This is not written to diagnose or treat a condition, but only for informative purposes. Please consult your doctor before stopping or starting medications or supplements, and before making dietary or lifestyle changes based on the information provided. – Meredith Arthur, MS, RD, LD
Now for the various ways that we can alter Vitamin A Metabolism…….
- Oxalate
- vitamin C (excess from supplements)
- Glycine
- Miralax or other PEG products
- Thiamine deficiency
- B6 deficiency
- Iron deficiency
- Zinc deficiency
- H2 Receptor antagonists
- High dose melatonin
- Gut dysbiosis
- Acetaldehyde (and alcohol)
Under each section there is a mechanism of action, followed by a possible solution. Of course, talk with your health care provider before making any changes.
OXALATE from plants or made from VITAMIN C or GLYCINE or Miralax (PEG) in the body can impair Vitamin A metabolism
Oxalate is a component of plants that is impossible for the body to completely break down. It is a poison. We absorb it at variable rates, but some of us make it in our bodies from vitamin C and glycine. Excess vitamin C becomes oxalate through direct breakdown and without enzymes. Usually this occurs in vitamin C over 2000 mg, but it can happen at lower doses as well. Never take vitamin C to “bowel tolerance” as this is likely actually death of the intestinal cells due to oxalate poisoning. Glycine is metabolized to oxalate in a B6 and thiamine deficient state, but when there is adequate B6 and Thiamine, it does not become oxalate.
When oxalate is high it impairs an enzyme called Lactate Dehydrogenase (LDH). We have to make some lactate to keep energy metabolism going. When the body is producing lactate, it also produces NAD+ which is what drives vitamin A (retinol and retinal) metabolism forward. What I found through a deep dive into literature is that Oxalate doesn’t directly inhibit alcohol dehydrogenase or retinol dehydrogenase or aldehyde dehydrogenase which was what I was searching for. Oxalate actually impairs lactate dehydrogenase (LDH) which lower NAD+ levels. I hypothesize that oxalate takes away the “energy” needed to drive those reactions forward by impairing LDH.
LDH is actually the last enzyme involved in the formation of oxalates. I believe that oxalate being able to have a feedback inhibition on LDH is a safety mechanism built into our human biology, but that it backfires and wreaks metabolic havoc on vitamin A metabolism and also energy metabolism.
Oxalate impairs LDH activity via NAD pathway
https://pubmed.ncbi.nlm.nih.gov/14646967/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC473141/
https://www.sciencedirect.com/science/article/abs/pii/0009898168903768?via%3Dihub=
Oxalate Pathogenic In Autism (Perhaps this is the connection! If oxalate impairs LDH, resulting in low NAD, then retinal levels increase. These complex with ethanolamine causing A2E and microglial activation resulting in neurological decline.)
https://pubmed.ncbi.nlm.nih.gov/21911305/
Lactate and pyruvate act as redox buffer to balance NADH/NAD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983055/
Jenny Jones, PhD, pointed the article below out to me as supporting evidence for the connection between need for normal LDH reaction to restore NAD levels.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869616/
The article bleow is an excellent article! This gives the big picture of NAD production, recycling, and salvage pathways. Amazing! LDH, which is inhibited by oxalate, plays a pivotal role in NAD recycling.
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
https://www.nature.com/articles/s41392-020-00311-7
Solutions:
1. Low oxalate diet
2. Avoid excess vitamin C in excess (variable per person, but most kids don’t need more than 500 mg per day)
3. Ensure adequate levels of B6 and thiamine (Seizure meds tend to deplete B6 – ask doctor about 50 mg of P5P, active form of B6) – ask doctor before starting supplements CAUTION – B6 in a low NAD state may be toxic.
4. Avoid glycine supplements and also collagen powders as these are high in glycine
MIRALAX can become OXALATE and also can tie up alcohol dehydrogenase and aldehyde dehydrogenase that are needed for Vitamin A metabolism
Approximately 3.7% of PEG based laxatives are absorbed. This can be metabolized by the body to glyoxylate and then to oxalate especially in a B6, Thiamine, or Niacin deficient state. This will impair LDH, subsequently lower NAD, and thus impair vitamin A metabolism, but also overall metabolism. In addition the first two steps of PEG metabolism involve alcohol dehydrogenase and aldehyde dehydrogenase. They are enzymes used in vitamin A metabolism. So Miralax may tie up these enzymes for an unknown period of time. This would be an interesting study in a rat lab.
So many people with Autism take PEG (Miralax). PEG can also cause gut dysbiosis (see below for info on bacterial steal of NAD+) Perhaps many have A2E complexes of the essential ether lipid ethanolamine due to increasing retinal levels (this is a hypothesis).
