**Draft WIP / Work in progress Part 2 of 4**
Following from part 1, the discussion continues in two sections – general overview of Vitamin D metabolism followed by insights from opposition to Vitamin D supplementation.
What is Vitamin D? Overview & Metabolism.
(Condensed) Metabolism pathway.
- Sunlight. UV light absorbs through the skin, where the initial form 7-dehydrocholesterol is formed then transforms to the following metabolites in their respective order ~
- 7-dehydrochoelsterol (skin) then;
- 25 OHD / Calcifediol (found in blood tests) then;
- 1,25 OHD / Calcitriol (the end / active form).
- Exogenous – diet and supplemental. Both the kidney and liver converts the inactive to the active forms through the following order:
- Cholecalciferol (found readily in supplemental form, dry powdered version, in oil delivery vehicle eg. EVOO or sunflower oil, etc)
- Calcifediol (the abundant plasma version)
- Calcitriol. (the end / active form).
- Before then the complex series of calcium, phosphorus, and bone absorption /resorptions (Osteoblasts vs Osteoclast) activities becomes enabled.
(Elaborate) Metabolism pathway.
In a more elaborate overview, referring to (Arnson Y et al 2007) :
- The very first / initial exogenous precursor – 7-dehydrocholesterol forms within the skin upon exposure to the UVB Sunlight radiation.
- Conversion (initial). Then Cholecalciferol, the initial form of Vitamin D; is formed as commonly found in supplemental form ~ dry, water soluble, or with fat as delivery vehicles (EVOO, PUFAs, etc).
- Conversion (intermediary). The inactive to active form manifestation begins. Starting with:
- “25 OHD” ~ the Calcidiol ~ the “inactive” form. This will not be active until the enzyme 25(OH)D3‐1‐α‐hydroxylase takes place in the kidneys.
- “1,25(OHD)” ~ the Calcitriol ~ is then formed by the above enzyme.
- Mobilisation, storage then reception. The active Calcitriol then circulates and binds via Vitamin D Binding Protein (or VDP for short) towards all Vitamin D reception / docking sites throughout all tissues; enabling all mediation of calcium, phosphorus and thereby~ bone remodelling.
What / which genes / enzymes are responsible throughout Vitamin D metabolism?
A number of key genes thought responsible throughout Vitamin D metabolism are shared below. Be aware these are for preliminary reading only and remain subjected to further scrutiny as new information, understanding and/or research proceeds.
- Early stage (Sunlight to Skin or food source to Liver) = 7-DHCR / 7-dehydrochoelsterol
- Conversion (initial) = CYP2R1 / 25-hyrozxylase.
- Conversion (intermediary – conversion of 25OHD calcidiol into calcitriol in the kidneys, primarily) = CYP27B1 /1 alpha hydroxylase
- Catabolism stage (inactivation and excretion of 25OHD to urine; from the kidneys) = CYP24A1 / 24-hyroxylase
- Storage / reception / mobilisation = Vitamin D binding protein and the Vitamin D receptor.
Vitamin D & Immune Health
Given our state of the COVID19 pandemic, at least one definitive randomised trial strongly suggests Calcifediol (the main metabolite, not the precursor of Vitamin D) at eliminating all ICU / intensive care hospitalisation (Castillo ME et al. 2020). Other supporting evidences in favour of Vitamin D can be found for further readings at Vitamin D Wiki (vitamindwiki.com/calcidiol).
Glycation End Products
In addition, Vitamin D’s other supporting roles outside of immunology ~ namely dietary glycation end products protectant (Owusu J et al. 2020), psychology (Gracious BL et al 2012), muscle and bone health (Tanner BS & Harwell SA 2015) ~ all nevertheless suggest pragmatic maintenance dosages. Interestingly, Owusu J et al. 2020 concluded that supplementing 4kIU Daily is less effective at mediating plasma AGEs within first three months of the study, but not until six months of supplementation is reached. Hence this implies there may yet be some sort of acclimatising period and/or dosing consistency required to achieve said protection.
Mineral absorption competitions.
It is unknown at this stage, or at least difficult to ascertain if there are mineral-to-fat soluble interactions which may prove detrimental. Of particular mention is that of potassium and copper depletion as briefly speculated in a recent lengthy debate (Deering K et al 2021).
The above concludes the interim Self-Meta of This Author (AW) pragmatic course of action. Despite all convictions, all of this certainly warrants for more re-examining, exploration and adjustments as future confounders unfolds.
