Symptoms of Retinoid Toxicity
Symptoms are throughout the body if there is a gene change in the liver and the whole body is getting too much active Retinoic acid. It might not occur if the change was only in cancer cells.
This is a new area of research - which means people are in pain and don’t know why, or mentally distressed and may be given psychiatric drugs that would likely just make things worse. It is dangerous to have mental illness symptoms in the current system that separates physical illness from mood or psychiatric symptoms. Many can have physical or nutritional causes.
The histamine excess problem would be worsened by an excess of retinoic acid, but someone with histamine excess may not also have a gene change that is leading to excess retinoic acid. NMDA receptor activity can increase it though and infection would also. Retinoic acid excess would increase mast cell problems.
“Neurodevelopmental disorders—A review of the role of retinoids in NDDs [58] includes the suggestion that an abnormality in the interplay between retinoic acid and sex hormones may cause ASD [59].
As noted in our review on GWI [41], mast cells are increased in patients with atopic dermatitis and express high levels of retinoic acid receptor-alpha. Retinoic acid (RA) also interferes with the proliferation of skin mast cells and promotes their degranulation, supporting the concept that RA has a pro-allergic and pro-inflammatory-maintaining function in skin mast cells. The retinoid toxicity hypothesis of vaccine injury is depicted in the figure below” (2)
I may have been vaccine injured as a child, I had odd symptoms my entire life that are included in the symptom list later in this post. My problems got worse after having mononucleosis in my teen years. It is similar to Epstein Barr Virus and also may leave a person with symptoms of Chronic Fatigue Syndrome which I had symptoms of as an adult or fibromyalgia like muscle pain.
I was able to help my mother in the Tale of Two Porridges post because I recognized her symptoms as being similar to my mood issues, once I learned of the histamine trigger foods and tried the diet changes myself. I knew my dad’s routine porridge recipe and already had been trying to get more protein added to his routine. Once I knew more specifically that walnuts, cranberries and chocolate daily could be leaving my mother in a panicky state of paranoia - for no need. I swapped pecans for the walnuts and raisins for the cranberries, but the chocolate mix was a favorite of my dad’s and was still a trigger for her. Carrots and peaches are not a problem for her though. For me the earliest obvious symptoms that I have been eating too many foods with carotenoids is getting chapped lips with nonhealing crevices at the corners - rapidly growing tissue.
Symptoms of excess Retinoic Acid include thin peeling skin with the characteristic cracked and chapped lips, also thinning and loss of hair:
“Acute retinoid toxicity has resulted in mucocutaneous and laboratory abnormalities. Mucocutaneous effects include dry lips, cheilitis, and dry oral, ophthalmic, and nasal mucosa. The putative mechanism is decreased sebum production, reduced epidermal thickness, and altered barrier function. Other cutaneous effects seen include overall skin dryness and pruritus, peeling of palms and soles, and fingertip fissuring. Telogen effluvium may be seen with higher doses.” (9) [Telogen effluvium is a hair loss and thinning without scarring, the problem may be acute or chronic. (10)]
A more complete list of the mental and other organ damage that may occur with long term excess Retinoic acid is included later in the post.
Excess active vitamin A is very dangerous to a developing fetus as it is critical during development - so too much would be causing too much to happen potentially - too much that might go wrong. Birth defects are possible. Medications for skincare that use active retinoic acid should not be used if pregnancy might be a possibility.
Sources of Pre-formed vitamin A and Provitamin A – beta-carotene and other carotenoids.
Beta-carotene, is an inactive form of vitamin A that is generally considered non-toxic, it provides the orange color of carrots, and since it is a fat soluble nutrient it can collect within our skin if eaten in excess and cause an orange color to the skin. (8, 13) It is unlikely to eat enough of the nutrient to cause the skin color change unless regularly drinking juice made with carrots, or kale or other fruits and vegetables that are very rich in beta- carotene. It is unlikely to cause any health problems other than to appear orange for a while (stop drinking so much carrot juice to make it fade). Infants and toddlers who are fed limited numbers of foods but daily may also develop the problem if carrots and sweet potatoes are given consistently instead of including more variety.
