Demystifying Vitamin A

Vitamin A was the first vitamin discovered and the well-known study in 1925 by Wolbach and Howe set out to establish its relevance for the population. The researchers isolated milk casein from milk fat with the intention of providing the study subjects vitamin A free casein, many decades later we found out that this did not isolate vitamin A from their study. Therefore the results of the study are invalidated. The rats in the study went blind and died in a matter of weeks, could this be due to retinol and retinoic acid overload? 

Once hepatocytes reach maximum saturation, the body begins converting retinol to retinoic acid at a higher rate overwhelming detoxification pathways like aldehyde dehydrogenase. Uncontrolled reactivity generates a significant amount of damage to the mitochondria. 

Beta Carotenoids ----> BCMO1 -----> Retinol ----> ALDH -----> Retinoic Acid

The study was repeated with vitamin A successfully isolated from the diet more recently and the rat subjects had several times greater life span and were healthy until death. Grant Genereux also repeated his own personal rodent study. His subjects lived 10X longer than in the 1925 study but unfortunately a window was closed in his garage and they died from heat. He has a blog www.ggenereux.blog with a forum and 3 free eBooks sharing his personal view on vitamin A toxicity.

Vitamin A toxicity can be observed visually in babies and adults a phenomena known as cradle cap appears on the scalp. Children have very small livers and low capacity to store A. It is absurd that we continue to flood the population with vitamin A fortification in processed foods given its already strong presence in most of the basic food that we eat. My personal view on Vitamin A is that I believe it is essential at at least one third the RDA and that someone is usually toxic with heavy metals and/or mold before they become toxic with vitamin A. It is rarely the main cause of someone's disease unless they really consumed supplements with vitamin A or lots of foods highlighted purple in the chart below.

Understand Vitamin A Pathogenicity🥕🍠🍅

• Excess Vitamin A is  a SIGNAL of abundance with no SUBSTANCE of abundance resulting in potential burnout or deficiencies.

• Bacterial and fungal overgrowth in the GI producing acetyl aldehyde damages retinol rendering it a toxin to pyruvate dehydrogenase complex crucial for metabolism. This corrupted form of retinol (anhydro retinol) also damages the mitochondria while the acetyl aldehyde is doing the same.

• Excess vitamin A may exacerbate a deficiency of vitamin D critical for immune function and growth.

• Uncorrupted retinol in the appropriate quantity enhances the splitting of cells and transport of certain minerals across cell membranes and the BBB.

Vitamin A Content of Foods  (Updated May 21st 2024)

Lets go over the current theories on modulating mechanisms of Vitamin A

Interactions with the Thyroid:

Thyroid Peroxidase (TPO) Activity: Vitamin A can modulate the activity of thyroid peroxidase, an enzyme essential for the synthesis of thyroid hormones. Thyroid peroxidase catalyzes the iodination of tyrosine residues in thyroglobulin, a precursor protein, and the coupling of iodotyrosine residues to form T3 and T4. No human clinical studies have a direct link to Vitamin A's ability to modulate Thyroid Peroxidase and neither has the modulation reaction been proven to be positive.

Thyroid Hormone Metabolism: Vitamin A status may affect the conversion of thyroxine (T4), the inactive form of thyroid hormone, to triiodothyronine (T3), the active form. This conversion primarily occurs in peripheral tissues, where the enzyme 5'-deiodinase catalyzes the removal of an iodine atom from T4 to generate T3. Retinoic acid receptors can influence the expression of deiodinase enzymes, however the relationship in human clinical studies remains unclear.

Thyroid Stimulating Hormone (TSH) Regulation: Vitamin A may influence the hypothalamic-pituitary-thyroid (HPT) axis, which regulates thyroid hormone production. While the direct mechanisms are not fully elucidated, vitamin A deficiency and excess has been associated with alterations in the HPT axis, including increased levels of thyroid-stimulating hormone (TSH), which stimulates the thyroid gland to produce thyroid hormones. 

Immune Modulation: Vitamin A's immunomodulatory effects may indirectly influence thyroid function, particularly in autoimmune thyroid diseases such as Hashimoto's thyroiditis and Graves' disease. Adequate vitamin A is crucial for maintaining the integrity of epithelial tissues, including those in the respiratory, gastrointestinal, and urinary tracts. These tissues act as barriers against infections. Vitamin A is involved in the differentiation and function of various immune cells, such as T lymphocytes and macrophages, contributing to immune responses against pathogens. Further research is needed to understand the mechanism behind how vitamin A stimulates these components of the immune system and at what level is the stimulation is appropriate. Vitamin A cannot make up for deficiencies in dietary collagen, copper and manganese when it comes to the maintenance of epithelial tissues.