PEG with weights greater than 4000 aren’t absorbed (1960 studies), but somewhere along the way a manufacturer changed it out for PEG 3500, probably due to cost, and the researchers felt absorbing 200 ml out of 5400 ml was no big deal.
I propose that 3.7% absorbed of the PEG laxative are causing a big deal. And the unabsorbed product is causing gut dysbiosis.
Ever notice that the label says not for use in children? Also to not use more than a week?
Studies…
https://onlinelibrary.wiley.com/…/3527600035.bpol9012
https://www.gastrojournal.org/…/S0016-5085(17…/fulltext
Solution:
1. Ask your doctor if you can stop Miralax
2. Ask your doctor for alternatives such as magnesium, senna, glycerin suppositories, etc.
B6 DEFICIENCY
B6 deficiency can cause increased production of oxalate from the amino acid glycine. Also, thiamine is needed to activate B6 into pyridoxal-5-phosphate. In addition, B6 and thiamine deficiency can prevent the production of NAD from tryptophan. High losses of B6 can occur when oxalate clearing through the kidneys is high. B6 is also depleted by birth control. Many seizure medicines deplete B6.
Solution:
– Ask physician about taking P-5-P. (However, I believe at this time that supplementing P-5-P in a NAD deficient state due to alterations in dietary factors that prevent NAD recycling can cause B6 to become toxic. See this post for that hypothesis. CAUTION – B6 in a low NAD state may be toxic.
– Ask physician about thiamine supplementation
– Avoid glycine supplements or collagen powders which are high in glycine
Graphic source: https://www.researchgate.net/figure/The-OADHC-dependent-pathways-of-the-lysine-and-tryptophan-catabolism-interacting-with_fig6_339050266
THIAMINE DEFICIENCY
Thiamine is needed to activate B6 to its P5P form. Thiamine is also needed to help pyruvate become lactate, which leads to adequate levels of NAD+. Thiamine deficiency can be caused by drinking too much coffee, tea, or caffeinated soda. It can also be depleted by the drugs lasix and metformin.
Solution:
– Talk with your doctor about thiamine supplementation (there are four forms, thiamine HCL, thiamine mononitrate, benfotiamine, and TTFD)
– Stop drinking so much caffeine!
– do not stop a medication without talking with your doctor
ZINC DEFICIENCY
Zinc is needed to metabolize vitamin A into retinoic acid. However, excess dietary zinc can cause a copper deficiency which can cause microcytic anemia and also neurological damage. Excess iron supplementation can cause zinc deficiency, so if you are on iron, then Zinc deficiency is possible.
Solution:
1. Ask your doctor to check ceruloplasmin and plasma zinc levels to evaluation zinc and copper
2. Ask your doctor about starting a Zinc:Copper Balance supplement. It should be about 10 to 15 mg of Zinc to every 1 mg of copper. THe amount of zinc and copper you need may need to be adjusted.
IRON DEFICIENCY
Iron deficiency impairs the mobilization of vitamin A from the liver. This can lead to a functional vitamin A deficiency, and excessive liver stores of vitamin A. The functional vitamin A deficiency worsens iron deficiency because retinoic acid, active vitamin A, down regulates the production of hepcidin by the liver, but also adipose tissues. Hepcidin increases. Hepcidin essentially locks iron into the cells of the intestine or liver so it can impair iron absorption, but also can lead to iron toxicity in the liver. (Never blindly supplement iron. Always ask for iron studies.)
Once liver capacity for vitamin A is reached, the body will increase cholesterol production in efforts to send vitamin A to fat cells for storage. If there is not enough choline to make cholesterol, fat will accumulate in the liver causing fatty liver disease. This can occur with or without iron deficiency. There are many other factors that contribute to poor vitamin A metabolism beyond iron deficiency.
Also, iron deficiency causes slowing of TCA cycle and build up of citrate which becomes a building block for triglyceride production. Less energy is also produced from food eaten because of this slowing of the TCA cycle that makes ATP in the body.
Sometimes iron deficiency that isn’t responding to iron supplementation is actually copper deficiency. If you have been on iron a long time, you should have your copper levels checked (ceruloplasmin) due to high dose iron supplements impair copper absorption. Once copper is low, then iron can’t be absorbed.
Vitamin A can’t be mobilized during iron deficient state
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330461/
Retinoic acid (active form of vitamin A) is needed to regulate hepcidin (hormone that blocks iron absorption)
https://pubmed.ncbi.nlm.nih.gov/30446224/
Solution:
– Ask doctor to check iron studies (ferritin, transferrin, TIBC, % iron saturation)
– If iron deficiency is found, then don’t dose iron every day. This will increase hepcidin levels and because retinoic acid is low, hepcidin won’t be regulated well and iron deficiency will worsen.
