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"Vitamin D" - Marshall Protocol perspective
Interesting correlations between A and D VS the levels of pro infl. cytokines:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074219/
Circulating concentrations of 25(OH)D3 and 1,25(OH)2D3 were higher during summer (P < 0·05) and a down-regulation of TLR-4-mediated IL-1β, IL-6, TNF-α, interferon (IFN)-γ and IL-10 production in summer was observed compared to winter (P < 0·05).
The repressed cytokine production during the summer months could be explained partly by the reduced cell-membrane expression of TLRs.
Physiological variation in vitamin D3 status through the four seasons of the year can lead to alteration in the innate immune responses. Elevated vitamin D3 level in vivo is associated with down-regulation of cytokine response through diminished surface expression of pattern recognition receptors.
Variation in cytokine responses to lipopolysaccharide (LPS) stimulation during the four seasons of the year. Peripheral blood mononuclear cells (PBMC) were isolated from 15 healthy volunteers during each of the four seasons and stimulated with 10 ng/ml LPS. (a) Interleukin (IL)-1β, (b) IL-6, (c) tumour necrosis factor (TNF)-α, (d) interferon (IFN)-γ and (e) IL-10 were measured. Data show results from 15 healthy donors. *P < 0·05 compared among the respective seasons.
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Inflammation and Vitamin A
https://journals.sagepub.com/doi/10.1177/0379572115597514
We observed that elevated acute-phase protein (APP[*]) concentrations often accompanied low retinol concentrations, and we developed a model of the inflammatory response to categorize 4 groups of participants termed reference (no raised APP), incubation (raised acute APP only), early convalescence (both acute and chronic APP raised), and late convalescence (raised chronic APP only). We identified 7 studies with participants who could be allocated to the 4 groups, and using meta-analysis methods we calculated correction (ie, multiplication) factors 1.13, 1.24, and 1.11 to remove the influence of inflammation from the incubation, early, and late convalescent groups, respectively.
[..]
The APPs(acute-phase proteins) are biomarkers of disease and mostly increase following infection and trauma. The first APP we looked at in relation to vitamin A was α1-antichymotrypsin (ACT). Workers examining the merits of 5 different APPs in the recognition of inflammatory conditions reported that while all had similar specificities, ACT was more sensitive than the others, including C-reactive protein (CRP), as ACT had a longer half-life. Both CRP and ACT responded rapidly to infection (within 6 hours).
[..]
In sick patients, it is widely accepted that metabolism is disturbed and that inflammation will interfere with measurements of nutritional status. However, inflammation may also be present in apparently healthy people and depress serum retinol concentrations; therefore, it is very important that workers in national surveys should measure one or more APP to ensure that the true level of deficiency can be established in a community. Incorrect data on vitamin A status can only lead to false assumptions on status which might divert attention from the true cause of low retinol concentrations and promote the unnecessary use of supplements where none may be needed.
Removing the effects of inflammation from serum retinol concentrations is also necessary in vitamin A intervention studies. First, it is useful to confirm the presence of VAD by prior correction of serum retinol concentrations to remove the influence of inflammation, which may show the intervention to be unnecessary. Second, as low retinol concentrations will be influenced by the prevalence of inflammation and infection in a community, seasonal variations will potentially have more influence on the study outcome than the intervention. Even if a follow-up assessment is planned at the same time of year as the baseline study, the prevalence of inflammation may not be consistent year to year, resulting in variation in the apparent prevalence of low serum retinol concentrations.
[..]
We began by trying to understand why serum retinol concentrations in some developing countries were lower than those in developed countries when there is no evidence of VAD in the community. We observed that serum biomarkers of inflammation were lower at those times of the year when there was a rich dietary source of vitamin A available and that serum retinol concentrations were transiently lower following surgery. Using CRP and AGP, we developed a model of an inflammatory response to categorize the serum retinol concentrations by inflammatory status into 4 groups. The 4 groups comprised a reference group where there was no inflammation and 3 groups where inflammation was detected. Using meta-analysis techniques, we compared serum retinol concentrations between the 4 groups in 7 studies, where retinol and an acute and chronic APP had been measured. The comparisons enabled us to calculate multiplication factors to remove the influence of inflammation from serum retinol concentrations in the 3 groups where raised APPs were detected.
Changes in serum retinol and C-reactive protein (CRP) concentrations following uncomplicated orthopedic surgery.19 This figure shows fall in plasma retinol concentrations accompanied by a rise in plasma CRP concentrations following surgery in previously healthy and well-fed people. After 48 hours, retinol returns to normal as CRP concentrations fall.
[*]: https://en.wikipedia.org/wiki/Acute-phase_protein
Acute-phase proteins (APPs) are a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the acute-phase reaction (also called acute-phase response). The acute-phase reaction characteristically involves fever, acceleration of peripheral leukocytes, circulating neutrophils and their precursors.[1] The terms acute-phase protein and acute-phase reactant (APR) are often used synonymously, although some APRs are (strictly speaking) polypeptides rather than proteins.
