, and they used 500 mg/kg, 100x. Our estimated requirement is 15 mg, so it would be like using 1500 mg/2200 IU: hospitalizing dose. They have tried lower doses, it was way less inhibitory. I don't know if once in the body and in physiological amounts it's dispersed enough to not cause this:

[8]​

And if it does, it also increased the proportion that's found esterified, perhaps it's something advaohjwagous and the only problem might be the obscene amount used.

[8]​

- "In Deficiency Of Vitamin E, The Vitamin A Reserves Of The Liver May Be Much Reduced" (by the one and only: Thom Moore)

I feel tempted to mess with the titles but I would not be able to search for them later((

 

[sunraiser]

According to cronometer I'm getting about 200% of daily copper intake, most of it coming from short grain rice and celeriac.

By nutritiondata, you'd need nearly a kilo of cooked weight white rice and the same of celeriac to achieve 1mg copper intake, so 500g of each. That sounds like an awful lot.

How long have you been doing this diet and do you enjoy it? Also, how do you feel on it?

 

[Makrosky]

Over the past 3 weeks (ish) my mood and skin problems have been improving noticeably and by a week or so ago my mood has returned to what I would call 'normal', which I haven't experienced for some years. After reading this I added up how long I'd been low Vitamin A and it's been 9 1/2 weeks. So 8 weeks seems about right

So you have been following a low A diet ? What was your diet like ?

 

[Lynne]

So you have been following a low A diet ? What was your diet like ?

Yeah, low VA diet consisting mostly of white rice, potatoes, beef, a bit of low carotene fruit, mushrooms, coffee, sugar, a small amount of low fat milk (~125ml/day) and a very small amount of coconut oil.

 

[postman]

By nutritiondata, you'd need nearly a kilo of cooked weight white rice and the same of celeriac to achieve 1mg copper intake, so 500g of each. That sounds like an awful lot.

How long have you been doing this diet and do you enjoy it? Also, how do you feel on it?

On the days I eat rice I make a lot of it, about 750 grams (dry). When I eat celeriac I usually eat the whole head in one day, about 30-45% of the head is the stringy part though which i discard so I eat roughly 400-600 grams. Avoiding VA is the best thing I've ever tried for inflammation, it's even more effective than avoiding all PUFAs. Now I eat almost no VA and no PUFAs either.

 

[Blossom]

Vitamin A lab results after 7.5 months of eating 0-4% daily on average of my RDI per cronometer.

 

[Kyle Bigman]

Wow; it's still quite high. Why do you think this is ? this is disturbing

View attachment 12419 Vitamin A lab results after 7.5 months of eating 0-4% daily on average of my RDI per cronometer.

 

[Orion]

Wow; it's still quite high. Why do you think this is ? this is disturbing

Depletion equations vary, but at zero % intake some rates show 1 to 2 years to get levels below deficient values. Lots of variables will affect this, sunlight, smoking, alcohol, vitamin D E K status, body fat %, protein and zinc intake.

 

[Peater Piper]

View attachment 12419 Vitamin A lab results after 7.5 months of eating 0-4% daily on average of my RDI per cronometer.

Did you test before you started restricting?

 

[Amazoniac]

View attachment 12419 Vitamin A lab results after 7.5 months of eating 0-4% daily on average of my RDI per cronometer.

- Grant Genereux's Theory Of Vitamin A Toxicity [Fig. 6.5, but (as you know) it should be less predictable than that]

µg/dL(100 ml) * 0.0349 → µmol/L
µmol/L * 28.6533 → µg/dL(100 ml)

Where there's a [?], it was typo by them, they meanted 20 µg/dL, which is the threshold of your lab.​

 

[Amazoniac]

- Retinoic Acid and Affective Disorders: The Evidence for an Association

Spoiler

"Isotretinoin is a retinoid that occurs naturally in the body; retinoids are a group of molecules derived from vitamin A that are essential in regulating the function of multiple organ systems in the embryonic and adult mammal.[1]"

"It is the all-trans isomer of RA that has a high affinity for the RA receptor to regulate transcription and the bioactivity of 13-cis RA is most likely achieved via isomerization in tissue to all-trans RA.[10, 11]"

