CoV, ACTDs, calcinosis, secondary hyperparathyroidism, albumin and Retinoid Toxicity - new news to use.
*This post got long when I started looking into why I had stopped using animal products in my diet. Calciphylaxis/Calcinosis. Albumin autoimmune molecular mimicry.
This post took a long walk around the block from my initial reply to a comment.
Summary point: Two recent review articles state that the prevalence of calcinosis in autoimmune connective tissue disease and other autoimmune conditions has been increasing - and therefore more attention is needed for the issue - as it is disabling, often missed as a diagnosis, and frequently becomes deadly. The cause is not known, and treatments are oriented towards surgeries or immune suppression (Mormile, et al., 2023) and vitamin K and hyperbaric oxygen treatment were mentioned. (Zhou, et al., 2023)
I would suggest if any of the following sounds familiar, or if you are a researcher in this field - test for albumin autoimmune antibodies: (Albumin polyclonal antibodies: tests for sale, ~ $300-500) And maybe anti-phospholipid antibodies too.
What could possibly have happened in the near past that might have increased autoimmune connective tissue diseases (ACTDs), and particularly in young woman? The easy and obvious Answer: COVID-19. (Kouranloo, et al., 2023)
I had already noted in a post about LongCovid ‘fingers’ (and toes) that there has been a trend towards anti-phospholipid autoimmune antibodies in patients with LongCovid or possibly post CoV jab issues. The LNP carrier for the mRNA injections include phospholipid, which being part of a foreign particle with toxic effects, it may be helping to set up autoimmune antibodies against the person’s own phospholipids which are found in cell membranes and within endocannabinoids.
I needed THC without excess CBD in proportion and also better magnesium intake, for my own finger symptoms to improve. Methyl B12 was also helpful. Finger numbness is still a bit of an issue but it is not ‘pain’ or reddening or bruising as occurred when I stopped using THC to travel out of a legal state in 2020.
LongCovid ‘fingers’ - is a little like hypothermia/frostbite or other types of vasculitis that affect the extremities first. It is a survival instinct to shunt necessary nutrients to the brain, heart, and lungs, at the expense of the fingers and toes. Cannabinoids & Blood Vessels and LongCovid, Feb 16, 2021, (Substack).
This post turned up while looking: LongCovid and excess acidity/lactate theory - the positive feedback hyperinflammation loop by another name. Interview by Gez Medinger with Vicky Van der Togt, a LongCovid patient, and Jeremy Rossman. June 23, 2023, (Substack). Pertinent to my last post’s discussion of sodium bicarbonate and lactic acid in LongCovid patients.
Secondary hyperparathyroidism
- is an elevation in parathyroid hormone (PTH) in response to a deficiency in either low calcium or low vitamin D or both. An endocrinologist is likely to prescribe high dose of each whether you need both or not. And high dose of calcium or high dose of active forms of vitamin D may increase risk of calcification of soft tissue, which may present as cardiovascular atherosclerosis, or as calcium deposits in skin tissue, calciphylaxis, or in joint tissue or on bones, calcinosis or bone spurs. More vitamin K in an active form is likely needed to help keep the calcium in the bone matrix. More magnesium is likely needed to help keep the body from artificially suppressing blood levels of calcium in an effort to protect the body and blood vessels from too much electrically active calcium from causing trouble intracellularly as magnesium is needed to shot the ion channels that allow calcium entry. Too much calcium in a cell over-activates it possibly to the point of cell death.
Calciphylaxis are necrotizing wounds - non-healing, in or under the skin surface. Calcinosis is calcium deposits within joints or tissue areas and it causes inflammation and pain in the area and can be disabling or limit range of motion. Too much calcium can cause cell death…do you see the connection with a necrotizing wound?
Necrotizing means dying tissue/decomposing either from a bacterial infection or in response to some other injury, radiation or chemical damage. You do not want a diagnosis of “necrotizing ulcer”.
*Warning - very graphic images of necrotizing wounds are in this review article: Calcinosis Cutis and Calciphylaxis in Autoimmune Connective Tissue Diseases, (Mormile, et al., 2023).
This recent review has additive value: Calciphylaxis and its co‐occurrence with connective tissue diseases, (Zhou, et al., 2023).
Summary points to help reduce risk of secondary hyperparathyroidism:
Have adequate calcium and vitamin D - which means probably avoid glyphosate and get sunshine or vitamin D, not in excess, and with adequate magnesium and protein for vitamin D metabolism to function properly. Also avoid end-stage renal disease with hemodialysis.
Summary points to help reduce risk of calciphylaxis/calcinosis:
Have adequate vitamin K2 (Zhou, et al., 2023), how much? A pharmaceutical dose of vitamin K2 (100 mg/kg b.w.) and estradiol (83 micrograms/kg b.w.) may have combined benefits against arteriosclerotic risk - animal-based study. “Moreover, vitamin K2 and estradiol inhibited the increase of Ca and P in the aorta and the elastin fraction.” (Seyama, et al., 2000) The same dose of vitamin K2 was found helpful against calcinosis and aortic Calcium and Phosphorus levels, when hypercalcemia was induced by high dose vitamin D2 (2.5 x 10(5) I.U./ kg b.w.) in an animal-based study acting as a model for cardiovascular disease. “A high dose of vitamin K2 (100 mg/kg b.w.) inhibited the increase in the aortic Ca and P or in the renal Ca and P induced by vitamin D2, and a low dose of vitamin K2 (10 mg/kg b.w.) showed the same tendency, but the degree of the efficacy was small. It may be suggested that a high dose of vitamin K2 suppressed experimental calcification of soft tissues induced by vitamin D2.” (Seyama, et al., 1996)
Oddly, the amount of vitamin K2 available in human supplements tend to be fairly low, 100-300 micrograms is standard. But humans are large, 70 Kg, as an average, would make the 100mg/kg body weight dose used in the animal studies, successfully, 100mg x 70Kg = 7000 mg, or 7 grams. What? Life Extension has 45 mg as a ‘high dose’ for preventing fracture. (LifeExtension) also cited by Paul, 2020, viewable at Sciencedirect/K2, The dose has been used for 20 years in Japan for bone health or reversal of arteriosclersis.)