– Instead ask your physician about low dose iron supplementation such as 40 mg of iron bis-glycinate every other day in the morning. Dosing in this manner will not increase hepcidin as much. This iron can also be paired with vitamin C (but not more than 250 mg) to enhance absorption.
H2 RECEPTOR ANTAGONISTS (Pepcid, Famotidine, Zantac, ranitidine, Tagement, cimetidine, Axid, nixatidine, Duo fusion
H2 receptor antagonists have been shown to impair the conversion of retinol to retinoic acid by altering NAD+ levels in cells. One of these studies said that famotidine didn’t cause this, but another study did, and so I don’t feel comfortable with famotidine (Pepcid). Also these medications can cause iron and copper deficiency leading to iron deficiency which worsens vitamin A mobilization from the liver.
https://pubmed.ncbi.nlm.nih.gov/14646967/
https://pubmed.ncbi.nlm.nih.gov/11410737/
Solution:
1. Wean off of H2 receptor antagonist if possible with your doctors permission
2. Possibly change to a proton pump inhibitor (although these still can cause iron and copper deficiency) **** Proton pump inhibitors actually increase ALDH enzyme activity and can lead to a rapid conversion of retinal to retinoic acid. This is something to consider if you are vitamin A toxic and have very poor detoxification pathways. This could cause retinoic acid poisoning. Symptoms would be peeling skin, blisters, headache, and nausea.**** https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9290858/
HIGH DOSE MELATONIN impairs Vitamin A metabolism
(This could pertain to individuals who take more than 5 mg per day. Also anyone who doses melatonin multiple times a day. Monitor yourself for symptoms of overdose such as headache, hypotension, hypertension, drowsiness, vomiting, alopecia.)
Melatonin overdosing is another possible mechanism by which vitamin A metabolism can be impaired. Melatonin is metabolized in the Kynuric pathway which uses the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. These enzymes are also used in vitamin A metabolism. Large doses of melatonin could compete with Vitamin A for metabolism resulting in a retinoic acid deficiency. Alopecia and dermatological manifestations of melatonin overdose could actually be related to retinoic acid deficiency.
In addition, when metabolizing large amounts of melatonin, NAD is used which may contribute to low cellular levels of NAD. This can result in impaired energy (ATP) levels leading to the symptoms described in melatonin overdose such as fatigue. This could also cause buildup of lactate resulting in lactic acidosis which would account for the vomiting seen in melatonin overdose.
https://www.sleepfoundation.org/melatonin/melatonin-overdose
Solution: Don’t go over 3 mg of Melatonin per day for kids. Work with a sleep psychologist on sleep hygiene.
GUT DYSBIOSIS impairs Vitamin A metabolism
Another possible mechanism by which vitamin A metabolism can be altered is when NAD levels are low due to gut dysbiosis. It is possible for pathogenic bacteria to “steal” the NAD that is needed to metabolize vitamin A.
Bacteria steal NAD
https://pubmed.ncbi.nlm.nih.gov/34223888/
Solution: Start a probiotic. Preferably a well researched probiotic such as MegaSporeBiotic. I’m working with microbiome labs (MegaSporeBiotic). They know that their product lowers a toxin that is produced by bad bacteria and so it should lower NAD+ steal. It is clinically proven. However, Kara, one of their dietitians, is going to help me research other bacteria strains that they know don’t steal NAD.
FERMENTED FOODS CAN IMPAIR VITAMIN A METABOLISM
Fermented foods, tea, soda, and coffee contain acetaldehyde. Acetaldehyde metabolism uses up NAD+ resulting in less NAD+ available in the conversion of retinol and retinol to retinoic acid. It also uses alcohol dehydrogenase and aldehyde dehydrogenase that are needed for Vitamin A metabolism. Fermented food: Kefir, Kombucha, sauerkraut, yogurt, etc.
Alcohol actually causes the same problem. It uses up NAD+ and also ties up enzymes so that less vitamin A is metabolized to retinoic acid.
Interestingly, foods high in acetaldehyde are avoided on a low histamine diet because they tend to “release” histamine. Perhaps this is because retinol triggers mast cells to release histamine.
https://www.sciencedirect.com/…/abs/pii/0014482768903595
https://keio.pure.elsevier.com/…/nicotinamide-adenine…
Solution:
1. Avoid these beverages and foods if you know vitamin A is not being metabolized
- Tea
- Coffee
- Soft Drinks
- Kombucha
- Yogurt
- Vinegar
- Fish products such as fish sauce
- Fermented mushrooms
- Fermented soy products
- Pickled vegetables
- Canned vegetables
- Kimchi