"Referring to the spectrum of retinoids used in the pharmacological treatment of dermatologic disorders, Silverman et al[28] in their 1987 paper entitled, “Hypervitaminosis A syndrome: A paradigm of retinoid side effects”, stated that “although each new retinoid is developed with the aim of maximizing specific therapeutic effects and minimizing toxicity, the fact remains that the major side effects of retinoid treatment are those of hypervitaminosis A syndrome. There appear to be no “new” side effects or toxicities encountered during the clinical use of first-, second-, or third-generation retinoids that cannot be found in the hypervitaminosis A literature. Hypervitaminosis A was described as being “most commonly” associated with symptoms of lethargy, depression, cyclothymia, insomnia and hypersomnolence, skin changes, hair loss, headache, bone and joint pain, and liver enlargement. It was also noted that it could cause irritability and frank psychosis. The authors noted that mental symptoms could be subtle and not attributed by the patients to hypervitaminosis A, and therefore clinicians should specifically ask about them. Other retinoids have also been associated with depression (in one case with a positive rechallenge)[29] as well as suicidality,[30] providing evidence for a “class effect”, or common occurrence of side effects, with the retinoids."

"A number of cases have been reported in the literature of mental symptoms associated with vitamin A toxicity, including irritability, depression, lethargy, mood lability, and psychosis.[31-39] These symptoms resolve with discontinuation of vitamin A.[36, 38, 40-42] For instance, Restak[40] reported a case of vitamin A toxicity associated with the development of aggression, personality changes, and depression, which resolved with discontinuation."

"The dermatology literature has frequently emphasized the potential for positive behavioral effects with isotretinoin because of the effectiveness of this drug in clearing acne.[106-109] Although acne is associated with a decrease in self-esteem, anxiety about appearance and unhappiness about appearance,[110-112] studies have not been able to demonstrate a correlation between symptoms of clinical depression and objective severity of acne, or an improvement in clinical depression with treatment. Furthermore, although studies have shown improvements in self esteem and anxiety about appearance with acne treatment, they have not clearly shown an increase in actual cases of depression based on standardized structured clinical interviews in non-cystic acne patients. For instance, studies have not shown an association between dermatological conditions and psychiatric disorders in long term care psychiatric patients.[113]"

"Overall, review of [] cases indicates that depression and suicide do not follow immediately after treatment but commonly 1-2 months after commencement, sometimes with a longer delay. This suggests that the biological mechanism may not be via immediate influence of 13-cis RA on a crucial neurotransmitter or other signal pathway but may be through a secondary system or possibly alteration of neuroplasticity or metabolic process known to be influenced by RA, as previously described[27] and discussed [] in section 3.3. Alternatively, changes in neurochemical systems may occur more rapidly, but it may take weeks or months before a behavioral effect is seen, as is the case with the mechanism of action of antidepressants."

"The fact that higher doses of isotretinoin are associated with a greater risk of depression is further indication that isotretinoin is responsible for the development of depression. For example, when doses were as high as 3 mg/kg/day, which is 3-6 times higher than the standard dose, then 25% of patients[92] exhibited depression, contrasting with the 3-4% that is described in several other reports."

"Brain regions that are endogenously regulated by RA, and which may be disrupted by isotretinoin to potentially promote depression, have been described in our previous review and include the striatum, hippocampus and frontal cortex.[27] An area of the brain, however, that has been little considered for retinoid action is the hypothalamus. The hypothalamus is the hormone regulatory center of the brain and, as part of the hypothalamus/pituitary/adrenal (HPA) axis, is a central component in the response to stress. Hyperactivity of this system is a reproducible finding in depression."