“Vitamin K: There are three types of vitamin K, vitamins K1, K2, and K3. They are well known for regulating blood clotting. They also can reduce adverse effects of pre-diabetes and diabetes such as lowering blood glucose, increasing fasting insulin, reducing HgA1c, and increasing β-cell functioning (Karamzad et al., 2020).
Vitamin K2 acts through gene expression to reduce risk of calcification of blood vessel walls (Wallin et al., 2008). There is mounting evidence that it also plays roles in reducing risk of cancer, diabetes and osteoarthritis (Schwalfenberg, 2017),
Vitamin K1 is found in many green vegetables. Vitamin K2 is found in nattokinase, cheese, beef liver, chicken, butter, sauerkraut, and egg yolk.” (Grant, 2022; viewable at Sciencedirect/K2)
and magnesium. Assure adequate magnesium intake is being absorbed well. Many conditions can cause poor magnesium absorption with increased calcium absorption, making topical sources more helpful. Chelated supplements may also be better absorbed but I really seem to need the Epsom salt baths and chelates are more expensive supplements.
Avoid excess phosphate, avoid high dose calcium supplements or excess active form of vitamin D supplements (D3) any of which can add to hypercalcemia risks. (Mormile, et al., 2023); Zhou, et al., 2023)
Examples of high phosphorus foods (healthadvance)
Phosphorus content in mg and low, medium high categories for common protein choices, grains and a few other foods (commercial products mainly. (nephrologyonline.com) The phosphorus in plant foods is less bioavailable than from meat and dairy or from additives, only about 50% is absorbed. (thekidneydietitian)
Carbonated soft drinks and other beverages can be a significant source of phosphorus and may replace calcium rich beverages. An excess of phosphorus to calcium ratio can be a factor in secondary hyperparathyroidism. Soft drink consumption was linked to increased risk of fractures in a seven year study with a Chinese cohort. (Chen, et al., 2020)
Pyrophosphate may be low in SSc patients with calcinosis and has regulatory effects on mineralization. Treatment with it may be helpful. (Hsu, et al., 2022) Pyrophosphate inhibits mineralization by osteoblasts in soft tissue while promoting it in bone, seemingly, see excerpt below. That would be helpful if someone were growing a bone spur instead of bone matrix. It also inhibits alkaline phosphatase which would be helpful, (Addison, et al., 2007), or promotes it in varying circumstances. (Pujari-Palmer, et al., 2016) Eating less retinoids and not over-expressing alkaline phosphatase in the first place would be more helpful. And excess pyrophosphate would eventually precipitate out and add to an excess phosphate problem in soft tissue.
Avoid other reasons for hypercalcemia which includes excessive active retinoids from medications/topical cosmetics, or other reasons for excess activation of dietary vitamin A and carotenoids. Viral infection, liver injury, and alcoholism may cause over activation. Immobility is a cause of hypercalcemia which lifestyle changes could likely improve. If bedbound gentle range of motion exercise with the help of a caregiver would be better than not moving, for mitochondria and apparently calcium balance. (Borgan, Khan, Makin, 2022)
Vitamin C adequacy has epigenetic control over bone matrix formation (Thaler, et al., 2022) and would help therefore at keeping minerals within the bone matrix instead of adding to hypercalcemia or phosphate.
Hyperbaric oxygen therapy may help by providing more oxygen to tissue that isn’t being nourished properly. (Zhou, et al., 2023)
AND I would recommend getting tested for autoimmune antibodies against egg and/or bovine albumin
and phospholipids. (Zhou, et al., 2023).
“Many diseases can mimic calciphylaxis, including warfarin‐ and heparin‐induced skin necrosis, pyoderma gangrenosum, peripheral arterial disease, systemic lupus erythematosus, antiphospholipid syndrome, autoimmune vasculitis, and lower‐extremity involvement associated with diabetes. 23 , 24 , 25 , 26 Patients on dialysis with severe pain associated with skin lesions should be vigilant against calciphylaxis.” (Zhou, et al., 2023).
*Re the phosphate - “alkaline phosphatase” is elevated when calcinosis is present in autoimmune conditions and elevated alkaline phosphatase is also seen in bone or liver disease. It is an enzyme that causes dephosphorylation of chemicals with a phosphorus group. I asked Bing “Does retinoic acid increase expression of alkaline phosphatase” Answer: Yes, 8 sources. By my cutting out animal products to reduce albumin and autoimmune flair-up, I also coincidentally greatly reduced my intake of vitamin A, but I was still eating a lot of carrots and kale at the time.
