Retinoid Toxicity, COX2 inhibitors, and adrenal insufficiency (alcoholism too).

Greens are quite rich in carotenoids and likely have been adding to the salicylate/puffiness & the calcification symptoms for me too. *Post got long, but it is partially the reference list.

Deep green herbs and veggies have 500-1000 mg of carotenoids, even a few spoonfuls of minced herbs may add significant vitamin A intake to a diet. Which is a good thing for most people - spice and herb up your life for better overall and cognitive health!

Severe stress leading to autoimmune and intestinal symptoms put me in a category other than “most people”. The information that I provide here may help others who also have chronic illness symptoms and otherwise could be viewed as simply informative for others. And a prompt to add more variety to your diet, or maybe to add more of the healthier ones. More unique foods within a diet generally are helping provide a wider range of trace nutrients.

Fennel bulb and fennel greens would likely have different amounts of carotenoids.

My boring breakfast - onion, fennel bulb hold the greens, and tofu. With olive oil. I also refrained from using salt or apple cider vinegar. *Yesterday’s breakfast. I am feeling better today and less pain in my early calcinosis sore thumb.

Fennel bulb is a low histamine diet food and is rich in vitamin C and folate and carotenoids - but there is likely in the greens which are used minced fresh, to add more flavor to the lightly steamed bulb (celery like texture, sweet licorice flavor).

Nutrient content for Fennel, bulb, raw includes 963 Vitamin A, IU from combined carotenoids, (USDA), but I think that would have to be specifically when the greens are used too. Fennel leaves are a good source of myricetin and quercetin. (Fennel Leaves/checkyourfood.com)

Carotenoids are red/orange pigments and chlorophyll is a green pigment - magnesium rich and coincidentally a green mineral.

Carotenoids are pigments, not translucent white like the bulb. The deep green of leaves hides the reds and oranges that are revealed in autumn foliage as the green chlorophyll breaks down.

Photo by Timothy Eberly on Unsplash

What do quercetin, luteolin, bromelain and hesperidin all have in common? Besides being recommended to avoid on the St. Armand fibromyalgia/guaifenesin protocol?

The St. Armand protocol for fibromyalgia has the confusing point that patients need to avoid salicylates, but also quercetin, luteolin, bromelain and hesperidin which are not salicylates.

Answer: Like pomegranate peel and salicylates, quercetin, luteolin, bromelain and hesperidin are also COX2 inhibitors. Salicylates are also COX1 inhibitors. Details are included later.

What does the COX2 enzyme do when activated?

The COX2 enzyme can cause inflammation and neuroinflammation. See: ‘Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype’. (Kang, et al., 2017) or (Fries, Grosser, 2005)

COX2 inhibitors may have too many side effects for people with cardiovascular conditions as use of the medications may cause elevated blood pressure and increased risk of heart attack or stroke. (Fries, Grosser, 2005) *The paper is about pharmaceutical COX2 inhibitors but might suggest that potent phytonutrients may need cautious use for people with cardiovascular issues.

“Thus, COX-2 inhibitors depress the vascular biosynthesis of PGI₂, leaving platelet COX-1-derived TxA₂ unaffected—in contrast to tNSAIDs or aspirin, which inhibit both COX-1 and COX-2.^8,9 The actions of PGI₂ oppose all mediators that stimulate platelets, elevate blood pressure, and accelerate atherogenesis, including TxA₂.^10,–12 Thus, drug selectivity for inhibition of COX-2 may increase the likelihood of hypertension, myocardial infarction and stroke.¹ Three structurally distinct compounds, rofecoxib, valdecoxib, and celecoxib, have increased the incidence of these cardiovascular complications significantly in controlled trials,^4,13,–15 suggesting that the entire class of COX-2 inhibitors confers a cardiovascular hazard. (Fries, Grosser, 2005)

Coincidentally or causally for some people, activated vitamin A can induce COX2 and prostaglandin E2.