In response to injury, local inflammatory cells (neutrophil granulocytes and macrophages) secrete a number of cytokines into the bloodstream, most notable of which are the interleukins IL1, and IL6, and TNFα. The liver responds by producing many acute-phase reactants. At the same time, the production of a number of other proteins is reduced; these proteins are, therefore, referred to as "negative" acute-phase reactants. Increased acute-phase proteins from the liver may also contribute to the promotion of sepsis.[2]
Interesting. Fits with my understanding that low serum retinol can be a sign of good health (Grant) or a sign of really bad health, with vA stuck in storage. It’s a useful test only with proper interpretation. Sadly it’s often used to suggest supplementation which is the very last thing a vA toxic person needs.
I've communicated with someone really knowledgeable about the statistics of the protocol and for CFS based on the meta data they have the progress is like 10..15% of health recovered per year, at the best case scenario.
Fits with my understanding that low serum retinol can be a sign of good health (Grant) or a sign of really bad health, with vA stuck in storage.
Yes, exactly, there is an association between low serum retinol and various markers like CRP, and some chronic diseases:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566922/
Result of uncontrolled D25-> D1.25 conversion(via VDR):
Severe Hypercalcemia Following Vitamin D Supplementation in a Patient With Multiple Sclerosis
A Note of Caution:
https://jamanetwork.com/journals/jamaneurology/fullarticle/1107961
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Association of Vitamin D Deficiency and Mood Disorders: A Systematic Review
The cells of our body comprise calcitriol (1,25(OH) vitamin D2), the active form of vitamin D, an integral biological substance that has an impact on a large number of biological processes. While high prevalence of vitamin D deficiency is detected in population worldwide, the reports from sun-soaked countries like India are also alarming to note that the deficiency of vitamin D as high as 70 to 90% is observed leading to several chronic diseases in the majority of people. Deficiency of vitamin D is observed not only because of low levels of vitamin D in the diet, less exposure to sunlight, reduced cutaneous vitamin D synthesis, but also due to consumption of particular medicines, undue alcohol intake, and tobacco smoking. Vitamin D is known to affect estradiol, dopamine, and pro-inflammatory cytokine levels, besides being involved in the regulation of mechanisms pertaining to hormones like glucocorticoids. When vitamin D binds to vitamin D receptors (VDR) present in the central nervous system, it is noted to be responsible for the regulation of brain neuronal functions. Low 25-hydroxy vitamin D levels are found to have a higher incidence of various mood disorders. This review focusses on vitamin D receptors, VDR gene mutations, and pathophysiology causing vitamin D deficiency disorders.
Vitamin D deficiency and fatigue: an unusual presentation
https://pubmed.ncbi.nlm.nih.gov/26543719/
Fatigue is a vague but common complaint that is poorly characterized by physicians as well as patients. While fatigue may result from a number of different etiologies, at the present time, a comprehensive approach to each patient with fatigue does not include routine measurement of serum vitamin D levels. A 61-year-old man was evaluated for excessive daytime fatigue. No features characteristic for depression, sleep apnea, or narcolepsy were present. A comprehensive work-up, including thyroid function tests and testosterone levels, did not reveal any abnormalities. However, serum 25-hydroxyvitamin D level was low, at 18.4 ng/mL. Vitamin D supplementation was initiated. At follow-up in 3 and 12 months, the patient reported complete resolution of daytime fatigue, corresponding to an increase in his vitamin D levels. Possible mechanisms for clinical improvement include effects of vitamin D on components of inflammatory cascades, including tumor necrosis factor-alpha and prostaglandin D2, which result in decrease in central nervous system homeostatic sleep pressure. While more research is needed to determine if patients presenting with fatigue should be routinely screened for vitamin D deficiency, clinicians should consider obtaining vitamin D levels in patients with unexplained fatigue, nonspecific musculoskeletal pain, and risk factors for vitamin D deficiency.
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Vitamin D also has immunomodulatory activities (Holick 2007). Deficiency of vitamin D might be associated with diseases of immune dysregulation, one manifestation of which could be excessive daytime sleepiness (Zitterman and Gummert 2010; Hoeck and Pall 2011). We present a case of daytime fatigue in an otherwise healthy male who was found to be vitamin D deficient.