“The exact mechanisms underlying the gene expression and protein activity changes in response to extracellular pyrophosphate exposure are not well understood. In the present study the expression of pyrophosphate transporter, ANK, was not affected by pyrophosphate, suggesting that ANK does not participate in the osteogenic response to extracellular pyrophosphate. The products of pyrophosphate cleavage, calcium and inorganic phosphate, can stimulate gene expression changes directly. Elevated phosphate can stimulate COL1, OPN and ALP [47, 48]. Both excessive calcium and phosphate can activate Erk1/2 [9, 47–49]. However, phosphate uptake blocker and pyrophosphate analog, foscarnet, does not inhibit the effects of exogenous pyrophosphate, suggesting that breakdown of PPi into inorganic phosphate may not explain observed gene expression changes [8, 50].” (Pujari-Palmer, et al., 2016)
Coincidentally, or causally, ALP expression is promoted by active retinoids. (Zhang, W., et al., 2010, Figure 1) And OPN may have increased expression caused by active retinoids, but it was variable depending on the amount of E2F1 that was present in a study on retinoid treatment for osteosarcoma cells. Low levels of E2F1 led to more expression induced by all-trans Retinoic Acid, while high levels of expressed E2F1 led to almost no increase in OPN with ATRA treatment. (Zhang, L., et al., 2014)
“To further evaluate the relationship between E2F1 expression and the sensitivity to cyto-differentiating activity of ATRA, the protein levels of OPN were also detected after ATRA treatment in 9 selected primary osteosarcoma cultures (Fig. 3D). The relative increase of OPN protein level in each culture were summarized in Figure 3E, and the results showed that primary osteosarcoma cultures with low E2F1 expressions displayed remarkably more relative increased OPN protein level, while almost no increase in OPN expression were observed in cultures with high E2F1 expressions (Fig. 3F).” (Zhang, L., et al., 2014)
That makes levels of all-trans Retinoic Acid and levels of E2F1 potentially confounding variables for the studies by Pujari-Palmer, et al., 2016 and Addison, et al., 2007. “What is E2F1?” says Alice, looking into the rabbit hole. ‘E2F1, a Novel Regulator of Metabolism’, “The transcription factor E2F1 is a central player involved in cell cycle progression, DNA-damage response, and apoptosis.” (Denechaud, Fajas, Giralt, 2017) Like vitamin D receptors and Retinoic Acid receptors can interact with each other’s gene transcription effects, likely E2F1 and Retinoic acid also modulate each other’s gene transcription, up or down regulating expression of a protein potentially.
Isn’t this fun? Like solving a mystery.
Let’s do another: “Does retinoic acid increase expression of BMP4?” Answer: Yes, 1 source. (Giacomini, et al., 2006) *Relevance of this point is at the end of this Too-long- for-email post. Spoiler it is an over-expressed gene/protein seen in early stages of vascular calcification in Chronic Kidney Disease (CKD). (Li, et al., 2023) What is it? “BMP4 (Bone Morphogenetic Protein 4) is a Protein Coding gene.” (Genecards/BMP4) What does it do? promotes new bone cell growth - a lightbulb moment regarding the bone spurs.
I asked a third question and received a great reference about retinoid toxicity as an often missed cause of hypercalcemia. Immobility is another cause, and hyperthyroidism and granuloma conditions like sarcoidosis. (Borgan, Khan, Makin, 2022) Details are included later.
How common is hypercalcemia due to retinoid medication treatment? - very common.
A third to half of patients put on retinoid treatments for cancer seem to develop hypercalcemia. (Borgan, Khan, Makin, 2022) It is worth noting that both lack of vitamin A and excess active retinoids can cause some similar symptoms - so lack may not have been a problem. The authors do point out that a lab test for serum levels of retinoids or vitamin A may not be conclusive as excess retinoids can be a localized problem. Like in skin cells maybe (Amann, et al., 2011), or ovarian cells.
How do you know if you have enough vitamin A or carotenoids in your diet? Night vision.
Alcoholics tend to have night blindness - no night vision. Alcohol causes overactivation of retinoids in the liver, leading to low levels of inactive forms and excess of active forms.
Do your eyes adjust to low light settings so what had seemed dark black now has some faint moon-light visibility? If so, you have enough vitamin A to supply your retina with rhodopsin which contains a molecule of retinal.
Bonus tip: Maintain your night vision and it may help protect your brain too.
Degeneration of retinal and rhodopsin in the retina has been linked to Alzheimer’s dementia and other degenerative neurocognitive disorders. (Lenahan, et al., 2020)
This post got really long as I explored current research and followed my questions about the information. I moved most of the important points to the above summary section. The following 2/3rds goes into more of my background health history, journey towards better health, chit chat, and more in depth excerpts from the research links. I learned a lot about why I have been having bone spur problems and joint pain - I seem to have early calcinosis symptoms and immobility is likely part of my recent worsening health - sitting too long at the computer and staying inside with my mother who doesn’t like to go outside.
Read on if interested - this is fascinating stuff and likely is impacting the Long Covid or CoV injured community in addition to people with ME/CFS or autoimmune connective tissue disorders.
Aside - as a specialist in my field, what is this post on calcinosis, albumin autoimmune antibodies, secondary hyperparathyroidism and “Why I don’t eat a Carnivore Diet” worth? My standard-of-care endocrinologist charged ~$300/hour, so I decided at the time that would be my fee too, as I provide better results. This post took about 6 hours this morning of additional research and was a little traumatic to revisit such a difficult time of my life, so, this post is worth $1800 to me. *I have spent more time on editing it. The fun is in the hunt for the answer.
You’re welcome. You may not find the same value in it, in which case, count your blessings. It is nice to be able to grow skin - of any color. Love the skin you’re in - it protects you, can help nourish you, and it feels nice to touch when it is healthy.
