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**Draft WIP / Work in progress Part 1 of 4**
**Undergoing writing & readibility amends December 2023**

I hereby present a writeup series "Self-Meta" ~ a self-research initiative on differing sides, opinions and/or sentiments. It is not intended to bypass further reading, nor act as academic substitute over any existing established literatures. For those who are new to this initiative, please consider reading the limited-indemnity disclosures and a brief disclaimer below. Live-it-forward, AW

DISCLAIMER
- "Self-Meta" is highly individual, and never suggest anything as concretely "final" of an "opinion" be it however fixated or disclosed by one (N=1) subject, or data.
- (Disclaimer continued) This self meta does not imply nor suggest its readers to adopt an exact replica of its pragmatic course of actions; as it is entirely and unfortunately ~ remaining strictly subject to individual nuances and that thereby no individual may react in manners that is guaranteed to repeat.
- Subject to periodical revisions for readability, this is an initiative entirely made from one (1) individual. This is NOT an official "research review", or peer-reviewed by third party affiliation.

(Self-Meta) Vitamin D ~ the case for and against supplementation ~ Introduction

For many years Vitamin D, both supplemental and/or natural by sunlight have been thoroughly praised as essential to human health. However, concerns of toxicity and the paradoxical immune and metabolic syndrome response/s to supplementation (Marshall, T. 2018), remains undiscussed amidst mainstream medium.

In response to the above climate, I (This Author / AW / nutritional-humility.me) demonstrate, out of personal initiative to conduct self-review on concerns of Vitamin D toxicity, and reserve a separate discussion on whether auto-immunity condition (in particular, Ankylosing Spondylitis) warrants this supplementation. In addition, general overview of Vitamin D metabolism, and any other discussions relative to the above theme and train of thoughts are provided.

Althought this Self Meta never proclaims as prescription(s) in place over readers own subjectivities, a distinction of this Self-Meta is that it proposes an anecdote course of action, that is solely based on the context of This Author (AW)'s own and only his own health encumbrance, namely:

• Autoimmunity ~ specifically Ankylosing Spondylitis defined as a genetic HLA-B27 protein carrier; consequenting intermittent "flare/s" (idiopathic inflammation episodes) on lower lumbar spines.

This Self-Meta is "WIP", or work in progress; subject for amends to maintain readability. Throughout this feature write up ~ a separate header temporarily labeled as either "WIP" or "draft began <date>" will be made prominent as pledge for transparency, and obligation for This Author (AW) to fullfil to suffice completion; although only strictly under This Author's own (AW) limited time and discretion amidst non-disclosure obligations (as well as ongiong significant rebranding of Nutritional-Humility™). I hereby look forward for any correspondence and feedbacks should my endeavours relates to all scientific interests.

Sincerely,
AW.
nutritional-humility.me

References cited within this Self-Meta:

As this Self-Meta curates the following featured references and citations throughout this multi-part writeup.

• Deering K, Roddy K, Dinkov G & Blackburn M (2021) ~ The Great Vitamin D Debate
• Holick MF (2015)  "Vitamin D Is Not as Toxic as Was Once Thought: A Historical and an Up-to-Date Perspective.
• Scottmann Pharmaceuticals (2010) "Full interview with Dr. Holick on Vitamin D"
• Marshall, T (2018) ~ "Vitamin D ~ Why does it "work" so well?"
• Masterjohn C. (2014) "Resolving the Vitamin D  Paradox"
• Marcinowska-Suchowierska E, et al. (2018) ~ " Vitamin D Toxicity - clinical perspective"
• Razzaque MS (2018) "Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D?"
• Vitamin D Wiki (Vitamindwiki.com)

Cliff notes and highlights thus far (WIP)

• Vitamin D is widely recognised as a steroid hormone, classified as either inactive, stored or "active" forms (Deering K et al 2021). However besides from conventionally known forms (D2 as plant based, D3 as animal based source) ~ there appears up to seven (7) Vitamin D# variants that have been identified  (Nara EK et al. 2021). However it remains difficult to gain general information on the lesser known variants, particularly D1, D4 to D7.
• Therapeutic interventions exist from both opposing spectrums. It is interesting to note that both, we shall repeat "BOTH" stances Pro and Against ~ share the same overarching concern at treating Autoimmune Diseases.
  • The "Pro" Proponent ~
    Those advocating supra physiological dosages most well known being the Coimbra Protocol. At least 40,000 to hundreds of thousands of IU supplementations.
  • The "Against" Proponent ~
    Those advocating complete abstinence, including sunlight exposure (Marshall Protocol).
• The main argument from those in opposition or "Against" Vitamin D supplementation is :
  • that of supplementation's U-shaped auto-immune severity response. In short term, Vitamin D ingestion appears to suppress the innate immune system (Marshall, T. 2018) (16:00 onwards). However in long term may, counter to predominant belief ~ raise autoimmunity responses to the point of harm (Marshall, T. 2018).
  • The allegedly adverse counter-interactions of other mineral absorption; specifically as mentioned in a podcast (Deering K et al 2020) ~ potassium, and copper have been raised. But literatures on these appear to be somewhat scarce. At the very least ~  a review paper countering this view (Schwalfenberg GK & Genuis SJ 2015) maintains current consensus that Vitamin D nonetheless supports Calcium, Magnesium, Copper, Zinc, Iron and Selenium uptake. But on the downside also claimed that Vitamin D raise the uptake of toxic industrial metals ~ notably Lead, Arsenic, Aluminium Cobalt and Strontium.