• All-trans retinoic acid induces COX-2 and prostaglandin E2 synthesis in SH-SY5Y human neuroblastoma cells: involvement of retinoic acid receptors and extracellular-regulated kinase 1/2. (Alique, Herrero, Lucia-Cazana, 2007)

COX1 and COX2 inhibitors are anti-inflammatory and pain relieving for people who aren’t salicylate sensitive and prone to excess accumulation causing toxicity symptoms at low doses compared to typical.

Activated retinoids can lead to an increase in cortisol production - helpful in the case of ACTH-dependent Cushing’s disease (rare) which causes reduced cortisol, (Pecori, et al., 2021), but it may be adding to adrenal symptoms in the case of chronic excess activation.

“Retinoids play a pivotal role in adrenal development and differentiation. Recent clinical trials revealed therapeutic potential of both all-trans and 9-cis retinoic acid in patients with cortisol excess due to a pituitary ACTH-secreting adenoma and indicated that retinoids might act also on the adrenal. Aim of the present study was to evaluate the effect of 9-cis retinoic acid on adrenals from patients with ACTH-dependent Cushing’s syndrome.” […]

“9-cis Retinoic acid increased cortisol secretion in adrenal primary cultures from patients with ACTH-dependent Cushing’s syndrome.” (Pecori, et al., 2021)

What is ‘Adrenal fatigue’?

- Debunked according to staff of cedars-sinai.org, yet the article closes with the fact that some people can be low in cortisol output. In chronic stress, the body is putting out excess cortisol in earlier years, but the longer the chronic stress progresses, the more likely the adrenal glands may shift to producing too little cortisol.

Cortisol is our daytime get-going, there is work to be done, activating chemical - inflammatory, but working is inflammatory. That is the “day” part of our circadian cycle. Chronic stress keeps us in one mode too long and the body and adrenals get no rest, until collapse occurs, and rest is forced. To check cortisol levels accurately a blood test is needed at different times during the day to see the pattern of production in relation to normal health. Normally it is peaked in the morning and gradually drops towards afternoon and then remains lower into evening.

»The point - Chronic Retinoic acid excess replicates the symptoms of ‘adrenal fatigue’, I think, as it prmotes cortisol output, which then might conk out with chronic retinoid excess signaling ongoing excess. Rash is the main difference between adrenal symptoms and retinoid symptoms. Retinoids affect the ability of skin to grow normally.

Acute vitamin A toxicity symptoms

• Headache.

• Rash, which may cause the affected skin to peel later.

• Drowsiness.

• Irritability.

• Stomach pain, nausea and vomiting. (clevelandclinic)

Adrenal insufficiency

The most common symptoms of adrenal insufficiency are:

• chronic, or long-lasting, fatigue

• muscle weakness

• loss of appetite

• weight loss

• abdominal pain

Other symptoms of adrenal insufficiency can include:

• nausea

• vomiting

• diarrhea

• low blood pressure that drops further when you stand up, causing dizziness or fainting [*POTS is seen in conditions that might involve Retinoid excess.]

• irritability and depression

• joint pain

• craving salty foods

• hypoglycemia, or low blood glucose

• irregular or no menstrual periods

• loss of interest in sex

‘Symptoms & Causes of Adrenal Insufficiency & Addison's Disease’, (niddk.nih.gov)

Alcoholics are like a human version of an animal-model of chronic retinoid toxicity, as alcohol causes the liver to over-convert vitamin A and carotenoids to the active retinoids, leaving the alcoholic person with low vitamin A in the retinas and night blindness and excess active retinoids everywhere else. Adrenal insufficiency is observed in later stage alcoholism. (Kumar, et al., 2019) Thanks, alcoholics, for you contribution to science.

Cortisol levels change over the course of the day.