The post hops around a bit and has an intermission about mitochondria and movement (another comment, thanks). It tells a story, though, which might help other LongCovid sufferers get solid answers. I leave some carrots along the route to add color to the journey.
Bad news - autoimmune antibodies means you are attacking your own proteins - take that really seriously. “Necrotizing” - like death, like decomposition is already happening in the wound. Graphic images of calciphylaxis, necrotizing wounds are included in this article: (Mormile, et al., 2023), *disturbing.
Good news - knowing which proteins or other chemicals are involved can help clarify if something in the diet needs to be avoided like albumin in this post’s example or Vitamin A and carotenoids as I am also pointing out in this post - excess of the activated form directly causes overexpression of many inflammatory proteins and it seems to be a causal factor for calcinosis risk. Press on to find out more about alkaline phosphatase and BMP4’s role in calcinosis or calciphylaxis - similar but slightly different problems.
Or to know to avoid CoV jabs…. when autoimmune antibodies have been formed to an external protein then strict avoidance of that protein is needed - forever after. The memory B cells hang around ready to make more antibodies against the protein anytime it is identified by the memory immune cells.
It helps to know if adding something may be needed in an autoimmune condition that is causing a protein essential to health to be broken down too much - like endocannabinoids leaving a need for an external source of cannabinoids (in balance, THC/CBD both) or maybe phosphatidylserine as a precursor.
Re a comment on my last post: “Why not try the Carnivore diet?”
My reply is background info about why I took animal-based foods out of diet due to non-healing skin rash that was approaching open wound stage:
Thanks, BUT you missed a major point in my list of things my body can't handle anymore - "albumin" - causes molecular mimicry autoimmune antibodies against my own body albumin causing me to not be able to grow skin. I like having skin. That may be an odd quirk of mine, but no skin in high friction zones of the body is uncomfortable (armpits).
Albumin is in plasma and it is in fish, scallops and all animal-based foods. I have also found that it is why hemp kernels are complete protein because there is a plant version of albumin in hemp, and in ginger and wheat.
I am not 'vegan' by choice or officially as I do use fish oil for omega 3 fatty acids - being pure oil it seems to not contain albumin. I might be able to use a few other extract type products, but I haven't experimented further. I tried scallops on the hope that I might be able to eat them, but the rash returned.
It takes about six months for autoimmune antibody flare-ups to reside again, so autoimmune disease is not something I feel like experimenting with. Again, I like being able to grow skin effectively. I enjoy having skin. I stopped eating eggs first, then realized chicken was likely adding to the problem, and then all meat. And it was a year or so later that I started eating enough hemp kernels consistently to have the "I can't grow skin" problem return. When I looked up protein content of hemp kernels it was a clincher for me that I have molecular mimicry antibodies against albumin as a for-life problem. Autoimmune memory cells don't just go away.
The plant chemicals that are troublesome are avoidable compared to albumin being in all mixed animal-based foods. Being forced to go mostly vegan did get me in trouble with the increase in oxalates and likely an increase in salicylates too.
Otherwise, I really am not a big fan of the carnivore diet as humans are omnivores. It might be particularly dangerous for pregnant women due to effects on the developing fetal brain (or lead to miscarriage) and a vegan diet is not recommended during pregnancy either. The WEF pushing veganism on the world is not okay or safe in my opinion.
~~
More on the topic of “diagnosis” - If the medical industry doesn’t know what causes a problem and has no good solution to help, then what is the point in seeking a “diagnosis” that they can’t help you with anyway?
A diagnosis like that can often just mean the physician is now going to ignore your needs or may experiment on you with whatever trendy new medication is being pushed by pharma representatives.
I have not been ‘tested’ to prove to a doctor or health insurance company that this a real problem of mine. Testing for albumin antibodies seems to be still only for research purposes (Albumin polyclonal antibodies: tests for sale, ~ $300-500) and testing for autoimmune antibodies only works when the person is currently flared-up and I don’t want to make myself sick again just to “pass a test”.
I was never officially diagnosed with fibromyalgia because the insurance guidelines required the person to report muscle knot pain in a certain number of specific areas - like have 8 pain spots out of a body map of 13 specific pain spots. I already knew that white potatoes seemed to make me worse, so I could have made myself worse in order to “get a diagnosis” but then I would have felt more pain and what sense would that make? None, in my opinion, so I just kept trying to figure out what made me worse and what made me feel better and to make changes.
Dietitian work is detective work or more apt a differential diagnostic process based on visible symptoms, interview, and diet history/routine, and sometimes tracking physical measurements and labs too. Food and symptom logs or diaries can also be helpful to see patterns of change.
What happened? What changes preceded the symptom? If something is excluded, does improvement in symptoms occur? Does a retrial of that substance or habit cause the symptoms to return? If so, stop doing that for an ongoing basis. If pounding your thumb with a hammer hurts, stop doing that. Difficult if you are bad at hammering nails and need to do that anyway, or do you? Find a work around in life to remove things that are inflammatory - pain inducing.
What happened to me? Hard-boiled eggs plus stress = a leaky gut and molecular mimicry, is my theory, and reason for stopping use of animal-based foods in my diet.
I was under a huge amount of stress at the time of the onset of the nonhealing rash (which was unlike my life long off-and-on eczema) and in thinking about what else was different in my daily routine at that time - hard-boiled eggs was the answer.