Vitamin D “resistance” & Coimbra Protocol
There is a noteworthy discussion suggesting that under some genetic polymorphisms ~ “acquired” resistances to Vitamin D metabolism can occur amidst context of autoimmunity disease treatment. One study (Lemke D et al. 2021) successfully presents this hypothesis and alongside evidence(s) of successful records at treating Multiple Sclerosis patients in Brazil and Germany; by way of supra-physiological Vitamin D dosages (Coimbra protocol) alongside a calcium restricted diet. The amount given was up to 1000IU per kilogram of body weight supplementation which equates to 68,000-70,000 IU per day for a 68kg male.
“Resistance” as according to the cited research above refers to a disturbed feedback system between PTH / parathyroid hormone and the 25OHD. This was first proposed in 1937 by researchers Albright, Butler and Bloomberg when treating rickets by way of very high Vitamin D dosages. Generally speaking, when 25OHD are high, PTH levels should ideally be low. PTH is primarily responsible for maintaining plasma calcium. PTH is raised when plasma calcium is low and consequently ~ a leaching of calcium from the bones are inevitably needed to maintain the plasma calcium. In individuals with auto immune diseases however, it is the paradoxical feedback disturbance between the PTH and the 25OHD ~ in that PTH levels remain high despite Vitamin D supplementation. High PTH is believed to be associated with higher risk of death.
Factors that contribute to the resistance include but are not entirely restricted to ~ genetic polymorphism, environmental, ageing & seasonal factors. Genetic polymorphism suspects include CYP2R1, CYP231, CYP27A1, CYP27B1, CYP24A1 and the VDR receptors all appear to be prime suspects; according to the above cited research ~ the VDR is thought to be the most sensitive and “vulnerable” to manifest such a resistance. Environmental factors include toxicity coming from pathogens, and glucocorticoids. Lastly, ageing & seasonal factors refer to general inactivity, sedentary lifestyles and a lack of sun exposure.
Due to the limited capacity of this Self-Meta, readers are encouraged to read in further detail at their own end ~ at the above cited published research (Lemke D et al. 2021).
This mini section is reserved for enlightening those especially surrounding absorption, synergy with other nutrients and/or other nuanced enquiring that remains largely unaddressed. Be aware however these are not in anyway defenitive but only at best for (preliminary) convenience insights. All discerning readers must exercise further research collating at their own end.
What other minerals or synergist factors are there to Vitamin D utilisation and/or absorption?
So far, a comprehensive research review on micronutrient interactions (Watts, D. 1990) reports that:
- Vitamin B12
- Vitamin E
All appears to be synergistic. However bear in mind that this agonist / antagonism remains highly subject to interpretation nuances.
As far as toxicity management ~ Magnesium appears essential as it appears to help prevent hyperphosphatemia events (a marker of hypercalcemia) in the context of preventing CVD / cardiovascular events (Sakaguchi Y. et al 2017).
Other minerals and/or micronutrients (WIP). Perhaps a rarely discussed trace mineral worth mentioning is Boron (Pizzorno, L. 2015) & (Dessordi R & Navarro MA 2017). Found only amidst select foods particularly raisins, pitted dates, almonds and select nuts ~ Boron appears to inhibit the 24-hyroxylase enzyme; which is thought reponsible for the catabolic (note: catabolism – inferring to excretion as indicated) reactions on the plasma 25OHD.
What minerals that are anta-gonistic or those that conflicts with Vitamin D?
Once again referring to the micronutrient interactions research (Watts, D. 1990). Chromium, and Vitamin A appears to be antagonistic. Further research appears unfortunately rare and few. At the very least, only drugs – particularly pharmacological ones are ~ able at inhibiting select genes and/or enzymes responsible for the utilisation and conversions. These granular topics are beyond the scope of this Self-Meta.
What delivery vehicle factors does Vitamin D require for maximal their GIT (gut) absorption?
Vitamin D has been widely delivered in three common delivery methods as dry (powdered using gluten or cellulose), lipid in various triglyceride formats (PUFA, MUFA and SFA) and ethanol (Grossman, R & Tangpricha V 2010). According to conventions, Vitamin D relies on lipophilic (meaning soluble in lipids) thought needed for its best activation (Maurya KV & Aggarwal M 2017) . Interestingly, the study shared a hypothesis that acidic pH, alongside enzymatic release usually associated with protein digestion ~ especially trypsin, Pepsin both appears to support Vitamin D absorption in the GIT.
