Impaired Vitamin A Metabolism, Retinoic Acid Deficiency, and Neurological Decline.

Vitamin A metabolism is an important pathway for anyone with a neurological disorder or neurodivergent. It is possible that unmetabolized retinal (one form of vitamin A) is complexed with ethanolamine, an ether lipid that is needed for brain function. Low ethanolamine is implicated in Autism and Alzheimer’s disease as well as neurological diseases as one of the causative factors of neurological decline. I hypothesize that unmetabolized retinal is stealing ethanolamine from the brains of individuals with neurological decline IF their vitamin A metabolism is impaired. It would be important for anyone with neurological decline to evaluate their vitamin A metabolism to ensure they are converting dietary and supplemental sources of vitamin A (beta-carotene, alpha-carotene, and beta-cryptoxanthin, retinyl palmitate, Vitamin A acetate, Vitamin A palmitate) into retinoic acid.

In addition, I hypothesize that poor vitamin A metabolism is a contributor to chronic disease. As I continue in research on the impairment of vitamin A metabolism, I am finding that alterations in vitamin A metabolism are causing many of the chronic diseases in this world. I will expound on this in later posts.

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 

Symptoms of Impaired Retinoic Acid Synthesis

It is possible for us to consume plenty of carotenoids from plants and performed vitamin A from animals in the form or retinyl esters, as well as from supplements  (Vitamin A palmitate, Vitamin A acetate, etc), but not be able to convert it to retinoic acid in the body. This causes a functional vitamin A deficiency. Retinal helps in our visual cycle and so it plays its own unique role in eyesight, but retinoic acid is the active form of vitamin A that helps us to transcribe different genes. It plays a huge role in our bodies.  It is especially important for growth.  It is also needed for healthy skin, hair, eyes, and nails.  We need retinoic acid to have a healthy immune system because it helps our immune cells to differentiate.  We also need it for healthy blood vessels, red blood cells, and muscles.

Sometimes we assume based on symptoms that we are deficient in vitamin A, but in reality, it is hard to become deficient in this vitamin. Vitamin A is a fat soluble vitamin and it stays in the body a very long time. It can’t leave the body in the form that we eat it (beta-carotene or preformed vitamin A), and it can’t leave the body as retinol or retinal.  It can only leave the body after it has been metabolized to retinoic acid and then broken down further by enzymes in the liver.  After that it is excreted through bile acid into the intestines, and it comes out in the toilet. 

If we aren’t metabolizing vitamin A into retinoic acid, it will build up in the cells of the liver that hold vitamin A, stellate cells.  As the levels in these cells increase, the body wants to make sure levels don’t get too high and so it packages it into a carrier called retinol binding protein (RBP).  RBP then complexes with transthyretin, a carrier for thyroid hormone (carries T4).  This complex floats around the vascular system waiting for cells to take up retinol to be used as retinoic acid.  When the body can’t make anymore retinol binding protein, and if vitamin A levels are still too high either from excess in the diet, or from not metabolizing it right, the body will start to increase the production of VLDL.  It will package retinol into VLDL to be transported to fat cells for storage.  This will eventually look like high LDL on laboratory work ups.   Very high levels of RBP can actually cause insulin resistance which makes it hard for the fat that is on VLD to be taken up by the cells. The fat then spills into the blood and causes high triglycerides. 

Symptoms of Vitamin A excess (all or some of these):

– iron deficiency with or without anemia

– high VLDL or LDL

– high triglycerides

– high blood calcium 

– high alkaline phosphatase

– high Triglyceride:HDL ratio (greater than 3.5) indicates insulin resistance which can be from high retinol binding protein

– fatigue

– inability to lose weight despite calorie restriction

– poor growth (resistant to growth hormone treatments)

– elevated T4 (not free T4) due to more circulating RPB4 which is bound to Transthyretin 

– keratosis pilaris

– thinning hair

– dry heels and elbows with thick white skin

– constant illness 

– weak blood vessels that break easily

– bleeding gums

– blood clots

Late Symptoms:

– elevated liver enzymes

– diabetes (retinol binding protein 4 can trigger insulin resistance and metabolic syndrome)

– fatty liver disease

– obesity

Labs to definitely check:

– serum vitamin A

– retinol binding protein

Additional labs that are helpful to check:

– plasma amino acids (looking for high tryptophan, high serine, low ethanolamine)

– urinary organic acid (looking for low glutaric acid and also ketones)

– pyruvate/lactate (if lactate is low, LDH is likely impaired by oxalate – see below). If lactate is high, then NADH levels will be too low which will impair reactions dependent on NADH for energy. If lactate is too low, then NAD levels will be too low leading to impaired Vitamin A metabolism. Similarly, if Pyruvate is too high, NAD levels will be too low leading to poor vitamin A metabolism. There is a balance needed between pyruvate and lactate to normalize cellular processes that depend on NAD and NADH.

( ****THIS BALANCE of NAD/NADH PLAYS A PIVOTAL ROLE IN WHETHER OR NOT A PERSON CAN METABOLIZE VITAMIN A. The majority of my research has shown that NAD is being impaired in some way which alters vitamin A metabolism**** )  

– spot morning urinary oxalate OR 24 hour urinary oxalate (to see if oxalate metabolism is the problem)

– CBC (looking for signs of zinc deficiency such as low lymphocytes, also looking at MCH, MCV, MCHC for signs of iron deficiency or folate or B12 deficiency, although the latter two aren’t directly related to this pathway, but I still like to see them)

– CMP (looking for elevated alk phos and elevated calcium, kidney issues, and liver issues)

– If MCH, MCV, or MCHC are low, definitely ask for iron studies (ferritin, transferrin, TIBC, % saturation)  – I would actually ask for these anyway because iron deficiency anemia is the very LAST sign of iron deficiency in the body

– plasma zinc (zinc is needed for Vitamin A metabolism)

– ceruloplasmin (to assess copper status – low copper can impair iron absorption, and low iron can cause vitamin A to be trapped in the liver)

– B6 levels

– Thiamine levels won’t be accurate because they change based on what is eaten.  Thiamine transketolase is a better measure, but is usually not covered by insurance

– B12 and folate levels (B12 and folate work together in a one carb transfer pathway. If folate is low, or if a person has MTHR polymorphisms, then glycine isn’t metabolized to serine efficiently, this can lead to high endogenously made oxalate which impairs LDH leading to decreased NAD and poor vitamin A metabolism.

– Lipid Panel (Looking for high VLDL, LDL, Triglycerides and a high Triglyceride:HDL ratio of greater than 3.5)

– Possibly genetic testing for gene alterations in glyoxylate pathway and vitamin A metabolism

ETHANOLAMINE and VITAMIN A (RETINAL) – This is the reason to monitor vitamin A metabolism in individuals with cognitive dysfunction. This is a hypothesis. 

This is a hypothesis on nervous system manifestations of poor vitamin A metabolism, that is the inability to convert retinol to retinal, and then to retinoic acid.  There are many ways by which we can impair our ability to metabolize vitamin A.  Excess retinal levels in the body may be contributing to neurological decline.  I believe that this is a contributor to Autism and neurological diseases. 

(For 2q23.1/MBD5 deletion group — I know that our kids have neurodevelopmental disorders, but that doesn’t mean that they can’t have other health conditions that cause brain injury. I’m checking with the Elsea lab to see if MBD5 may be modulating some of the genes that involve these pathways.)

High levels of retinal can form a complex with ethanolamine to form A2E. This may decrease levels of ethanolamine containing ether lipids which may lead to neurological decline in and of itself. Low ethanolamine levels have been found in individuals with Autism and Alzheimer’s disease.

In addition, there is evidence that A2E stimulates microglia cells of the immune system to dysfunction in the eye resulting in macular degeneration. In Alzheimer’s disease, microglia cells have been implicated in neurodegeneration.  Perhaps this is by an A2E mechanism as well. Individuals with Alzheimer’s disease typically do have higher levels of retinol binding protein 4 (some retinal is converted back into retinol and can be bound to retinol binding protein).  