At that time, I had gradually started making a dozen boiled eggs for the family and using them plain or in egg salad a lot more often than I had previously been using in my own diet routine. It was an obvious stand-out as to what was “different” besides the stress level. At the time I had also learned that secondary hyperparathyroidism had been an ongoing reason for some of my odd symptoms and that may have been an additive factor in risk for the nonhealing rash/wounds. In hyperparathyroidism research I found references for calciphylaxis - nonhealing wounds that included excess calcium build-up. In that research, autoimmune antibodies against albumin came up somehow or dysfunction of albumin like proteins.
Albumin is a blood plasma protein that helps keep fluid where it belongs - in the blood, not in puffy edema ankles. Low levels of albumin is associated with being near death - nothing works or heals as well when albumin is low.
What is calciphylaxis? Generally seen in end stage renal disease in patients on hemodialysis. Non-healing wounds can lead gangrene and death.
“Calciphylaxis is a rare, severe complication of secondary hyperparathyroidism. Patients present with painful, violaceous, mottled skin lesions of the upper and lower extremities, which become necrotic and produce nonhealing ulcers. Gangrene of fingers and toes frequently requires amputation, produces nonhealing wounds, and can lead to sepsis and death.”
“Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007).” [*Study group included end stage renal disease patients who may also have been on hemodialysis. Albumin would be lost in hemodialysis fluid. (Kalantar-Zadeh, et al., 2021) As a dietitian I knew that.]
“At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P < 0.001).”
Risk factors and mortality associated with calciphylaxis in end-stage renal disease (Duh, et al., 1991)
Hyperparathyroidism is generally involved in calciphylaxsis or calcinosis and removal of the parathyroid gland is a standard treatment.
Both conditions involve excess calcification of soft tissue, causing pain and risk of infection. Calcinosis is seen in autoimmune conditions, and calciphylaxsis is seen more in kidney patients. Neither are common conditions.
The solution in 1991 (Duh, et al., 1991) and in 2023 is to surgically remove the parathyroid gland. (Li, et al., 2023/calcinosis in hemodialysis patients) I did not go that route, as I like maintaining both my skin and my body parts intact and I was not on hemodialysis or as severe a case. Calciphylaxis is primarily seen in kidney patients while calcinosis is also seen in autoimmune patients and diagnosis is frequently missed and treatment delayed. (Mormile, et al., 2023)
“The etymology of the word “calciphylaxis” is derived from “calci”, a Latin word semantically related to the process of calcification, and “phylaxis”, a Greek word meaning protection. The term means protection by calcification and was first used by Dr. Seyle [8,9] in 1961 to describe the formation of a calcium shell on rat skin [10]. […] However, rather than a protective response, calciphylaxis in humans appears to be the skin equivalent of a myocardial infarction [11]. Calciphylaxis is rare, but it has a very high mortality rate due to the severe pain and propensity for infections, which lifts its annual mortality from 40% to 80% [12].” (Mormile, et al., 2023).
The known risk factors for calcinosis development in autoimmune conditions does not currently include albumin autoimmune antibodies per the review. Being an older female or someone using PPI medications are risk factors. (Mormile, et al., 2023) PPI medications can reduce magnesium, and deficiency would increase risk of soft tissue calcification.
Abstract: “Calcinosis represents a severe complication of several autoimmune disorders. Soft-tissue calcifications have been classified into five major types: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Autoimmune diseases are usually associated with dystrophic calcifications, including calcinosis cutis, occurring in damaged or devitalized tissues in the presence of normal serum levels of calcium and phosphate. […]
»Due to the potentially disabling character of calcinosis cutis and calciphylaxis, physicians’ awareness about the clinical presentation and management of these diseases should be increased to select the most appropriate treatment option and avoid long-term complications.” […]
“Regarding the association between calcinosis and autoimmune diseases, calcinosis cutis has been described in dermatomyositis (DM), polymyositis (PM), juvenile DM (JDM), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), overlap syndrome, mixed connective tissue disease, and rheumatoid arthritis [14,15,16]. The autoimmune connective tissue disorders most frequently associated with calcinosis cutis are DM and SSc [17]. On the contrary, calciphylaxis is mainly observed as a consequence of renal failure, often associated with connective tissue disease, while non-uremic calciphylaxis is rare.
»However, the prevalence of this condition is often underestimated, resulting in delay in diagnosis and long-term complications.” […]
“The authors reported that the most frequently involved sites were the hands (70%), particularly the thumbs (19%), representing a significant cause of functional dysfunction and a high burden of disability.” (Mormile, et al., 2023)
Aside/ ouch, my thumbs have been getting worse, like early arthritis or bone spurs - or maybe calcinosis. My left thumb has lost function due to the pain level with use. I think I need to increase my DMG use and vitamin K2 to help get calcium to stay in my bone matrix and take my Epsom salt soaks more often. I was going too long in between soaks, regularly, while taking care of my parents. It never seemed to fit in the day. I have asked my family doctor about bone spurs and the response was ~ “That bonespur isn’t so bad and there’s nothing we can do besides surgically cut off some of the bonespur if it was bad enough to warrant treatment.” Okay, thanks, but no thanks.
“Recently, a single‐center retrospective cohort study found that vitamin K antagonists can easily cause calciphylaxis in patients with ESRD and that the role of coumarin anticoagulants in the pathogenesis of calciphylaxis can be underestimated. 51 However, studies have found that vitamin K supplementation 52 or the early use of direct oral anticoagulants 53 may be beneficial in preventing calciphylaxis.