“Baseline serum cortisol level was higher in patients with severe [Alcoholic Hepatitis] AH compared with mild AH, which is suggestive of a state of stress in the severe AH group. In patients with severe illness, activation of the HPA axis is an important feature in host adaptation to acute illness. Activation of this axis initiated by the action of cytokines on the hypothalamus promotes the release of corticotrophin-releasing hormone, corticotrophin, which acts on the pituitary gland, in turn increasing cortisol secretion by the adrenal glands. During an acute illness, negative feedback of cortisol on corticotrophin-releasing hormone and corticotrophin is depressed, which keeps a sustained activation of the HPA axis. Consequently, in well-compensated adaptation response to optimize the effect, the cortisol level in the circulation and in the tissue is increased.^{32, 33”} (Kumar, et al., 2019)

Key point in the quote below: “This hypoadrenalism is transient and is not caused by a structural lesion…”, (Kumar, et al., 2019) , means that the adrenal glands in cirrhosis are dysfunctional due to aberrant signaling or something other than a tumor on the adrenal gland as seen in some cases of adrenal illness. Retinoid toxicity in alcoholism would fluctuate with dietary intake. Did the alcoholic person eat liver and tomatoes yesterday (vitamin A rich meal) or just a burger with no catsup, green leaf lettuce or tomato (lower vitamin A meal)?

The good news with “…not caused by a structural lesion…”, (Kumar, et al., 2019), is that if the alcoholic person changes their diet and lifestyle soon enough their negative adrenal symptoms should normalize. Liver conditions may be reversible in early stages but once fibrotic buildup is occurring (cell death/scar tissue build up), in any inflammatory condition, some of the organ damage will be irreversible.

“Adrenal dysfunction/adrenal insufficiency (AI) in cirrhosis, also described as hepatoadrenal syndrome, is a well-recognized entity. AI is defined as an inadequate glucocorticoid activity with respect to the severity of illness in a patient with liver disease.^{6, 7, 8} This is also termed as critical illness–related corticosteroid insufficiency (CIRCI) and occurs because of either reduced adrenal steroid production or tissue resistance to glucocorticoids in patients with systemic inflammation.⁹ AI is frequent in compensated (31–60%)^{10, 11, 12, 13} and decompensated cirrhosis (26%–64%).^{14, 15.}

[KEY POINT]» This hypoadrenalism is transient and is not caused by a structural lesion but could increase the risk of circulatory failure, infections, and further decompensation. It substantially increases the risk of death during acute illness as an increase of the cortisol level in acute illness is an important protective response.^{16, 17}

Severe [Alcoholic Hepatitis] AH is associated with an increased level of endotoxin and proinflammatory mediators, which is quite similar to that observed in sepsis. Steroids (produced by adequate adrenal function) are associated with improved short-term mortality in patients with severe AH.^{18, 19} (Kumar, et al., 2019)

Prenatal aside: Alcohol is a teratogen for fetal development because of the activation of excess retinoids. Adequate zinc is somewhat protective against more severe birth deformities when alcohol was used during a pregnancy. Zinc is protective against damage from Retinoid excess during fetal development. (Blain, Kubow, Chan, 1998) Male drinking counts too. It takes 74 days to grow a healthy alcohol-free sperm or a DNA damaged drunken sperm which is associated with ADHD risk for the child. (Previous post)

Heavy metal toxicity aside: Large doses of all-trans Retinoic Acid can increase risk from cadmium exposure as the atRA increases metallothionein mineral transport proteins in the liver, concentrating the cadmium in liver tissue. (Sauer, et al., 1997)

The links about quercetin, luteolin, bromelain, and hesperidin being COX2 inhibitors:

Quercetin is however, a COX2 inhibitor (Xiao, et al., 2011) like pomegranate peel, and that may be increasing the salicylate excess symptoms associated with COX1 and COX2 inhibition.

“Quercetin also significantly inhibited COX-2-mediated angiogenesis in human endothelial cells in a dose-dependent manner.” (Xiao, et al., 2011)

Food Sources of Quercetin: Onions are a very good source and also have a healthy type of fiber for supporting beneficial microbiome species. Quercetin is a flavanol, a type of flavonoid, found in onions, garlic, green leafy veg, citrus peel, and figs. Quercetin represents a large group of similar chemicals and is fairly common in small amounts in many fruits, vegetables and leafy herbs. It is found primarily in the leaves or edible peels.

