Retinoic acid & toxicity - dosing - how much is too much for normal health?

Even in normal health, regularly eating too much active vitamin A foods such as liver or Cod liver oil, may lead to toxicity symptoms.

A question to my Telegram chat asked since goat liver is high in vitamin A, how much would be too much to eat regularly?

There is an estimated 12,120 mcg of Vitamin A in 100 grams (about 3 ounces) of goat liver curry. (1)

How much is too much?

Regularly taking too much active vitamin A in foods like liver or supplemental cod liver oil can build up to toxicity symptoms if continued over time. Other supplements with the active form of vitamin A instead of beta-carotene, or use of retinoid medications may also accumulate to an excess. Vitamin A is fat soluble so we store extra within our skin or fat tissue. More than 10,000 mcg daily over time may be too much, and lead to symptoms that might include: Bone thinning, Liver damage, Headache, Diarrhea, Nausea, Skin irritation, Pain in the joints and bone, [and] Birth defects." (4)

Single large doses greater than 200,000 mcg may also lead to some toxicity symptoms, “Nausea, Vomiting, Vertigo, Blurry vision,” (4), as an acute, short term problem.

"Too much vitamin A can be harmful. Even a single large dose — over 200,000 mcg — can cause: Nausea, Vomiting, Vertigo, Blurry vision. Taking more than 10,000 mcg a day of oral vitamin A supplements long term can cause: Bone thinning, Liver damage, Headache, Diarrhea, Nausea, Skin irritation, Pain in the joints and bone, [and] Birth defects." (4)

So having a portion of goat liver curry everyday might be within the chronic toxicity risk range of "more than 10,000 mcg a day regularly”. (4)

Photo by Jochen Gabrisch on Unsplash

Toxicity of Vitamin A, overview: (2)

Topical or oral retinoid medications may lead to toxicity symptoms in some people. (7) Efforts have been made to produce retinoid medications that have fewer adverse effects.

"Since retinoids are analogs of vitamin A, their potential to produce liver disease is reviewed. Animal and human studies of liver function tests suggest some abnormalities in the liver in about 25% of patients treated." (6)

Older retinoid medications led to liver damage more consistently than more recently developed retinoid meds.

“Retinoids are both natural and synthetic derivatives of vitamin A, several of which have been developed for medical uses, largely to replace vitamin A which in high, therapeutic doses is associated with considerable toxicity. Retinoids have multiple actions and play important roles in regulation of cell proliferation and differentiation, vision, bone growth, tumor suppression and immunity. The effects of retinoids are thought to be mediated by their binding to and activation of the retinoic acid and retinoid X receptors which regulate gene expression, important in normal growth and differentiation. Vitamin A in doses that have medical effects was found to be toxic, particularly when given long term. Modification of the vitamin A structure led to retinoid molecules that had many of its beneficial, but fewer of its adverse effects.

Oral retinoids in use in the United States include acitretin for psoriasis and isotretinoin for severe nodular acne. Tretinoin is used topically and several other retinoids have been developed for therapy of uncommon forms of cancer (alitretinoin, bexarotene). The commonly used retinoids have many of the side effects of vitamin A including dry skin, cheilosis and nosebleeds and hair loss, but are not stored in the liver and do not cause the typical form of chronic liver disease associated with excessive vitamin A intake. Both acitretin and isotretinoin are teratogenic and embryotoxic and are contraindicated in women who are or intend to become pregnant.” (5)

Individual Lab Testing for Vitamin A excess.

Patients can have their own level of vitamin A in the blood checked to see if excess is present.

Liver enzyme levels may be able to show whether the over-activation to Retinoic Acid due to viral or vaccine injury is a personal problem. In Epstein-Barr virus it has been found that the “gene (DHRS9) encoding an enzyme that mediates conversion of retinol into RA,” is promoted. (8) An enzyme over-activation problem can lead to excess Retinoic acid even from eating carotenoid rich foods like carrots, kale, and cantaloupe, (inactive beta-carotene), not just the active retinol found in liver and other animal based foods. In normal health extra carotenoids can turn your skin orangish color and the solution is to cut down on carotenoids and the excess stored in the skin will slowly be used up and the skin will return to normal.

To check a patient’s blood levels of vitamin A, the safe range is considered to be 20-60 mcg/dL and a toxic level is more than 60-100 mcg/dL, (3), suggesting that some people within the 60-100 mcg/dL range may be fine, while others may be experiencing some symptoms - borderline above average - normal for some and elevated possibly for others.

"The reference range for vitamin A is 20-60 mcg/dL, and a toxic level is higher than 60-100 mcg/dL. Obtain a complete blood count (CBC) to rule out leukopenia. Also perform calcium, glucose, and liver function tests (LFTs). levels are affected by liver stores and dietary intake of vitamin A." (3)

Retinoid toxicity due to use of retinoid medications may effect liver lab tests temporarily but does not cause a change to the enzyme as has been seen following an Epstein Barr viral infection.