Although there may be an interaction between the hypercoagulable state and the progression of calciphylaxis, systemic anticoagulation therapy is not recommended for all patients. In addition, it has been reported that kidney transplantation, 54 parathyroidectomy, 55 and hyperbaric oxygen therapy 56 may be effective treatments.” (Zhou, et al., 2023)
It looks like treatment is primarily immune suppression or TNF alpha inhibition (which any Nrf2 promoting foods do for us). (Mormile, et al., 2023). The vitamin K and “hyperbaric oxygen therapy 56 ” (Zhou, et al., 2023) sounds better to me - more oxygen to tissue in a state of hypoxia.
“The common rationale for using immunosuppressive therapies in patients affected by calcinosis cutis and autoimmune diseases is reducing the inflammatory component by inhibiting different molecular targets. However, the pathogenetic pathways leading to the development of calcinosis in patients with an underlying connective tissue disease remain largely unknown.” (Mormile, et al., 2023).
Prevention works best in the very early stages of a problem and the medical system doesn’t treat patients early - you get more the “Stop bothering me you hypochondriac, I am a busy important physician” response. The medical/insurance industry wait until the person is extremely bad and wait for those really bad lab tests before saying, too often, “We don’t know what causes this or how to help you, but here is some drugs for symptom management.”
I would have to reread my old posts on the topic that I wrote at the time, but it was enough clues to cause me to stop eating eggs, and then chicken, and then all meats, and a year later hemp kernels. *My archives are a record of my personal health journey and may also be a mental health example of hypergraphia at times or more disjointed thinking. Some I have edited but not many - it is my journey, my external memory and I simply share it in hope that it might help someone else too. *Continued after the next section on a different reply about fibromyalgia and exercise.
Pain hurts, health is better.
Remember that the medical industry may be what is standing in your way to figure out your body’s needs rather than being a safe and effective guide to follow.
Fibromyalgia and gentle flowing exercise.
Another Reply reminded me of the importance of gentle repetitive exercise for fibromyalgia or other mitochondrial dysfunction. Our mitochondria seem to need us to move regularly for them to keep functioning normally. If we are their functional host, we would be busy doing things, not sitting in a lump like a body ready to be decomposed.
Movement is life signaling to our energy producing mitochondria and the gentle Qi Gong and yoga style flowing exercises seem to be particularly effective at promoting the return of health. The Feldenkrais method is another one found to be helpful for people with chronic health issues. The Pete Egoscue method seems helpful to me too.
I have a mitochondria and movement series about this topic.
Mitochondria, movement, the cerebellum and dystonia. Dec 13, 2022, (Substack).
Mitochondria, bone cells, and movement.
FGF23 is promoted by exercise, promotes Nrf2, and enhances mitochondrial function. & Inversion boards are a fun way to exercise your abs. *Video of me. Dec. 17, 2022, (Substack).
Secondary Hyperparathyroidism, gene alleles, and low calcium. How is albumin involved? The medical industry doesn’t know.
But they do know that albumin levels are correlated to risk of the non-healing calciphylaxis, and excess phosphate increases the risk:
“Each increment in serum albumin by 0.1 g/dL was associated with an approximately 25% lower likelihood of developing calciphylaxis (OR = 0.76, 95% CI, 0.64 to 0.94). A 2.7-fold higher risk of developing calciphylaxis was observed with each increment in serum phosphate level by 1 mg/dL (OR = 2.73, 95% CI, 1.28 to 5.78).” (Mazhar, et al., 2001)
Gene differences are likely involved in my susceptibility to secondary hyperparathyroidism. Something I forgot in my self-quiz (last post) is calcium supplements. I do seem to need some, and on an ongoing basis, but I use 250 mg daily. One of the patients in the study below had been put on 1000 mg of calcium for five years prior to the severe calcinosis condition being diagnosed.
Dose makes the poison or the medicine.
Secondary hyperparathyroidism symptoms start to return anytime I miss my supplement routine too many days in a row. So, it does seem like a genetic “for-life” issue. Symptoms, when more severe, included feeling an internal pressure or jitteriness that gave me hard t control urges to ‘pop’ myself - to relieve the pressure maybe. At the time I also found a reference to patients with autism trying to gouge their eyes and calcium supplements helped them. Secondary hyperparathyroidism was not mentioned but the symptom of “wanting to gouge out my own eyes” was so unusual and such a horrible feeling to experience and have to control, that I included that in my clues towards my own better health journey.
The jitteriness was also in my thinking. ADHD makes me forget what we were talking about in the last sentence, the hyperparathyroidism made me even worse - what was the first half of the sentence that I just had said? My train of thought was derailed. Trying to cure yourself when you are not thinking normally just makes it that much more difficult. I am glad to have survived those bad years - ungouged. It probably helped me that even as a teen I had had some bad scary thoughts about ending my life impulsively and I always didn’t - thinking “it was just bad thoughts, don’t do that”.
Labeling a feeling can help you gain more control over it. I started calling the weird urges my ‘stabby’ mood and that helped a little to ignore it rather than get more anxious as to WHAT IS GOING ON? Before I learned of the secondary hyperparathyroidism (that was an endocrinologist finally checking it after several repetitions of “Your thyroid levels are normal now, so you must be fine, (just crazy).” *I was committed against my will sometime around this point for talking too fast and getting upset at the government too often for my spouse’s feeling of safety. The PTH test came after I was released for good behavior after TEN days in lock-up.
Good behavior for females in a psych ward is wearing makeup, a bra, and walking and talking slowly. So, I did that and accepted olanzapine (but declined something else I knew was bad). I later learned that I had been started on the highest typical dose of olanzapine and it ultimately made me much worse after withdrawal with akathisia/histamine excess suicidality, 1000 times worse and I am VERY GLAD to have survived that.