Perhaps Alzheimer’s and autism are vitamin A metabolism related diseases. 

Ethanolamine low in Autism and Alzheimer’s 

https://europepmc.org/article/med/28796901

Brain ethanolamine https://pubmed.ncbi.nlm.nih.gov/33319663/

Retinal and Ethanolamine complexes to make A2E

In skin https://www.sciencedirect.com/science/article/pii/S1873506118300205

In eye https://pubmed.ncbi.nlm.nih.gov/10887199/

In eye https://pubmed.ncbi.nlm.nih.gov/11006290/

Microglia Cells Implicated in Alzheimer’s disease

https://pubmed.ncbi.nlm.nih.gov/29196460/

A2E accumulation influences retinal microglial activation and complement regulation (in eyes)

https://pubmed.ncbi.nlm.nih.gov/22819137/

Brain levels of retinol binding protein 4 higher in Alzheimer’s disease 

(mouse study) https://pubmed.ncbi.nlm.nih.gov/21538175/

(human study) https://pubmed.ncbi.nlm.nih.gov/3119778/

Solution:

– At first I thought about liquid sunflower lecithin which is a good source of choline and also ethanolamine to help with low levels, but now I’m not sure about this yet because by doing this, it will increase ethanolamine levels. This may cause more damage by increasing  A2E complexes while retinal is still high in the body and cause a huge flair in microglia cells

However, increasing overall choline intake is important because ethanolamine can be a precursor for choline synthesis. Low levels of choline will impair acetylcholine production. When acetylcholine is low, there will be impaired autonomic nervous system function leading to slow gut motility, GERD, constipation.  The best dietary source of choline is egg yolks. Do NOT use liver without considering your total body vitamin A status. Liver is extremely high in vitamin A.

– Also address impaired vitamin A metabolism and fix areas that you are able such as low oxalate diet, B6, thiamine, and stopping melatonin or miralax (see below)

– If carotenoid levels are high, possibly go on a low carotenoid diet (but also will have to go on a low animal source of vitamin A diet as if there is evidence of retinol toxicity.  This is because retinol is converted to retinal to some degree during impairment, but also it is highly likely as this metabolic pathway is restored, then retinal levels will increase)

Now for the various ways that we can alter Vitamin A Metabolism…….

OXALATE from plants or made from VITAMIN C or GLYCINE 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/

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

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

– 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)

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

KERATOSIS PILARIS – how to deal with this itchy skin condition and also keratin building up and causing crusty heels and elbows

If you have this skin condition, consider having your vitamin A levels checked before allowing a doctor to prescribe vitamin A supplementation or even topical vitamin A creams. It may not be a deficiency at all. You may have plenty of retinol in the body, if not too much, but may be low on retinoic acid. I propose that this “vitamin A deficiency” associated skin disorder, Keratosis pilaris, is actually retinoic acid deficiency, and not necessarily preformed vitamin A or carotenoid deficiency.  Consider getting your vitamin A levels checked and look at your diet and medications to evaluate if you have inhibitors of retinol and retinal metabolism due to NAD+ depletion or due to tying up alcohol dehydrogenase and aldehyde dehydrogenase which are used to metabolize vitamin A. 

Solution: 

1. Check with your doctor about using topical lactic acid lotion – Lactic acid lotion is thought to help decrease keratosis pilaris by “dissolving” the keratin plug. I hypothesize that it increases lactate, a product of lactate dehydrogenase reaction, within local skin cells. This increasing amount of lactate is then converted to pyruvate and then back into lactate which increases NAD+ which helps to drive retinol metabolism forward to retinoic acid. Then, retinoic acid can then help skin to form normally without excess keratin production.

1. Use EWG skin deep database to avoid lotions that have excess toxins. 

https://www.ewg.org/skindeep/search/?search=lactic+acid&search_type=products