“The three active forms of vitamin A in the body are retinol, retinal, and retinoic acid.” … “Retinol and retinyl esters are often referred to as preformed vitamin A. Retinol can be converted by the body to retinal, which can be in turn be oxidized to retinoic acid, the form of vitamin A known to regulate gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. β-Carotene and other food carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids (see the article on Carotenoids). ” (8)

Malfunction of CYP enzymes could increase the risk of excess retinoic acid as they are required to break down the active forms of vitamin A. (9)

“Control of the RA concentration in tissues is performed by a group of enzymes that belong to the cytochrome P450 family 26 (CYP26), including subfamilies A1, B1, and C1 (CYP26A1, CYP26B1, and CYP26C1), which catalyze RA present in the cytosol to generate the oxidized forms (5,8-epoxy RA, 4-oxo RA, 4-hydroxy RA, and 18-hydroxy RA) [34, 35]. The action of these enzymes prevents RA accumulation in the organism and maintains optimal physiological RA concentrations for the best performance.” (9)

Glyphosate residue, if incorporated into amino acid structure instead of glycine, can lead to misfolded protein structure and dysfunction of the resulting protein. Enzymes are proteins, and the CYP enzymes may be affected by a glycine/glyphosate substitution.

More study really is needed - checking for enzyme levels, retinoid levels, and glyphosate residue.

In the mean time - most people could probably enjoy Goat Liver Curry, 3 ounces, on a weekly basis rather than a daily basis. And most people could have carrots, moringa leaves, and sweet potatoes on a daily basis with no problems, but maybe not all three everyday in large portions or you might turn orange temporarily.

Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

1. Calories [and nutrients] in Goat Liver Curry, apollosugar.com, https://apollosugar.com/food-fitness/calories-in-goat-liver-curry/

2. Olson JM, Ameer MA, Goyal A. Vitamin A Toxicity. [Updated 2021 Dec 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532916/ “Skin irritation in the form of peeling and erythema is the most common adverse effect from topical vitamin A use. The peeling from topical retinoids is secondary to the hyper-proliferation of the epidermis mediated by retinoic acid receptor stimulation [3]. Interestingly, the erythema may be mediated through a different mechanism.

   The risk of teratogenicity from the use of topical retinoids is extremely low given that systemic absorption has been inconsequential in animal and human studies [4]. Topical retinoid application has not been proven to cause congenital disorders when used during pregnancy. Other adverse effects include transient hypopigmentation and hyperpigmentation, Koebnerization of psoriasis, allergic contact dermatitis, and ectropion.”

3. What is the Toxic Level of Vitamin A? medscape.com, https://www.medscape.com/answers/819426-102405/what-is-the-toxic-level-of-vitamin-a

4. Mayo Clinic Staff, Vitamin A, mayoclinic.org, https://www.mayoclinic.org/drugs-supplements-vitamin-a/art-20365945

5. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Retinoids. [Updated 2020 Nov 10]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548568/

6. Roenigk HH Jr. Liver toxicity of retinoid therapy. J Am Acad Dermatol. 1988 Jul;19(1 Pt 2):199-208. doi: 10.1016/s0190-9622(88)70165-6. PMID: 3045164. https://pubmed.ncbi.nlm.nih.gov/3045164/

7. 9-Olson JM, Ameer MA, Goyal A. Vitamin A Toxicity. [Updated 2020 Oct 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532916/

8. 11-Jones RJ, Dickerson S, Bhende PM, Delecluse HJ, Kenney SC. Epstein-Barr virus lytic infection induces retinoic acid-responsive genes through induction of a retinol-metabolizing enzyme, DHRS9. J Biol Chem. 2007 Mar 16;282(11):8317-24. doi: 10.1074/jbc.M608667200. Epub 2007 Jan 22. PMID: 17244623. https://www.jbc.org/content/282/11/8317.long “Abstract: Lytic Epstein-Barr virus (EBV) replication occurs in differentiated, but not undifferentiated, epithelial cells. Retinoic acid (RA) induces epithelial cell differentiation. The conversion of retinol into its active form, retinoic acid, requires retinol dehydrogenase enzymes. Here we show that AGS gastric carcinoma cells containing the lytic form of EBV infection have enhanced expression of a gene (DHRS9) encoding an enzyme that mediates conversion of retinol into RA. DHRS9 expression is also increased following induction of lytic viral infection in EBV-positive Burkitt lymphoma cells. We demonstrate that the EBV immediate-early protein, BZLF1, activates the DHRS9 promoter through a direct DNA binding mechanism. Furthermore, BZLF1 expression in AGS cells is sufficient to activate DHRS9 gene expression and increases the ability of retinol to induce the RA-responsive gene, CYP26A1.”

9. 12- Oliveira LM, Teixeira FME, Sato MN. Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases. Mediators Inflamm. 2018 Aug 9;2018:3067126. doi: 10.1155/2018/3067126. PMID: 30158832; PMCID: PMC6109577. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109577/

10. *The extra numbers 9- 11- 12- are the references in Retinoid Toxicity, my original blog series on this topic. https://docs.google.com/document/d/1vmLyBzx_joI2sT83YUfnWAKrZVd6UTXZhfUDZw-RoA8/edit?usp=sharing