"Isotretinoin administration has also been shown to affect metabolic pathways, alterations of which have been linked to depression; two examples are given below involving biotin and homocysteine. Biotin, a member of the B vitamin family (vitamin B-7) is a required nutrient that is involved in the biosynthesis of fatty acids, gluconeogenesis, and metabolism of amino acids. Side effects of biotin deficiency include hair loss, conjunctivitis, neuromuscular dysfunction, skin changes, neurological dysfunction, and of note for this review, depression.[139-143] For instance, Baugh described a dietary induced case of biotin deficiency resulting in anorexia, nausea, vomiting, glossitis, skin changes and depression,[144] while Levenson[139] described a biotin deficiency case which was associated with depression and thoughts of suicide. These symptoms went away after biotin supplementation. One mechanism by which biotin is recycled in the body, maintaining its availability, is supported by the enzyme biotinidase.[145] Mutations in this enzyme result in biotin deficiency.[140, 145-151] Isotretinoin administration to human subjects is associated with a decrease of biotinidase,[152] and the presumed decrease in biotin that would result from this may contribute to depression."

"Homocysteine is a sulphur containing amino acid that is involved in carbon transfer reactions.[153] Homocysteine can receive a methyl group from 5′-methyltetrahydrofolate and become re-methylated to methionine, the immediate precursor of S-adenosylmethionine (SAM), a donor of methylation reactions involved in the synthesis of DNA, proteins, phospholipids, neurotransmitters and polyamines. SAM is involved in the synthesis in the brain of dopamine, norepinephrine and serotonin, neurotransmitters that have been linked to depression,[154, 155] and many studies have found a relationship between elevated homocysteine levels, lower folate concentrations, and depression.[153, 156-164] Increased concentrations of homocysteine have also been associated with attacks of violent anger.[165] Isotretinoin administration to human subjects was shown to be associated with increased concentrations of homocysteine,[166] as well as decreases in 5-methyl-tetrahydrofolate,[167] providing a potential metabolic mechanism by which isotretinoin may promote depression."

"There is evidence that some of the neurological side effects are not immediately reversible. Neurological events reported to the Norwegian Medicines Agency were assessed in patients treated with isotretinoin. There were 91 total adverse events reported from 1985-2005. Thirty nine included long lasting neurological or muscular symptoms. Long lasting neurological symptoms including memory loss, dizziness, headache, loss of concentration and ataxia were present in 17 cases. Symptoms persisted 2-18 months after stopping treatment.[173]"

"In the case of patients reported to the Norwegian Medicines Agency, single photon emission computed tomography (SPECT) of the brain was performed in 15 cases who reported lasting neurological symptoms. Altered brain function was seen in all cases involving altered or reduced frontal lobe blood flow.[173] Ten of these patients were evaluated to have organic brain damage."

[27] The Neurobiology of Retinoic Acid in Affective Disorders

Spoiler

"This paper has reviewed the evidence for a link between retinoids and affective disorders. A number of lines of evidence are consistent with such a relationship. This evidence is as follows:

1. Preclinical and clinical results suggest that either an excess or deficiency of RA is associated with behavioral changes that include symptoms of depression.
2. Studies in animal models, in particular the mouse, indicate that exposure to 13-cis RA results in depressive-like behavior and well as a decline in learning and memory.
3. RA can enter the brain and directly modulate neurotransmitter systems hypothesized to mediate symptoms of depression, in particular the dopaminergic pathways but also, to a limited extent, serotonin and norepinephrine pathways. Further, RA can act on neurotransmitters in brain regions associated with depression including the hippocampus and striatum.
4. The prefrontal cortex is a third region influenced by RA, in which isotretinoin treatment in the human results in a decline in metabolism."

"The role of RA in regulating CNS development has been extensively investigated (as reviewed by Maden (Maden 2001)) but, until recently, it was scarcely considered that RA may [] influence neuronal function in the adult brain. Accumulating evidence has shown, however, that RA signaling occurs in the brain of the adult (Krezel et al 1999; Luo et al 2004a; Sakai et al 2004; Thompson Haskell et al 2002; Zetterstrom et al 1999; Zetterstrom et al 1994), suggesting that the adult brain, like the embryo, may be sensitive to exposure to excess RA."