The type of fats also appears an important confounding factor; although recent studies proclaim mixed conclusions. One trial amongst senior subjects (Sathit Niramitmahapanya S et al 2011) finds that MUFA, compared to PUFA and SFA appears to improve the most in terms of Vitamin D absorption. However another found no appreciable difference in 25(OHD) status inbetween PUFA and MUFA dominant meal intakes during Vitamin D supplementation (Dawson, H 2014 et al).
Does Vitamin D affect sleep? Does timing of intake affect sleep quality?
Sleep issues / insomnia as possible side effects has been a much under discussed topic to Vitamin D supplementation during nighttime intakes. Unfortunately literatures on these so far appears to be far and few at discerning whether Vitamin D, especially on high dosages to show such correlation. At the very least we have a number of strongly reported anecdotes (1,2) proclaiming that Vitamin D do interfere with melatonin production; effectively meaning that it may affect certain individuals response to sleep quality especially when taken at night.
This remains WIP work in progress. To be continued on Part 3 we will proceed into the “Discussion” and Conclusion chapters of this Self-Meta.
The negative correlation between Calcium intake and 25OHD status : an unresolved paradox.
(WIP began 25th September)
Of the more perplexing nuances here in this Self-Meta deservedly belong to several key observational findings (Jorde R & Grimnes G 2020) that dietary calcium intake appears to impose negative association to plasma (25-OHD) Vitamin D status. Meaning ~ that as dietary calcium increases, the 25OHD status decreases. The main calcium source the study examined are dairy products.
Upon examination, it appears that whilst the author’s conclusion for providing mechanism rationale as difficult ~ there are nonetheless key findings for readers to take away from this paradox. Firstly, in that the study appears to find that females are less affected by this paradox. And that
This Author’s (AW) own very first nutrigenomics report suggests that his existing CYP27B1 (the activation from 25OHD >1,25D pathway) status appears compromised at “50%” and thus suggested that further Calcium intake may be detrimental because of its inhibitory effect on the enzyme. Unfortunately, there has been no research citations provided, at the time of consultation ~ at proclaiming this negative assocation between calcium intake and 25 (OHD) status.
To add complexity ~ not all literatures share the same findings. A study examining Vitamin D enriched Gouda Cheese intakes on postmenopausal female subjects (Moschonis, G et al. 2021) suggests a positive correlation with 25OHD with the dietary intake, alongside beneficial reduction in PTH marker. And there are several internal references that the authors of our first cited research (Jorde R & Grimnes G 2020.) have collated for convenient surface / bird’s-eye awareness on this subject.
Irrespective, in light of the above equivocal findings ~ it is perhaps safer for us to pragmatically suggest there may yet be other far more nuanced mechanism and/or confounding metabolism to Vitamin D interplaying with Calcium ~ that we are yet to sufficiently understand. As the authors conclude from the first citation (Jorde R & Grimnes G. 2020):
“It is difficult to find a plausible explanation for the mainly negative association between calcium intake and serum 25(OH)D. One could hypothesize that in a situation with a low calcium intake it would be important for the body to conserve its 25(OH)D stores and therefore reduce the 24-hydroxylation of 25(OH)D to the inactive 24,25(OH)2D form. However, low calcium intake and thereby low serum calcium levels stimulate the PTH secretion which increases the renal 1-hydroxylation of 25(OH)D to the active form 1,25(OH)2D which in turn increases the intestinal calcium absorption. This process cause removal of 25(OH)D from the circulation.” ~ (Jorde R & Grimnes G. 2020)
One way we can extrapolate however, as both peace of mind and assurance for general view of nutritional science ~ is that strictly dietary, more so than supplemenetal form of calcium as accordingly to rigorous bird’s eye view / systemic meta-analysis ~ has been favourably associated as protective against various mortality markers not necessarily confined to bone related metabolism; but far and reaching to that including Diabetes / insulin resistance (Hajhasphemy Z et al. 2022) and especially synergistic also with Potassium for specifically addressing diabetic retinopathy (Chen YY & Chen JY 2022). However the mechanistic explanations so far at enlightening the how or why ~ behind the above seemingly unresolved paradox of calcium intake’s negative correlation to 25(OHD) status remains unfortunately confusing and not always accessible for the lay yet enthusiast nutritional science audience.