• Currently, Hypervitaminosis D is clinically defined as the 25-OHD "Calcidiol"  (a step before the active version ~ Calcitriol)  plasma readings higher than 150 ng/ml (375 nmol/l).
• Trials involving 50,000 to as high as 100,000 IU supplementation ~ Per Day ~  resulted in very few / less than 5% of all subjects reporting clinical calcium toxicity (hypercalcemia) (Holick MF 2015).
• There are few specific genetic or congenital conditions that may warrant individual variance to Vitamin D sensitivities.
  • "Williams-Beuren syndrome" ~ rare genetic disorder involving calcium metabolism during infancy. One case study appears to suggest reducing Vitamin D and calcium intake to "bare minimum" (Lameris LLA et al 2014).
  • Mutations of the CYPA31 gene ~ affecting Vitamin D's fate in its metabolism.
• Common signs of Hypervitaminosis D include
  • hypercalcemia, hypercalciuria, hyperphosphatemia;
  • osteoporosis, diarrhea, vomiting, lack of appetite, mental confusion, polydipsia, and/or unexplained weight loss;
  • Less commonly reported ~ gastrointestinal bleeding (Holick MF 2015).
• Vitamins A, K2 and particularly a mineral in its close interactivity to Vitamin D ~ Magnesium (Sakaguchi Y et al. 2017) ~ seemingly remain as mediators against the above toxicity symptoms.

<WIP or work in progress.>

Opposition to Vitamin D supplementation.

Cliff notes from the opposition.

• Recalling from Part 1 Cliff Notes, the main rationale behind Vitamin D supplement opposition appears to be immunological and bacterial related (Timpone, P. 2010) & (Blaney, G 2017). However, to understand and translate these complex mechanisms for public knowledge remains difficult to extrapolate.
• Within practical evidence  (Marshall Protocol)  ~ a decrease in Vitamin D supplementation (including exposure to sun) appears to play a role at improving and managing auto-immune conditions.
• When supra physiological Vitamin D dosages are administered consistently overtime may result undesirable weakness to the innate (note: not adaptive) immune system (Marshall, T. 2018).
• Vitamin D does not appear to be required for activating the VDR (Vitamin D receptor). Quercetin (12:16 onwards)~ a plant flavonoid found in apple, berries, and wine  appeared to be an alternative activator of VDR.
• A paper raised by (Proal, L. 2009) suggested that Vitamin D supplementation appears to worsen asthma.
• A clinical study and trial by (Heil, T. 2016) appears to support Marshall's hypothesis. Here in this experiment involving 60 subjects ~ Vitamin D supplementation abstinence led improvements in metabolic syndrome. This is paradoxical considering many others proclaiming the opposite (Prasad, P. 2016) and (Melguizo-Rodriguez L et al, 2021). 
• Another trivia raised according to a recent discussion ((Deering K et al 2020) ~ over twenty-five (25) different forms of Vitamin D was briefly mentioned. This adds further layers of complexity.
• The alternative / opposition to Vitamin D supplementation  (Marshall, T 2018) strongly suggested that whilst Vitamin D is not strictly speaking a "nutrient" 1:55 onwards) consensus appears maintained that Vitamin D is a steroid. 