Beta-carotene may be broken down to the active retinal form in the intestinal lining or in the liver. (13)
“…vitamin A toxicity can occur from either topical or oral use. Oral vitamin A delivery comes in two forms: provitamin A (a prodrug that is metabolized to vitamin A) and preformed vitamin A. Pre-formed vitamin A is obtained from animal food sources, including dairy products and liver, and in most supplements. A list of other foods containing Vitamin A includes milk, cheese, margarine, butter, eggs, chicken, chicken liver, beef, beef liver, processed meats, pizza, fish, and cold breakfast cereals [1]. Provitamin A (beta-carotene and other carotenoids), found in plants such as green leafy vegetables, sweet potatoes, and carrots, must be metabolized to vitamin A. As a result, it is less likely to cause toxicity.” (9)
Symptoms of Retinoid Toxicity
Generally Retinoid Toxicity has been studied with the use of retinoid medications. The active vitamin A is helpful topically for acne and other dermatologic uses.
Chronic retinoid toxicity can increase risk of bone spurs, calcinosis, and hypercalcemia. [6] Chronic intake of excessive dietary vitamin A may increase risk of osteoporosis and hip fractures. [7]
Headache, nausea, and vomiting may occur and pseudotumor cerebri syndrome infrequently has been seen. [8]
Hypothyroidism occurred with bexarotene treatment, reversible with cessation of the treatment. [9] Renal dysfunction with etretinate occurred, also reversible with cessation of treatment. [10]
Hypertriglyceridemia and other blood lipid changes have been seen with retinoid treatments: bexarotene, isotretinoin, etretinate, and acitretin, [11][12], and occasionally was accompanied by acute hemorrhagic pancreatitis and eruptive xanthomas.
Elevated serum transaminases may occur with retinoid treatments, and liver damage leading to fibrosis and hepatic stellate cell activation have both been seen in patients with hypervitaminosis A. [13]
No causal association has been found between the retinoid treatment isotretinoin and depression, psychosis, or suicide attempts, but a link has been suggested. [14]
Summarized from (9) – see the paper for more details and [ref] list.
“Disturbances related to nervous functions also appear on the list of side effects resulting from excessive vitamin A intake, as for instance confusion, irritability, anxiety, depression, and suicide ideation (Snodgrass 1992).” Effects on neuronal function may include: “impaired bioenergetic parameters related to mitochondrial function, oxidative and nitrosative stress, alterations of dopamine signaling, and behavioral disturbances.” Cell death may also occur as a result to excess Vitamin A. “Increased β-amyloid1-40 peptide [also found in Alzheimer’s dementia] and tumor necrosis factor-alpha (TNF-α) contents in substantia nigra and striatum” areas of the brain was found in an animal study. Increased “Mn-SOD and monoamine oxidase (MAO) enzyme activities may lead to increased hydrogen peroxide (H2O2) production, which may diffuse from mitochondria to other organelles.” (7)
“Vitamin A content in the liver of adult humans is about 100 µg/g (Furr et al. 1989). It was suggested that a concentration of vitamin A of roughly 300 µg/g in the liver reveals intoxication (Olson 1993). ” (7)
Much of this post is from an older post, Mast cell activity & Hyperexcitable mood, included in this document: Retinoid Toxicity. More recent information that I have written about MCAS/Histamine is on a webpage (jenniferdepew.com) and in a handout about the foods to avoid or use during a flair up.