"Retinoids are known to bind to retinoid receptors in the brain and to exert effects on gene transcription. Retinoid receptors are concentrated in limbic areas that have been associated with depression, including the amygdala, prefrontal cortex, and hippocampus. Retinoids also influence neurochemical systems that have been implicated in depression, in particular dopamine but to some extent serotonin and norepinephrine. According to the concepts proposed in this paper these effects can translate into behavioral effects, including symptoms of affective disorders. As we describe below, retinoids like all-trans-RA (the active form of vitamin A), an isomeric variant of 13-cis-RA, have psychiatric effects at high doses, and when deficient can lead to impairment of learning and memory. Studies in both humans and animals show that 13-cis-RA can induce depressive behaviors. Clinical evidence for an association between 13-cis-RA and depression in humans comes from similar neuropsychiatric effects with other retinoids in its class (e.g., Vitamin A), case reports in the literature, temporal association, challenge-rechallenge, and dose response cases. This report proposes RA as a previously under-recognized neurochemical system that is involved in the pathophysiology of depression."

"The RA receptors (RARs) are members of the nuclear receptor superfamily that includes the receptors for estrogen (ER), androgen (AR), mineralocorticoids (MR), glucocorticoids (GR) and thyroid hormone (THR). All of these receptors function in a similar manner (Bastien and Rochette-Egly 2004) — the receptor, either present in the nucleus, or moving from the cytoplasm into the nucleus, binds to a response element in the promoter of responsive genes. In the presence of ligand the receptor switches in conformation and releases corepressors that would otherwise keep the gene repressed in the absence of ligand."

"Although the RXRs can bind 9-cis RA, it is now considered unlikely that this is an endogenous ligand for the RXRs in most tissues. The RXRs can act independently of ligand and ligand activation may not be necessary for the function of this nuclear receptor (Rowe 1997). However, a potential group of ligands exists in the form of polyunsaturated fatty acids, including the omega-3 fatty acid docosahexanoic acid (DHA), and its affinity for RXR may account for some of the actions of DHA in the brain (Lengqvist et al 2004). It is of interest that omega-3 fatty acids have been shown to have efficacy in the treatment of depression (Stoll et al 1999); however this action may not necessarily be via the activation and interaction of RXR with RAR, but may be the result of RXR’s binding to the many other nuclear receptors to which RXR can heterodimerize including thyroid hormone, vitamin D and peroxisome proliferator-activated receptors (Rowe 1997)."

"As reviewed by William Blaner (Blaner 2001) there is very strong evidence that 13-cis RA [isotretinoin] is produced endogenously, and 13-cis RA is present in the plasma at higher or similar concentrations as the all-trans isomer (Eckhoff and Nau 1990; Tang and Russell 1991). Although 13-cis RA only weakly binds to the RA receptors, evidence indicates that 13-cis RA is isomerized to all-trans RA in tissues (Shih et al 1986; Tsukada et al 2000) and thus 13-cis RA acts like all-trans RA to regulate transcription via the RA receptors. An important physiological difference between the isomers is that 13-cis RA remains in the circulation much longer than its all-trans counterpart in humans, with an elimination half-life of 20 hours, versus 0.9 hours for all-trans RA while peak plasma concentrations are reached at 2-4 hours after an oral dosage (Weigan and Chou 1998)."

"[..]isotretinoin is the only non-psychotropic drug in the top 10 list of drugs most commonly reported to be associated with depression."

"If a drug in the same chemical class as isotretinoin had a similar side effect to the latter then this would provide evidence that isotretinoin was associated with this adverse event. Vitamin A is such a chemical, which is in the same retinoid class as isotretinoin. Because Vitamin A is the parent compound of RA increased amounts of this substrate would be expected to result in elevated levels of RA. Thus it would be predicted that many of the adverse side effects of isotretinoin will be similar to those of patients taking high doses of Vitamin A although, since it requires several metabolic steps for vitamin A to be converted to RA (Fig. 1), and several alternative pathways also exist into which vitamin A may be channeled, vitamin A would not be expected to be as potent as RA. Indeed, large doses of vitamin A can have a number of other neurological and mental effects including nausea, vomiting, weakness, fatigue, irritability, drowsiness, loss of appetite, ataxia, decreased interest, headache, and diplopia (double vision) (Bass 1959; Bendich and Langseth 1989; Fishbane et al 1995; Gerber et al 1954; Restak 1972; Rodahl and Moore 1943; Shaw and Niccoli 1953; Stimson 1961). These effects appear to be more common in children and adolescents (Lombaert and Carton 1976; Pasquariello et al 1977; Stimson 1961)."