Contextual background (N=1)

Context and Background of This Author (AW), including prior usage of Vitamin D are disclosed as follows:

• Nutrition ~ 2+ years overall of standard ketogenic diet then transitioned to 5+ years of  Cyclical Ketogenic with up to six (6) days of Intermittent Fasting 18 hours minimum.
• Exercise status ~ 2008 onwards ~ personal enthusiast, yet not competitive fitness training background towards endurance based resistance training.
• Vitamin D habitual intake status ~ Vitamin D 2k to 5kIU as maintenance dose circa approximately 2016 onwards. Increase from 5k to as high as 15kiu as sporadic and irregular supplementations 2017 onwards.
  • Time of intake. Have been taking the dosages during evenings, as opposed to daytime to coincide with fasting windows throughout the day to prioritise obligated productivity without food intake.
  • Have tried both powdered (dry tablet) versions, as well as oil based delivery vehicles. Notably ~ sunflower PUFA oil based, as well as EVOO.
  • On oil based vehicles ~ have used both oral method as well topically on skin application. Specifically ~ prying open the oil delivery capsule and directly rub on wrists and/or necks.
• On May 2020 ~ higher than average reading as per recently disclosed blood panel (175 NMOL). Calcium adjusted reading however appears maintained amidst the reference range (2.27) [ref range = 2.10-2.60 mmol].
• Any attempts to lower Vitamin D intake felt less than "optimal" ~ in terms of overall psychology, physiology surrogate markers of wellbeing.
• The highest frequent dosages are between 10,000 IU to 15K IU sporadically up to four to five days per week throughout winter seasons. But much less so during summers to leverage increased sun exposure.

Legitimacy for Supplementing: recap on consensus.

As brief preface it is worth mentioning that large research reviews and meta-analysis are not without their own disadvantages (Loannidis JP et al 2008) & (Fagard RH & Thijs JA 1996).  Hence it remains imperative for one to curate insight based from the totality of evidence, not just curated in conveniences of umbrella's or systematic reviews but to include any other insights that were frankly disclosed as "weaknesses" or "limitations" amidst each systematic review or meta analysis gathered.  

Here in this section discloses a cliff note presentation on the legitimacy surrounding Vitamin D supplementation especially on their (generally) favourable roles towards mediating or protective against “all cause mortality” outcomes, or events. These include but not limited (on top of ageing/frailty) ~ autoimmunity,  cancer, cognitive decline, neurodegeneration, metabolic illnesses, cardiovascular to name a few.

• (Khozam SA et al. 2022) Aim: Auto-immunity. # of trials / studies = 11 studies N=1952.
  Lower 25OHD readings appear to be associated with Hashimoto’s and Grave’s patients.
• (Guo Z. Et al. 2022). Aim: Cancer incidence mortality. # of trials / studies = 26 RCT Randomised trials.
  Supplementation “significantly” protects against total cancer mortality by 10%.
• (Zhang Y et al 2019) Aim: “All cause mortality”. # of Trials / studies = 50 / N=74,655.
  Vitamin D was not associated with all cause mortality compared to controls (no treatment and placebo). However, this meta-analysis suggests that cancer death is decreased by 15%.
• (Heath AK et al. 2019). Aim: “All cause mortality”.  # of trials / studies = 84.
  Higher plasma reading of Vit D 25(OHD) appear to be protective as suggested by the “majority” of studies included.
• (Silva FA et al. 2017). Aim: "Immune-mediated theumatic diseases". # of trials / studies = 9.
  Supplementation seems to help reduce occurence of arthritic episodes.
• (Wang, J. Et al 2015). Aim: “Auto immunity” and Thyroid disease.
  # of studies: 20 case control studies.
  Individuals affected under autoimmune thyroid disease (AITD); including Graves and Hashimoto’s have lower circulating plasma readings of Vitamin D [25(OHD)].

 Hypervitaminosis D

<WIP Began September4th 2022>

As a general "rule" ~ toxicity is typically defined as plasma 25OHD readings above 80ng/mL (>200 nmol/L) (Lee J et al. 2018).

However there are numerous variables that may confound or eludes causality that leads or precursors to risk of toxicitiy as each individual circumstances not necessarily confined to physiology, remains varied.  Compounding to this elusive topic also due to a fact that "Hyper" or studies and/or Research reviews on "supraphysiological" dosages are difficult to source other than a handful few that are accessible or open for public reading. Chiefly among them were a notable 16-year (2000-2016) retrospective review at highlighting the plausibility of toxicity symptoms  (Lee J et al. 2018).

However another reason behind these scarcity of literatures and/or research seem to derive from a fact that most published literatures typically address general concerns of absolute Vitamin D deficiency (Durup D et al 2012). But far less interest is invested on the investigating behind what constitutes individual optimization and/or range of dosages that appear to be efficaceous at mediating any of the above known mortality risk factors and/or outcomes. In light of these, these leaves us only sparse yet nonetheless valuable individual case studies (Joshi, R 2009), (Pettifor JM et al. 1995). However they may be perceived as less robust in terms of overall strength of evidence.

So what are the symptoms of Vitamin D toxicity?