Related Substack posts:
Hyperinflammation - a positive feedback loop leading to Alzheimer's? (substack.com)
Disclaimer: Opinions are my own and the 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
(2) Mawson AR, Croft AM, Multiple Vaccinations and the Enigma of Vaccine Injury. Vaccines, 2020, 8, 676; doi:10.3390/vaccines8040676, published online Nov 12, 2020, pdf https://t.co/sinJK6UTSc?amp=1
(7)OLIVEIRA, MARCOS ROBERTO DE. (2015). The neurotoxic effects of vitamin A and retinoids. Anais da Academia Brasileira de Ciências, 87(2, Suppl. ), 1361-1373. Epub August 04, 2015.https://doi.org/10.1590/0001-3765201520140677 https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652015000301361
(8) Smile S. Case 2: Persistent skin discolouration in a child with autism spectrum disorder. Paediatr Child Health. 2016;21(2):67-68. doi:10.1093/pch/21.2.67a https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807796/
(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/
(10) Elizabeth CW Hughes, MD; Chief Editor: Dirk M Elston, MD, et al., Telogen Effluvium. Sept. 17, 2020, emedicine.medscape.com https://emedicine.medscape.com/article/1071566-overview
(11) Vitamin A, Linus Pauling Institute, lpi.oregonstate.edu, https://lpi.oregonstate.edu/mic/vitamins/vitamin-A
(12) Oliveira LM, Teixeira FME, Sato MN. Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases. Mediators Inflamm. 2018;2018:3067126. Published 2018 Aug 9. doi:10.1155/2018/3067126 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109577/
(13) Charles Ophardt, Vitamin A: β-Carotene. Virtual ChemBook, Last updated Aug 10, 2020 https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Vitamins_Cofactors_and_Coenzymes/Vitamin_A
(14) Le C, Bedocs PM. Calcinosis Cutis. [Updated 2020 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448127/ https://www.ncbi.nlm.nih.gov/books/NBK448127/
addition: Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth | BMC Pediatrics | Full Text (biomedcentral.com) https://bmcpediatr.biomedcentral.com/articles/10.1186/1471-2431-14-214 *Vitamin A supplementation for newborns, if given in the rainy season seemed to worsen risk of a respiratory infection related death and growth was stunted whether dry or rainy season.
References [ref]
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[6] Scheven BA, Hamilton NJ. Retinoic acid and 1,25-dihydroxyvitamin D3 stimulate osteoclast formation by different mechanisms. Bone. 1990;11(1):53-9. [PubMed]
[7] Genaro Pde S, Martini LA. Vitamin A supplementation and risk of skeletal fracture. Nutr Rev. 2004 Feb;62(2):65-7. [PubMed]
[8] Chisholm JT, Abou-Jaoude MM, Hessler AB, Sudhakar P. Pseudotumor Cerebri Syndrome with Resolution After Discontinuing High Vitamin A Containing Dietary Supplement: Case Report and Review. Neuroophthalmology. 2018 Jun;42(3):169-175. [PMC free article] [PubMed]
[9] Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, Duvic M. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med. 1999 Apr 08;340(14):1075-9. [PubMed]
[10] Cribier B, Welsch M, Heid E. Renal impairment probably induced by etretinate. Dermatology. 1992;185(4):266-8. [PubMed]
[11] Koo J, Nguyen Q, Gambla C. Advances in psoriasis therapy. Adv Dermatol. 1997;12:47-72; discussion 73. [PubMed]
[12] Duvic M, Martin AG, Kim Y, Olsen E, Wood GS, Crowley CA, Yocum RC., Worldwide Bexarotene Study Group. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol. 2001 May;137(5):581-93. [PubMed]
[13] Nollevaux MC, Guiot Y, Horsmans Y, Leclercq I, Rahier J, Geubel AP, Sempoux C. Hypervitaminosis A-induced liver fibrosis: stellate cell activation and daily dose consumption. Liver Int. 2006 Mar;26(2):182-6. [PubMed]
[14] Bigby M. Does isotretinoin increase the risk of depression? Arch Dermatol. 2008 Sep;144(9):1197-9; discussion 1234-5. [PubMed]