Luteolin is also a COX2 inhibitor {and iNOS, (Pandurangan, et al., 2014)} and chrysin is a COX2 inhibitor too. (Harris, et al., 2006) Chrysin is found in honey and may be why Propolis (a honey product/byproduct?) is recommended to avoid. Bromelain is also a COX2 inhibitor. (Pezzani, et al., 2023)

Luteolin food sources: Luteolin is a flavonoid "found in celery, thyme, green peppers, and chamomile tea," (18) and "chrysanthemum flowers, sweet bell [green/red/orange] peppers, carrots, onion leaves, broccoli, and parsley [7 8]. (21) 

Hesperidin is also a COX2 and iNOS inhibitor. Citrus peel/pith is an excellent source of hesperidin.

“According to current studies, hesperidin, one of the most abundant polyphenols, can inhibit transcription factors or regulatory enzymes essential for controlling inflammation-linked mediators, including nuclear factor-kappa B (NF-κB), Inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). It also improved cellular antioxidant defences by activating the ERK/Nrf2 signalling pathway.” - ‘Current Update on Role of Hesperidin in Inflammatory Lung Diseases’, (Howasi, 2023)

Bromelain is an enzyme found in raw pineapple.

I don’t like dietary restrictions but knowing why something is a problem helps to accept that avoiding or limiting something might be important.

So far, my boring breakfast has left my gut feeling okay compared to instant gassiness after my tastier mixed dish that had asparagus, green peas, garlic, apple cider vinegar and green leaf lettuce.

Fennel bulb is yummy though, the dish worked in a simple, mildly sweet way.

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Retinoid Toxicity from medication use has been linked to calcinosis and bone spurs and over time can lead to osteoporosis and hip fractures.

“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.

Chronic retinoid toxicity can affect many organ systems. Bone effects include changes such as bone spurs, calcinosis, and bone resorption with resulting hypercalcemia[6]. Long-term consumption of high levels of dietary vitamin A may stimulate bone resorption and inhibit formation, contributing to osteoporosis and hip fractures[7]. Central nervous system effects include headache, nausea, and vomiting.” (Olson, Ameer, Goyal, 2023)

I likely have not cut down enough on green herbs and vegetables and have remained chronically elevated. Just not as elevated as the nausea and vomiting and fibromyalgia like pain stage maybe. In my past, I rarely vomited. Digestive trouble wasn’t an issue for me unless I overate. And I was not sensitive to spicy foods. Avoid stress - it can cause gut problems on its own. Now the combined oxalate and salicylate seem particularly likely to cause an upset stomach. The salicylates alone cause gassy bloating fairly instantly and the swelling edema in the lower legs or everywhere follows.

Sad news that I need to eat less green salad and so many other fruits and veggies too. However, I am feeling better, already! That is the good news. My pre-arthritic thumb is less inflamed and moving better again. Hopefully I will be able to reverse the calcinosis pain and bony spots with less phophorus in my diet and more use of calcium and topical magnesium. (*I need topical specifically due to a gene difference I think in my ion channels that transport magnesium in the intestines.)

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 *functional health professional for individual health care purposes.

Reference List

(Alique, Herrero, Lucia-Cazana, 2007) Alique M, Herrero JF, Lucio-Cazana FJ. All-trans retinoic acid induces COX-2 and prostaglandin E2 synthesis in SH-SY5Y human neuroblastoma cells: involvement of retinoic acid receptors and extracellular-regulated kinase 1/2. J Neuroinflammation. 2007 Jan 4;4:1. doi: 10.1186/1742-2094-4-1. PMID: 17204142; PMCID: PMC1769480. https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-4-1

(Blain, Kubow, Chan, 1998) Blain, D., Kubow, S., Chan, H. M., Zinc Pretreatment Inhibits Isotretinoin Teratogenicity and Induces Embryonic Metallothionein in CD-1 Mice2, The Journal of Nutrition, 1998:128(7);1239-1246, ISSN 0022-3166, https://doi.org/10.1093/jn/128.7.1239. https://jn.nutrition.org/article/S0022-3166(22)07267-4/fulltext?ck=nck

(cedars-sinai.org) Cedars-Sinai Staff, Debunking Adrenal Fatigue, Jan 16, 2018, Cedars-Sinai.org, https://www.cedars-sinai.org/blog/debunking-adrenal-fatigue.html