Adverse symptoms of Vitamin D toxicity could be categorised altogether as hypercalcemia, which consequent the effects and repercussions as outlined:

• Mental confusion
• Loss of apetite
• Mental apathy
• Vomitting
• Gastrointestinal
  • Abdominal pain
  • Constipation
  • Peptic ulcers
  • pancreatitis
• Polyuria (“urinating a lot”)
• Polydipsia (“drinking a lot” / extreme thirst)
• Hypercalcuria (high amount of calcium in urine)
• Coma (in worst case scenario).

To date, no experimental trial(s) ~ except N=1 case studies, anecdotes, and research reviews we’ve shared above on Vitamin D resistance and Coimbra Protocol ~ so far assess the toxicity potentials of Vitamin D supplementation.

Another plausible reason behind rarity of Vitamin D toxicity research on human subjects are tied to ethical grounds  (Suchowierska, EM et al. 2018) ., & (Chakraborty S et al. 2015).

"Clinical trials to study Vitamin D toxicity in humans is not possible ethically." ~ Chakraborty S et al. 2015

How prevalent are these recorded cases?

As accordingly to the above 16-year retrospective research (Lee J et al. 2018)., 89 patients whose plasma readings were above >120 NG/ML were studied for adverse symptoms of hypercalcemia. Only four (4) of the 89 (4.5%) manifested symptoms. One was deemed particularly "severe".

Only one (1) subject whose extremely high 25 OHD reading (850 ng/ml = 2122 nmol/L)  paradoxically displayed normal calcium levels at 9.0 mg/dl = 2.25 MMOL/L.   

Likewise, another case study (Chakraborty S et al. 2015) highlighting an adult 42 year old female patient was studied whose serum 25OHD was recorded as "746 ng/ML" (equating to 1862 NMOL/L, assuming no publication or calculation errors ). She was reportedly taking 60,000 IU of Vitamin D daily for four months. Despite this, there did not appear to be any "clinical symptoms" manifested and that serum calcium was found normal. 

"The clinical history and examination results for the patient were unremarkable for VDT. She did not report nausea, vomiting, weakness, fatigue, or constipation. We observed no evidence of any aortic calcification or nephrolithiasis in abdominal imaging. X-ray images of the spine and hips were also normal; we did not perform dual X-ray absorptiometry (DEXA) scanning. The patient had been consuming a normal healthy Indian diet that provided her sufficient calcium. " ~ Chakraborty S et al. 2015

One retrospective population study (Dudenkov DV et al. 2015) was conducted in Minnesota across a 10 year period (January 1st 2002 to December 31st 2011) examining a total  of 20,308 subjects reported four (4) cases (0.2% of total) with 25OHD reading above 50 ng/ml (which is comparatively very low), and they temporarily did exhibit symptoms of hypercalcemia. One (1) case of these four who were experiencing symptoms, was rated as clinical.

What is the possible rationale behind "normal" calcium reading, despite very high 25,OHD status?

As reminder this Self-Meta is entirely self-initiated insight and never proclaims as anyway prescriptive. Any research or suggestive insights are predominantly speculative, at best. The reason for this is the largely understudied effects of Vitamin D metabolism and the various confounders yet to be reconciled in concise terms for general readibility. 

One possible explanation is a genetic mutation of the CYP24A1 which precedes the increase of 24 hydroxylase activity. This is thought to prevent hypercalcemia, as suggested by the authors of the case study (Chakraborty S et al. 2015):

"24 hydroxylase is necessary for the catabolism of 1,25 (OH)2 vitamin D. Increased 24 hydroxylase as a result of CYP24A1 mutation, which prevented development of hypercalcemia, could have been possible in our patient." (Chakraborty S et al. 2015).

The J Shaped Mortality Association ~ what evidence is there for concern?

One source suggests a "J" Shaped mortality response to 25OHD status is available (Sempos CT et al. 2013.) "Reverse J" shaped association ~ meaning ~ that there appears to be risk of mortality association (death) on both very low and at very high 25OHD nnmol concentrations. Here in this study the number of participants totalled to 15,099 accross broad range of age groups (20 & 60+), and further sub categorised into ethnicity groups. Despite this study's conclusion that the risk of mortality appears to be "real"; there is still some admission of uncertainty(s) behind this review. As the # of participants who eventually died during 9 year follow up period appears to be carrying pre-existing comorbidities. As per to the statements extracted:

"As a result, it appears that participants who eventually died during the follow-up period were in poorer health at baseline."  ~ (Sempos CT et al. 2013.)

Furthermore, there were cautionary findings such that it appeared very difficult to distinguish / ascertain whether or not mortality were solely causal by high Vitamin D status alone. There may yet be  confounded by other mortality markers particularly cancer; as highlighted by the below statement extract.