General Biological Modulations:

Vision: Vitamin A is essential for the synthesis of rhodopsin, a pigment necessary for vision in low-light conditions. It also plays a role in maintaining the integrity of the cornea and other ocular tissues, supporting overall eye health. Deficiency can lead to night blindness and excess vitamin A can be just as detrimental.

Immune Function: 

Gene Expression Regulation an Cell Differentiation: Retinoic acid, an active metabolite of vitamin A, can influence the expression of genes involved in thyroid hormone synthesis. Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) form complexes that bind to specific DNA sequences, known as retinoic acid response elements (RAREs), in the promoters of target genes. This binding can activate or repress the transcription of these genes, including those encoding thyroid hormone synthesis enzymes like thyroid peroxidase. While baseline gene expression regulation can occur without vitamin A, it plays specific roles in fine-tuning gene expression in certain contexts, particularly those related to cell differentiation, tissue development, and immune function. Vitamin A, especially in the form of retinoic acid, acts as a ligand for nuclear receptors (RARs and RXRs).

Reproductive Health: In both males and females vitamin A contributes to fertility and supports the development of the placenta during pregnancy. Deficiency during pregnancy can lead to congenital malformations and other complications. Small amounts of Vitamin A metabolite retinoic acid may potentially be critical for sperm production.

Interactions with Minerals: Vitamin A interacts with minerals like zinc, iron, and iodine, which are also essential for various physiological processes. Deficiencies in these minerals can exacerbate the consequences of vitamin A overload. The relationship between ceruloplasmin and moderate amounts of retinol appears to be beneficial.

Histamine management:

Vitamin B5 is the cofactor for NAT2, a backup route for the excretion of histamine through urine, vitamin A in excess increases the expression of NAT2 because alternate pathways get burdened by retinol / retinoic acid. Therefore we can hypothesize that excess vitamin A depletes vitamin B5. Vitamin A in excess is harmfully upregulating NAT2 because retinoic acids / retinol byproducts of retinol / beta carotene are occupying Aldehyde Dehydrogenase (ALDH) an enzyme that detoxifies toxic aldehydes.  Retinoic Acids / Retinol ARE aldehydes that present toxicity at certain levels. ALDH cleans up the metabolites of DAO, MAOB and MAOA that are primary routes of histamine degradation. If ALDH is overburdened by retinol / retinoic acid this inhibits the action of DAO, MAOB and MAOA leading to the intolerance of histamines.

How do we mitigate cell damage from vitamin A?

Minerals are crucial for running enzymes involved in the metabolism and elimination of vitamin A.

Zinc is crucial for RBP synthesis, acting as a structural component and stabilizer. It maintains RBP's conformation, essential for its role as a retinol carrier. Zinc stabilizes RBP's tertiary structure, crucial for its functionality. Additionally, zinc is necessary for enzyme activity involved in RBP synthesis and processing, including glycosylation. 

Copper serves as a cofactor for RBP-modifying enzymes, crucial for stability and glycosylation. One such enzyme is lysyl oxidase, which catalyzes the cross-linking of lysine residues in proteins, contributing to protein stability, including RBP. It interacts with specific amino acids in RBP, aiding in its tertiary structure stabilization. Balanced intake of copper and zinc is vital for optimal RBP function; imbalances can disrupt synthesis and stability.

Magnesium, pivotal for diverse cellular processes, indirectly influences RBP production by exerting effects on liver function and insulin signaling pathways. These pathways stimulate RBP synthesis and secretion, underscoring the indirect yet significant role of magnesium in maintaining optimal RBP levels.

Manganese, while not directly linked to RBP, exhibits potential indirect influences on its synthesis and stability through its involvement in protein metabolism and oxidative stress regulation. Furthermore, manganese's role in collagen synthesis within liver tissue, where RBP is primarily produced and secreted, suggests additional pathways through which it might influence RBP dynamics, albeit indirectly.

Selenium is a cofactor for glutathione peroxidase, an enzyme involved in protecting cells from oxidative damage. While there's no direct evidence linking selenium to RBP synthesis, its antioxidant properties may indirectly support the stability and function of RBP.

The majority of vitamin A that is not absorbed and utilized by the body is typically eliminated through bile and ends up in feces. This is the primary route for the excretion of excess vitamin A. This means a beef only diet that includes liver and kidney is the quickest route to vitamin A toxicity as their is no soluble fiber to capture bile retinoids and maximum absorption.

Is it a vitamin? Is A a toxin? Is A a stimulant, steroid or hormone?

We cant know this with absolute certainty so it is wise to be mindful of its accumulation over time, less than 1200 IU's per day is likely more appropriate than 3000 IU's as the currently established RDA. One thing we can establish with certainty is that supplementation of vitamin A under normal circumstances is completely ill advised we know we have better ways to stimulate the immune system if that is required.