What the medical “evidence-based” averaging-of-patients strategy forgets, is that the individual patient really just wants to be able to grow skin well and not feel urges to poke holes in themselves with sharp objects. I don’t need proof that I developed autoimmune antibodies against albumin or that I have specific gene alleles that increase my risk for secondary hyperparathyroidism. I just need to fix the problem I mainly want to be able to grow skin and enjoy it. Knowing what caused the problem is key though.
Another additive problem would be the Retinoid Toxicity - it also causes you to not be able to grow skin as well and severely chapped lips are very common - but that would be the off-and-on eczema I had all my life. The non-healing wound like rash with elevated PTH and possibly autoimmune albumin attack was different than my long-term Retinoid Toxicity scaley eczema.
“To identify the underlying etiology of the different outcomes of the two patients, we performed whole-exome sequencing in both patients. The three variant genes in Case 1 were ATXN2L, POLR1B, and MMP19, which were different from the variants in Case 2, BMP4 and TXNDC2. Early development of vascular calcification is associated with overexpression of BMP4 in CKD [22]. Additionally, increased BMP4 in serum was strongly correlated with aortic calcium levels, suggesting that it could be used as a biomarker of calcification associated with CKD [23]. The present study raised an interesting question as to why Case 2 did not develop microvascular calcification before PTX. We hypothesize that the BMP4 mutant gene is repressed at high PTH levels. After PTX, the BMP4 mutant gene is activated, blocking the uptake of UTC and leading to excess calcium phosphate deposition in the vessel wall.” (Li, et al., 2023)
My gene differences don’t mention BMP4, but I have alleles for MMP genes.
MMP1–16071G/2G 1G2G
MMP2 Gly226GlyG>C GC
Matrix metallopeptidase enzymes help break down extracellular matrix debris - suggesting that I don’t clean up bad proteins as well and may have more risk of inflammatory buildup - fibrosis is a symptom of any type of inflammation that is getting more severe/chronic.
The present study raised an interesting question as to why Case 2 did not develop microvascular calcification before PTX. We hypothesize that the BMP4 mutant gene is repressed at high PTH levels. After PTX, the BMP4 mutant gene is activated, blocking the uptake of UTC and leading to excess calcium phosphate deposition in the vessel wall.” (Li, et al., 2023)
The last part of the quote doesn’t make a lot of sense to me. How do they know it is a mutant gene if is simply present in over-expressed amounts? (Li, et al., 2023) It might be a normal gene that retinoids are causing to be over-expressed.
Another trip to Bing to double check Li, et al’s hypothesis: search question: “Would elevated levels of parathyroid hormone suppress activated retinoic acid levels”
Answer - Jackpot! Not a yes though. It helps by adding other reasons hypercalcemia may occur in addition to excess calcium supplements, excess active vitamin D supplements or other inflammatory causes - vitamin A/retinoid toxicity also can cause hypercalcemia. And immobility - being bedbound or sitting too long at the computer is going to be a factor in excess calcium roaming the body, wreaking havoc if it is allowed by too little magnesium and cholesterol is likely protective rather than the cause of atherosclerosis.
“Vitamin A toxicity is often overlooked in the diagnostic evaluation of hypercalcemia, which itself is often detected incidentally during unrelated laboratory testing.1,2 The diagnostic evaluation of hypercalcemia starts with establishing the role of parathyroid hormone (PTH) in its pathogenesis. An elevated PTH level may indicate primary hyperparathyroidism, tertiary hyperparathyroidism, or familial hypocalciuric hypercalcemia. A low PTH should trigger an evaluation for hypercalcemia induced by PTH-related peptide (PTHrP).
»Vitamin A toxicity should be considered in the diagnostic workup along with malignancy, bone metastasis, vitamin D or calcium toxicity, increased 1,25-hydroxyvitamin D production (eg, from granulomatous disorders and lymphomas), hyperthyroidism, monoclonal gammopathy, and immobility.3” (Borgan, Khan, Makin, 2022)
We need to keep moving for better health. News to use!
That article is focused on retinoid toxicity due to supplements or medications. (Borgan, Khan, Makin, 2022) It does not include the theory of excess active retinoids being released from liver injury or virally induced liver gene changes causing ongoing overactivation from dietary carotenoids and vitamin A foods. It is a really good start though.
“Acute over-ingestion of vitamin A can affect multiple systems:
Neurologic—increased intracranial pressure, headaches, dizziness, vomiting, delirium, and confusion
Hepatobiliary—nausea, vomiting, and jaundice resulting from hepatitis progressing to cirrhosis
Musculoskeletal—periosteal bone resorption, osteopenia, elevated alkaline phosphatase, and hypercalcemia
Skin and mucous membranes—dry, fragile skin, brittle nails, loss of hair.10,27
In clinical practice, however, chronic over-ingestion of vitamin A is a much more likely cause of vitamin A toxicity.” (Borgan, Khan, Makin, 2022)
If the body is over-converting inactive forms of vitamin A and carotenoids into active forms with no brakes on, then any day following a large intake of A/carotenoids would be giving the body an acute dose of active retinoids - and if the person was eating vitamin A and/or carotenoid rich foods every day, then the acute overdose would be a chronic overdose too.
How much is too much? 1/4 of a peach, or 3 Peruvian ground cherries/Golden Berries and a large serving of broccoli. And even after that I bought a package of prewashed Spring Mix baby greens and had a couple bowls. The next morning, I had slight ‘everything hurts’ pain, not as bad as after the solanine rich Golden Berries though. I looked at the label and the greens closer - that mix had very little lettuce and a lot of spinach and kale and Swiss chard. I picked out the lettuce and will use the greens as salad or cooked greens for my mother who doesn’t seem to have the retinoid sensitivity that I do.