"RA has a variety of effects on brain neurochemical systems believed to be involved in depression, in particular dopamine (section 4.2) but also serotonin via induction of the serotonin 1A receptor (Charest et al 1993) and norepinephrine through the transporter for this neurotransmitter (Matsuoka et al 1997)."

- Massive isotretinoin intoxication


@Diokine

 

[Blossom]

Did you test before you started restricting?

Unfortunately no.

 

[Blossom]

- Grant Genereux's Theory Of Vitamin A Toxicity [Fig. 6.5, but (as you know) it should be less predictable than that]

µg/dL(100 ml) * 0.0349 → µmol/L
µmol/L * 28.6533 → µg/dL(100 ml)

Where there's a [?], it was typo by them, they meanted 20 µg/dL, which is the threshold of your lab.​

Thanks. No questions. I just figured I’d post the results.
Thanks @Orion. From reading here and elsewhere I gathered that blood tests are a poor way of measuring true VA levels. I probably won’t check again anytime soon.

 

[Amazoniac]

- Metabolic Effects of Inflammation on Vitamin A and Carotenoids in Humans and Animal Models (!)

"VA intake and metabolism are seriously altered during the acute-phase response (APR) to inflammation [] (6). The APR is a systemic metabolic response to infection, trauma, or tissue injury that induces fever, increases the synthesis of inflammatory cytokines, and enhances white blood cell production."

"Retinol-binding protein (RBP) and transthyretin form the plasma transport complex for retinol; both proteins are chiefly synthesized in the liver (8), the major organ involved in the APR (9). The APR results in dramatic alterations in protein synthesis and energy metabolism (10). A principal characteristic of the APR is the hepatic synthesis and secretion of acute-phase proteins (APPs) that play anti-infective roles and, consequently, function in response to tissue injury after trauma or infection (9). The leading regulators of the APR in hepatocytes are IL-1 and IL-6 (11). The kinetics of APP responses vary; C-reactive protein (CRP) changes most rapidly and increases dramatically in plasma within 8 h of APR induction. Other APPs, such as α1-acid glycoprotein (AGP), increase more slowly and remain elevated during convalescence."

"Both RBP and transthyretin R are negative APPs because their concentrations decline during the APR. Retinol binds nearly stoichiometrically to RBP; thus, they are equally affected. The reduction in plasma holo-RBP (RBP bound to retinol) occurs quickly, even before CRP and AGP have reached peak concentrations. The rapidity of the response may be caused by the inherently short half-life of RBP (∼12 h in adults) (12, 13), which must be continuously synthesized to maintain normal holo-RBP concentrations (14). The APR may reduce plasma amino acid concentrations (15), which further inhibits RBP synthesis, a process that is sensitive to protein and calorie malnutrition (16)."

"Low serum retinol (SR), i.e., hyporetinolemia, has been reported in children and adults in association with acute infections (e.g., measles, malaria, diarrhea, HIV), multiple morbidities (17), and trauma (18). Several studies have provided evidence that retinol and RBP concentrations are inversely correlated with serum concentrations of IL-6, the major regulator of the APR because it induces the gene expression of many APPs (9)."

"The most common experimental models of inflammation induce the APR with LPS, which is a natural component of the outer wall of gram-negative bacteria that causes sterile inflammation (19). The response to LPS is dose-dependent, wherein lower doses induce an APR and higher doses result in vascular collapse and death. LPS signals through toll-like receptor 4, which triggers signal transduction cascades that result in the activation and nuclear translocation of NF-κB, which induces the release of proinflammatory cytokines TNF-α, IL-1, IL-6, and type 1 interferons (20). LPS acts rapidly, triggering the APR within hours (21). In the liver, IL-6 alone is sufficient to initiate similar changes by signaling through glycoprotein 130 and signal transducer and activator of transcription 3 pathways (11, 21)."