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A 61-year-old Caucasian man presented to primary care office with complaint of fatigue and daytime sleepiness, especially in the afternoons. His symptoms began gradually 2–3 months prior to presentation, insidiously worsening to the point that he began having functional difficulties with his normal tasks at work in the afternoons. He reported napping almost daily after work and even skipping some of his regular exercise sessions due to fatigue. He denied changes in his weight, new familial or occupational stressors, difficulty falling asleep, snoring, apnea, sleep disruptions, nocturnal awakenings, depression, or anxiety. In fact, his review of symptoms was only positive for chest pain that was worse in the afternoon when he felt tired. He reported good sleep hygiene and was able to get his customary 7–8 h of sleep each night. Before the onset of his symptoms, he had worked fulltime and exercised on an almost daily basis, without experiencing any difficulties. His past medical history was only significant for colon cancer, in remission since surgical resection and completion of systemic adjuvant chemotherapy in 2005 (7 years prior to presentation). He did not take any prescription medications and denied use of tobacco products, alcohol, or recreational drugs
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Our case lends support to the one presented by McCarty that vitamin D deficiency might be an unrecognized and easily reversible etiology of fatigue. Although a causal relationship cannot be confirmed by this case alone, the temporal relationship as well as biological plausibility makes this a possibility. While further study is needed to elucidate the possible mechanism for this association, and whether widespread screening for vitamin D deficiency among patients complaining of daytime sleepiness/fatigue is warranted, clinicians should consider obtaining serum vitamin D levels in patients who present with daytime sleepiness/fatigue, nonspecific musculoskeletal pain, and risk factors for vitamin D deficiency
Chronic fatigue syndrome 'could be triggered by overactive immune system'
https://www.theguardian.com/society/2018/dec/17/chronic-fatigue-syndrome-could-be-triggered-by-overactive-immune-system
Writing in the journal Psychoneuroendocrinology, Russell and colleagues describe how they recruited 55 patients with a chronic hepatitis C infection. To treat the condition, all were given a six- to 12-month course of injections of interferon alpha, a protein that is produced naturally by the body and stimulates the white blood cells to provoke an immune response. The treatment has previously been linked to a side effect of ongoing fatigue in some patients.
While most patients recovered from hepatitis C, there was also an increase in fatigue during treatment, which reduced when the injections ended.
However, six months after treatment finished, 18 participants remained more fatigued than before treatment began. These patients had slightly higher levels of a protein linked to inflammation, called IL10, in their blood before treatment began, but, after four weeks of treatment, their levels of IL10 and another inflammatory protein called IL6 were twice as high as for those who recovered without persistent fatigue.
D25 seems to activate VDR too:
https://www.researchgate.net/publication/40037900_25-Hydroxyvitamin_D3_is_an_agonistic_vitamin_D_receptor_ligand
Also:
https://www.sciencedirect.com/science/article/abs/pii/S0960076009002829
Molecular dynamics simulations show the identical binding mode for both 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 with the larger volume of the ligand-binding pocket for 25-hydroxyvitamin D3.
So for those who can not tolerate D3/sun this could be a reason why.
Whenever I hear the words "overactive immune system" now I substitute "high VA" 🙂
BTW, it makes no logical sense for the immune system to treat D25 as VDR antagonist as prof Marshall claims - the body can't be an enemy to itself.
When we are terribly sick i.e. have no energy to move we are generally lying in sunless environment(home or cage), but when we have at least some energy we are moving out to get extra immune stimulation effect out of the Sun, not to have our immunity be suppressed and thus slow killed by it.
@rockarolla I don't think vit D is the main reason why we don't lay under the sun 24/7 hehe... It's mostly overheating(dehydration) for animals with coat and for people with exposed skin it's also damage to the skin.. UVB/UVA is source of oxidative stress and sick people can't tolerate much of it. I think how much sunlight you can tolerate and how much feels good to you is great indicator of antioxidant status and overall health.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279842/
Epidemiological studies have linked vitamin D deficiency to increased rates of cancer, as well as autoimmune and infectious diseases (29).
Insufficient vitamin D is related to some infectious disease such as tuberculosis. Associations between vitamin D deficiency and TB susceptibility were described over 20 years ago (30,31).
The activated form of vitamin D on calcium and bone metabolism has been described. In vitro, but also in vivo, 1,25(OH)2D3 has potent effects on cell proliferation and cell differentiation in normal cell types as well as in malignant cell types. Receptors for 1,25(OH)2D3 have been found in different immune cells such as the cells of the monocyte to macrophage lineage, (32) activated T and B lymphocytes. In vitro, clear effects can be seen, including the induction of monocyte differentiation and the inhibition of antigen presentation by antigen-presenting cells, inhibition of T-cell proliferation and cytokine production, and inhibition of secretion of antibodies by B-cells. These in vitro effects are reflected in vivo by a potential to prevent autoimmune diseases in different experimental models, and to prolong graft survival (33–34).
A major problem with the in vivo use of 1,25(OH)2D3 is the fact that the doses needed to see non-classical effect such as the immune effects are high, resulting in severe hypercalcaemia and accelerated bone remodeling. Due to the flexible structure of 1,25(OH)2D3, however, chemists have succeeded in synthesising analogues of the molecule, some of which share the mother molecules’ effects on the immune system, but not its effects on calcium or bone metabolism (35–36).
In the previous study we were found that in the wells treated with IFN-γ, replication rates of T. gondii were decreased significantly 72h post inoculation in comparison with control group (P<0.05). There was no significant difference among different groups in NO production (37).
In this study, the results in the first experiment showed that vitamin D3 had strong effect on the inhibition of tachyzoites proliferation and on the increase of NO production, and that the effect of this vitamin was more than IFN- γ. When IFN- γ was added to this vitamin, it showed potent effects on the inhibition of tachyzoites proliferation and on the increase of NO production. The results also showed that the use of IFN- γ and vitamin D3 can reinforcement each other.