Not knowing what is hurting you, just allows the pain and chronic damage to continue - forever or until death, or until someone plays detective and figures out what the underlying problems are.
Goal - not having unhealthy skin, hair, or internal body parts. Good energy mood and thinking are a bonus!
Even a great paper can get things wrong too - “Consumption of plant-derived precursor vitamin A (carotenoids) is harmless*, [*false with alcoholism and if overactivation is occurring due to a gene change following an Epstein-Barr viral infection, and possibly after a SRS-CoV-2 infection] but excessive consumption of preformed vitamin A commonly found in OTC supplements and some animal products can have negative multisystem manifestations.” (Borgan, Khan, Makin, 2022)
The standard treatment for Retinoid Toxicity following retinoid medication is to discontinue the medication - and then we are told that it can take weeks or months for the excess to dissipate. “Treatment involves withdrawal of vitamin A sources and supportive care. Given the long half-life of retinol, normalization can take several months.” (Borgan, Khan, Makin, 2022) Maybe that does include counseling on limiting dietary sources in addition to supplements and medications.
Reducing the dietary intake of active forms of vitamin A would likely help normalize the symptoms faster. Increasing sun exposure also helps use up stored vitamin A. But, overall, I really wouldn’t think it would take months to clear active Retinoic Acid if the medication was stopped unless the body was also activating more retinol/inactive vitamin A. Active retinoids are generally broken down fairly quickly and the stored retinol is not causing the immune havoc and bone and other symptoms. Retinol sits in our retina waiting for bright light in dim settings (rhodopsin) and wouldn’t cause gene transcription unless it was activated to Retinoic acid or another active form in the liver and in some tissue types. Excess overactivation in ovarian cells may be a causal factor in PCOS.
Retinol vs retinal - a Bing vs Google search engine contest. Bing lost.
The answer to my wondering about dietary inactive forms of vitamin A adding to how long it seems to take patients to recover from retinoid medication induced toxicity in the preceding paragraph gets lost in the following search engine discussion. The answer seems to be that even the inactive forms can cause gene expression in some keratinocyte skin cells (Amann, et al., 2011) and likely in some other cell types or dysfunctional cell types as seen in some ovarian cells in PCOS. So, I was wrong, inactive dietary vitamin A can also cause gene expression and potentially symptomatic problems. It doesn’t have to be converted to the all-trans Retinoic Acid. But that also means I am likely correct to suggest anyone with Retinoid toxicity symptoms should also reduce vitamin A and carotenoid sources in their diet while the symptoms are continuing.
Bing’s answer cites product pitch pages.
Bing AI’s answer to ‘retinol vs retinal’: “Retinol and retinal are both forms of vitamin A that can be converted into retinoic acid, the active ingredient that benefits the skin123. Retinal is closer to retinoic acid than retinol, so it acts faster and more efficiently134. Retinal also has antibacterial properties that can help oily or blemish-prone skin4. Retinol is more common and less potent than retinal, which is harder to find in products5.” from (2) “In the body, retinol is converted into retinaldehyde, aka retinal, that is further converted to retinoic acid. Retinal is the natural precursor of retinoic acid so it is the closest thing to a prescription strength retinoid.” (naturium)
from (3) - factually may be harming people as Retinoid Toxicity causes dryness, irritation progressing to skin rash and poor skin growth: ““Both retinol and retinal can cause skin dryness and irritation. It is a matter of getting used to the product and introducing it into your skin regime gradually over time,” explains consultant dermatologist Dr Alia Ahmed. “If skin is prone to being dry or irritated easily, it makes sense to use a less potent retinoid to start with.”” (myimperfectlife)
Bing gets a failing grade from me here - all five references are company blogs trying to sell cosmetic products. I gave Bing another chance with “retinol vs retinal PubMed” and got four citations about retinoids in cosmetics and two product review articles “Top five products”. Aside/ I use Google generally for research as Bing seems overly focused on selling me products with its search results. I got lucky with my other three questions to Bing. Probably the more specific questions helps to refine results.
Google provided a helpful link and only one sponsored product link.
Google provided some of the skin/cosmetic research and one ‘Sponsored’ product result but included several more general articles about retinoid metabolism or retinal disease also for ‘retinol vs retinal PubMed’.
One of those links helped - there are all-trans forms of retinol and retinal that can cause gene expression in skin keratinocytes “keratinocyte cell line HaCaT” (Amann, et al., 2011) - not just all-trans Retinoic Acid.
“We have shown that all-trans retinol (ATRol) and all-trans retinal (ATRal) are capable of modulating gene expression in keratinocytes, which is not because of vitamin A metabolism in the cells, and retinol and retinal modulate gene expression through nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs).” (Amann, et al., 2011)
Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health guidance.
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so Jennifer this looks like an interesting story - but I took a break from reading it to ask about Boron, because I read that Boron is to the parathyroid as iodine is to the thyroid. I got interested in using it with the horse for hoof health - Hair Skin and Nails right? then I found out that you can't grow Alfalfa without adding Boron to the soil, and wondered if that's why some horses do well with alfalfa. I'm a big trace mineral fan! I first found out some applied stuff about iodine from the horses as well. but my first interest in trace minerals was at Penn State when I was trying to study nutrition; micronutrients in the animal Nutrition department might have been my favorite class of all time.