"In rats treated with low-dose LPS sufficient to elevate body temperature but not cause serious lethargy or sickness, SR concentrations reached a nadir between 12 and 24 h, with a reduction ≥50% (22, 23). Serum RBP declined with similar kinetics (22), and although liver RBP synthesis was substantially reduced by 24-h post-LPS treatment, liver retinol concentration was maintained. RBP4 (Rbp4) mRNA concentrations in the liver were reduced to 50% of the control value by 12 h after LPS treatment. This work provided evidence that inflammation-induced hyporetinolemia is caused by a reduction in liver RBP synthesis that was initiated by the reduced transcription of Rbp4. Similar results were obtained in a rat model of inflammation induced by recombinant human IL-6 that caused a more dramatic and prolonged decline in SR, possibly caused by persistent inflammation (24)."

"A practical concern is that if SR and RBP concentrations are reduced by inflammation, the results lend a false impression regarding VA status. An experimental illustration is shown in Figure 3 [No (Wagner, 2018).] for an animal study in which low SR resulting from dietary restriction was quantitatively similar to hyporetinolemia induced by LPS in animals fed adequate VA. Whereas in experimental settings causality is known, in human settings, in which dietary intake often is uncertain or seasonal, low SR concentrations could easily be attributed to nutritional inadequacy when, in fact, they are caused by inflammation."

"In well-nourished humans, SR concentrations return to normal values during the convalescent/resolution stage of infection. This suggests that the APR involves a redistribution of retinol from plasma to other body compartments, from which it is later able to return to plasma. A redistribution rather than a net loss may also be inferred from the results of animal studies in which the urinary loss of retinol during infection was quantitatively small compared with normal VA turnover (23)."

"Mathematical modeling indicated a 79% reduction in the hepatic mobilization of retinol within 15 h after LPS administration and a 75% reduction by 5.6 h after the IL-6 injection. The results imply that retinol exits plasma transiently during inflammation and accumulates in the liver, but based on its reappearance there is not an appreciable irreversible retinol loss (24). It was hypothesized that inflammation-induced hyporetinolemia reflects a sequestration of plasma retinol that is associated with impaired mobilization of retinol caused by reduced RBP synthesis."

"VA deficiency and inflammation may interact to result in a quantitatively greater reduction in plasma retinol than from either condition alone (23)."

"Lipoprotein lipase activity [use of circulating poison A] is known to be reduced by LPS (34, 35). Consistent with the hypothesized delay in chylomicron clearance, liver retinyl esters were lower in the LPS- and VA-supplemented group (23). Reduced hepatic metabolism has also been suggested by the reduction in the liver of mRNA concentrations for several genes involved in VA uptake, β-carotene and retinol metabolism (e.g., β-carotene oxygenase 1, lecithin retinol acyltransferase and dehydrogenase/reductase 3), and retinoic acid (RA) oxidation (e.g., cytochrome P450 family 26) (36). In addition, studies in other models have shown that liver injury results in the gradual mobilization or loss of retinyl esters from stellate cells, which can eventually lead to liver fibrosis (37). Inflammation also alters the distribution and metabolism of RA, the major active metabolite of VA. When inflammation was induced by low-dose LPS in rats with marginal VA status, [3H]RA uptake and metabolism to polar metabolites were considerably reduced (38, 39)."

"Infections increase the risk of malnutrition by a variety of mechanisms that were originally described for vitamin B-12 (47) and reviewed for VA (6). Although the specific categories vary among authors, they generally include decreased food intake, impaired nutrient absorption, direct nutrient loss, altered transport to target tissues, and increased metabolic requirements or catabolic losses."