"At the upper end of the 25(OH)D concentration distribution, the causes contributing to the increase in risk appeared to be other and cancer. The association between risk of cancer death and 25(OH)D concentration was not statistically significant perhaps because of the small sample size and numbers of deaths, which is consistent with results reported by Freedman et al (32); however, the higher number of cancer deaths among those with a serum 25(OH)D concentration at or above 120 nmol/L was a major contributor to the upswing at the higher end of the 25(OH)D distribution, leading us to interpret this nonsignificant finding as potentially important and worthy of further investigation in larger studies." ~ (Sempos CT et al. 2013.)

From historical perspective, prescribed dosages ranging between 200,000 to 300,000 IU of Vitamin D supplementation per day, were commonly used to manage chronic illnesses (tuberculosis and rheumatoid arthritis) throughout the 1930s and 40s. However practitioners began to witness adverse symptoms of hypercalcemia; as reported in small number of infants in United Kingdom in the 1950s (Samuel HS 1964). Symptoms namely ~ growth abrnomalities, learning/cognitive difficulties and kidney dysfunctions. Restoration from these adverse effects appears to resolve only after few months of Vitamin D supplement abstinence, but then also followed the need with glucosteroids and other pharmaceuticals. These time span requirements however vary from individuals as there seem to be evidence that up to 18 months is necessary ((Suchowierska, EM et al. 2018).

Is sunlight exposure alone adequate?

<WIP> Began 13th Sept 2022

There are few studies proclaiming that sunlight exposure alone, so long as presumably more than a modest surface exposure, is warranted as "sufficient" to maintain adequate levels of Vitamin D status.

As accordingly to this source (Mead MN, 2008) ~ a 30 minute exposure, in summer, presumably whole body by modest bathing suit appears to produce up to 50,000IU equivalent of Vitamin D response within 24 hours. However upon examining further literatures on these possibilities do not necessarily arrive at the same consensus; mostly due to sub groups / sub population / specific cultural customs surrounding letigimacies for sunlight exposure. For instance, a large cross sectional study amongst UK population (Kift, R et al. 2018) suggests that those of South Asian descent and of generally healthy background ~ still statistically appear to be deficient, despite sun exposure; as accordingly to the authors of the above research, as well as others as raised from the highly prestige Nature publications:

"Given the very low 25(OH)D levels of the South Asian population, sun exposure is not enough, and alternative sources of vitamin D should be considered." ~ Kift, R et al. 2018

"To maintain optimal vitamin D status, use of vitamin D supplementation is often required, as sunlight exposure and dietary intake alone is usually insufficient in most individuals [29,30,31]."  ~ Amrein K et al 2020.

Other confounders which unfortunately this Self-Meta cannot adequately cover are the racial subgroups and other pre-existing comorbidities far too complex for condensed reading. One common observation despite remaining open for scrutiny (Kaufmann, B. 2017 et al.) ~ is that amongst African and/or demographics of dark colour appear to be consistently prone to 25OHD deficiency. And of particular noteworthy concern is that of skin cancers, which few studies interestingly raised concern that higher Vitamin D appears to be correlated with melanoma and "BCC" or "basal cell carcinoma" (Saleh YM et al 2020).

In light of the above it is unlikely, though remains open for scrutiny that relying on sunlight alone seems pragmatic across a broad range of population. This is likely due to a multitude of reasons as alluded to earlier ~ confusing mixed receptions of Vitamin D raising risk of skin cancers, as well as also amongst other reasons; of which are social customs and/or religion-based nuances which we shall not ably elaborate.

 The opposition's view. Sunlight as "questionable" requirement to human existence.

According to the opposition (Marshall, T 2018) ~ there is so far no study nor research surrounding sunlight’s importance for “existence” and “function” to human physiology . Whilst certainly controversial this may yet warrant further contemplation as it is within our best interest at examining both thesis - for and contra ~ thesis throughout this Self-Meta. 

In terms of general observational studies there appears a handful of studies in general agreement that sunlight does appear to produce more favourable than there are negative or harmful result or effects on both human physiology and/or psychology (Penckofer S et al. 2010), (Jahrami H. 2020).

However it is noteworthy to also consider there are also observational findings that does not agree with the prevalent consensus. One source suggests that Vitamin D status does not correlate with depressive symptoms amongst population in Kuwait (Al-Sabah R, et al. 2022)

<WIP>

<This is a work in progress section. Meanwhile, please proceed to the WIP version of Part Two>  

Work In progress ends here. I welcome and remain thankful for your supportive comments. AW. / nutritional-humility.me