(Fries, Grosser, 2005) Susanne Fries, Tilo Grosser; The Cardiovascular Pharmacology of COX-2 Inhibition. Hematology Am Soc Hematol Educ Program 2005; 2005 (1): 445–451. doi: https://doi.org/10.1182/asheducation-2005.1.445 https://ashpublications.org/hematology/article/2005/1/445/19280/The-Cardiovascular-Pharmacology-of-COX-2

(Harris, et al., 2006) Harris GK, Qian Y, Leonard SS, Sbarra DC, Shi X. Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E2 formation in RAW 264.7 cells. J Nutr. 2006 Jun;136(6):1517-21. doi: 10.1093/jn/136.6.1517. PMID: 16702314. https://www.sciencedirect.com/science/article/pii/S0022316622082815?via%3Dihub

(Howasi, 2023) Hosawi S. Current Update on Role of Hesperidin in Inflammatory Lung Diseases: Chemistry, Pharmacology, and Drug Delivery Approaches. Life. 2023; 13(4):937. https://doi.org/10.3390/life13040937 https://www.mdpi.com/2075-1729/13/4/937

(Kang, et al., 2017) Kang, X., Qiu, J., Li, Q. et al. Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype. Sci Rep 7, 9459 (2017). https://doi.org/10.1038/s41598-017-09528-z https://www.nature.com/articles/s41598-017-09528-z

(Kumar, et al., 2019) Kumar M, Gupta GK, Wanjari SJ, Tak V, Ameta M, Nijhawan S. Relative Adrenal Insufficiency in Patients with Alcoholic Hepatitis. J Clin Exp Hepatol. 2019 Mar-Apr;9(2):215-220. doi: 10.1016/j.jceh.2018.09.002. Epub 2018 Sep 19. PMID: 31024204; PMCID: PMC6477128. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477128/

(Olson, Ameer, Goyal, 2023) Olson JM, Ameer MA, Goyal A. Vitamin A Toxicity. [Updated 2023 May 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532916/

(Pandurangan, et al., 2014) Pandurangan AK, Kumar SA, Dharmalingam P, Ganapasam S, Luteolin, a bioflavonoid inhibits azoxymethane-induced colon carcinogenesis: Involvement of iNOS and COX-2. Pharmacogn Mag. 2014 Apr;10(Suppl 2):S306-10. doi: 10.4103/0973-1296.133285. PMID: 24991108; PMCID: PMC4078326. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078326/

(Pecori, et al., 2021) Pecori Giraldi, F., Sesta, A., Tapella, L. et al. Dual effects of 9-cis retinoic acid on ACTH-dependent hyperplastic adrenal tissues. Sci Rep 11, 14315 (2021). https://doi.org/10.1038/s41598-021-93672-0 https://www.nature.com/articles/s41598-021-93672-0

(Pezzani, et al., 2023) Pezzani, R., Jiménez-Garcia, M., Capó, X., Gürer, E.S., Sharopov, F., Rachel, T.Y.L., et al., Anticancer properties of bromelain: State-of-the-art and recent trends, Front. Oncol., 09 Jan 2023, Sec. Pharmacology of Anti-Cancer Drugs, Vol 12 - 2022, https://doi.org/10.3389/fonc.2022.1068778 https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1068778/full#:~:text=Bromelain%20downregulated%20COX%2D2%20and,mitochondrial%20death%20pathway%20(139).

(Sauer, et al., 1997) Sauer, J.M., Waalkes, Hooser, S.B., Baines, A.T., Kuester, R.K., Sipes, I.G., Tolerance Induced by All-trans-Retinol to the Hepatotoxic Effects of Cadmium in Rats: Role of Metallothionein Expression, Toxicology and Applied Pharmacology, 1997:43(1);110-119, ISSN 0041-008X, https://doi.org/10.1006/taap.1996.8050. https://www.sciencedirect.com/science/article/abs/pii/S0041008X96980503

(Xiao, et al., 2011) Xiao X, Shi D, Liu L, Wang J, Xie X, Kang T, Deng W. Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling. PLoS One. 2011;6(8):e22934. doi: 10.1371/journal.pone.0022934. Epub 2011 Aug 8. PMID: 21857970; PMCID: PMC3152552. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152552/