"Enteric infections can decrease the absorption of many nutrients. Enteric infections damage the intestinal epithelium and decrease the expression of brush-border enzymes such as lactase, as shown in a piglet model of neonatal diarrhea (52). Intestinal barrier damage during mild Ascaris infections of children also decreases lactose absorption, which recovers upon antiworm treatment (53). For VA provided as β-carotene, absorption may be improved by roundworm treatment (54). The absorption of physiologic doses of preformed VA is generally quite high (∼99%) [⇊] but is lower (70–80%) in children with diarrhea, an Ascaris infection, and nonenteric infections such as pneumonia (55, 56). Although the mechanisms of this absorptive defect are unclear, impaired absorption contributes to an increased risk of VA deficiency in children with low dietary intakes."

"After absorption, several infections can cause direct nutrient loss, perhaps from intestinal “leakiness” resulting in protein-losing enteropathy, which occurs with postmeasles diarrhea (57), or by the direct loss of blood, which occurs during hookworm infection and leads to iron-deficiency anemia (58). Considerable amounts of VA can be lost in the urine as a result of proximal tubular dysfunction in the kidney (6). Low-molecular-weight plasma proteins, including RBP, filtered through the glomerulus are normally reabsorbed in the proximal tubule (6). One hospital-based study (59) found that adults with severe infections, such as pneumonia or sepsis, excreted a mean of 223 μg retinol/d (presumably bound to RBP), which is 25% of the RDA for men and 32% for women. In that study, 24% excreted >1 RDA/d, indicating that severe infections could result in substantial urinary losses. (It should be noted that the use of aminoglycoside antibiotics, potentially toxic to kidney tubular epithelium, can be a contributing factor to urinary VA loss). Children with sepsis also excrete substantial VA in the urine, whereas children with pneumonia and diarrhea excrete lower amounts (60). Losses may continue for several days (61) and are associated with a high fever and evidence of kidney tubular dysfunction (e.g., increased urinary concentrations of β2 microglobulin)."

"During the APR, the decrease in SR concentration caused in part by the decreased mobilization from the liver (31) suggests that retinol availability in peripheral tissues may be diminished."

"It is possible that limited VA availability in the immune system might be beneficial, perhaps by altering the type of immune response to particular pathogens, because RA is produced by immune cells and directly regulates the differentiation and survival of particular subsets of immune cells, particularly T lymphocytes (63). Carotenoid concentrations may also be lower during the APR (64), but the implications of this lowered concentration are unclear. It is not known whether the decline in carotenoid concentrations is transient, as for retinol, or if it represents “lost” carotenoids from increased catabolism or diminished intakes during illness."

"As previously mentioned, VA deficiency is accompanied by immune deficiency and susceptibility to a wide range of infectious diseases (145, 146). In addition, marked atrophy of the thymus and spleen is observed in VA-deficient animals (147)."

"During infection, requirements for some nutrients may increase because of increased utilization or catabolism. The resting metabolic rate is increased during HIV infection (65), which demands increased caloric intake to prevent weight loss at equivalent levels of activity. In addition, classical studies of model infections of human volunteers have shown increased nitrogen loss as a result of protein catabolism (66). With regard to VA during the APR, consistent evidence of increased metabolism or catabolism has not been demonstrated. However, tissue carotenoid pools decrease during the induction of an APR in chickens (67), suggesting catabolic losses. Interestingly, tissue carotenoid pools are more resistant to change at low dietary carotenoid concentrations. Similar data are not available from humans, but oxidative metabolism induced during inflammation might result in decreased tissue carotenoids. Consequently, altered metabolism of provitamin A carotenoids during infection could adversely affect VA status."

"Both RBP and transthyretin are depressed during infection and inflammation. In the kidney, RBP becomes uncoupled from transthyretin, and during a high fever holo-RBP is not reabsorbed but excreted in the urine (6)."

"Because of limited carotenoid bioavailability [∼10–40% (108)] and low achievable plasma concentrations (∼2 μmol/L), [] direct antioxidant effects may not fully account for the attributed carotenoid-related health effects. Instead, other mechanisms, such as the alteration of intracellular-signaling cascades and/or gene expression, may be more important. Carotenoids interact with several transduction cascades, reducing NF-κB and stimulating Nrf2 translocation (5). Carotenoids can block signal transduction at various stages by binding to cysteine residues (Michael adduct reaction) of nucleophilic proteins, depending on their cellular concentration and the general inflammatory state."

"[..]lycopene at physiologic concentrations [in cell cultures] resulted in reduced TNF-α activity in inflammation-stimulated human mammary cancer and osteoblast cell lines. Interestingly, this effect was stronger for lycopene hydrophilic degradation products (after UV radiation) and its derivatives (109)."

"Many carotenoids escape absorption in the small intestine, and processes regarding carotenoid metabolism and degradation in the colon have been overlooked (114, 115). In vitro studies have suggested that carotenoids are only partly recovered in the colonic fraction (10–50%) (116, 117). From other phytochemical studies with polyphenols, it is evident that microbiota can promote molecular ring fission, deglycosylation, hydrolysis, deglucuronidation, and demethylation reactions (115). No data to our knowledge are available for carotenoids. It may be speculated that potential polar degradation products could be produced, which may be bioactive."

"Human milk contains various carotenoids, of which lutein is often predominant (174, 175)."

"In a rat study with lutein-derived products created by UV irradiation, degradation products more strongly ameliorated NO, malondialdeyhde, prostaglandin E2, TNF-α, and IL-6 than lutein itself (118). Contrarily, supraphysiologic RA doses (1–10 μmol/L) were associated with prooxidative effects (119) compared with lower doses (<1 μmol/L) (5), emphasizing the importance of exposure concentration. Other carotenoid metabolites, such as apo10-lycopenoic acid, were stronger activators of RA receptor (RAR) and retinoid X receptor in animal trials than lycopene (120, 121), suggesting VA-like behavior (122). In addition, apo10-lycopenoid acid upregulated sirtuin 1 enzymatic activity in ob/ob mice, preventing fatty liver formation (123). In liver cells, several β-carotene cleavage products (β-apo14′-carotenal, β-apo14′-carotenoic acid, and β-apo13-carotenone) competed with RA binding to RAR, highlighting their involvement in cell growth and differentiation (124)."

"Lower-to-intermediate concentrations may exert positive effects on gene expression and antioxidant effects, whereas higher concentrations act pro-oxidatively. Further nuclear targets, such as the implication of RAR/retinoid X receptor and potential VA-like effects, also deserve more attention. Finally, our knowledge on carotenoid processes in the colon and interaction with the microbiota is nil. As long as these aspects remain marginally understood, our comprehension of the role of carotenoids in chronic diseases and inflammation will be far from complete."​

- Subclinical inflammation affects iron and vitamin A but not zinc status assessment in Senegalese children and Cambodian children and women

 

[InChristAlone]

View attachment 12419 Vitamin A lab results after 7.5 months of eating 0-4% daily on average of my RDI per cronometer.

Wow, thanks for sharing! Looks to me like you have a large store of it. Could take many years to get to very low levels.

 

[Amazoniac]

Glocom, if the test is inexpensive and convenient for you, it might be worth tracking it as often as you wish. A single measure doesn't mean much, but various of them might show you how it progresses. In the experiment below, a soy diet (providing 25 mcg of poison A; 4% of the RDA is about 30 mcg) for some reason (that perhaps is not be related to the toxin burden) affected the poison A detox, not sure if it halted because it's just plasma. Apparently levels are supposed to drop as time passes, and not go from normal to critical all of the sudden.

- Grant Genereux's Theory Of Vitamin A Toxicity (in 'Spoiler')

 

[Amazoniac]

However! It just occurred to me that on low intakes much less (if any) is stored, so it's possible that all the amount ingested is being used and normalizing to some extent the plasma levels without repletion, in facto requiring some mobilization to make up for what diet isn't providing. Therefore on these low intakes (but not devote), there can be an abrupter und unexpected drop at some point.

 

[charlie]

Gallbladders, cholecystitis, cholelithiasis...caused by excess Poison/"Vitamin A", and the body tries NOT to absorb it and Vitamin D from the diet

 

[Amazoniac]

Tarmander's comment related to a loss of efficiency once you reach a certain degree of depletion is actually the stage when the body can't afford to store the amount ingested anymore, it has to nourish all tissues first (including the liver).