Diagnosis Of Vitamin D Resistance
Furthermore, the constellation of high serum 1,252D3 concentrations with a concurrently physiological 25D3 concentration is known to occur in hereditary forms of vitamin D resistance or VDR knockout mice it could therefore also be indicative of acquired vitamin D resistance. The 1,252D3 concentration is determined on the one hand by the activity of the enzymes CYP2R1, CYP27A1 and CYP27B1 that catalyze production of 1,252D3 and on the other hand CYP24A1 which catalyzes 1,252D3 degradation. The inactivation of 1,252D3 occurs either systemically or locally within the cells of target tissues. Because PTH negatively regulates CYP24A1 and positively regulates the hydroxylases converting 25D3 to 1,252D3, the presence of vitamin D resistance, which results in low intestinal calcium absorption and thus PTH stimulation, would lead to a constant elevation of 1,252D3.
How Much Vitamin D Is Too Much
Since relatively little is known about how vitamin D toxicity works, its hard to define an exact threshold for safe or toxic vitamin D intake .
According to the National Academy of Medicine, formerly known as the Institute of Medicine, 4,000 IU is the safe upper level of daily vitamin D intake. However, doses up to 10,000 IU have not been shown to cause toxicity in healthy individuals (
28 ).
Hypercalcemia caused by regularly taking high amounts of vitamin D supplements may take a few months to resolve. This is because vitamin D accumulates in body fat and is released into the blood slowly .
Treating vitamin D intoxication includes avoiding sun exposure and eliminating all dietary and supplemental vitamin D.
A doctor may also correct your calcium levels with increased salt and fluids, often by intravenous saline.
Summary
The main consequence of vitamin D toxicity is hypercalcemia, with symptoms including nausea, vomiting, weakness, and kidney failure. Treatment involves limiting all vitamin D intake and sun exposure.
Evaluation Of Vitamin D Status
Vit. D status can be categorized by evaluating serum 25OH-D levels . For many years, it has been argued that levels of 25OH-D should be at least 50 nmol/L, since this is sufficient to maintain good skeletal health in almost all individuals . However, many experts claim that levels of 75 nmol/L and above are those sufficient to ensure normal skeletal and muscular structure and function . There is growing evidence that minimum 100 nmol/L of 25OH-D levels are needed to reduce the risk of some cancers , cardiovascular disease, infectious diseases, pathological pregnancies , systemic connective tissue diseases, diabetes, and also COVID-19 . An optimal levels of 25OH-D mean that Vit. D is sufficient for all systems in the human body, not only for bones . Some authors speculated that a laboratory-determined concentration of 100 nmol/L indicates that the true serum 25OH-D levels of the individual are greater than 75 nmol/L . In summary, 25OH-D levels of 75150 nmol/L should be considered as normal. The term low vitamin D status used in the present paper comprises both Vit. D deficiency and Vit. D insufficiency, as defined in Table 2.
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Improving The Vitamin D Status Of Vitamin D Deficient Adults Is Associated With Improved Mitochondrial Oxidative Function In Skeletal Muscle
Twelve severely vitamin D-deficient patients complaining of fatigue and myopathy were put on an experimental vitamin D3 therapy regimen, taking 20,000 IU every other day for 3 months. All patients reported an improvement in their symptoms. Despite taking what most doctors consider a very high dose of vitamin D for three months, the average vitamin D level of the group failed to rise into the optimal range.
Vitamin D Prophylaxis During Infancy: Comparison Of The Long
60 healthy babies were given a single vitamin D3 dose of either 100,000 IU, 200,000 IU, or 600,000 IU. 2 weeks later their vitamin D levels were tested. The babies given 100,000 IU actually had a slightly subpar mean vitamin D level. The babies given 200,000 had an optimal mean vitamin D level. The babies given 600,000 had a toxicly high vitamin D level with 50% of them continuing to have vitamin D overload for up to 6 months. The babies given 600,000 IU experienced symptoms of hypercalcemia, whereas the babies given 100,000-200,000 IU did not. A 100,000-200,000 IU megadose of vitamin D3 every three months was found to be safe for infants with the researchers concluding that 100,000 IU presents the lowest risk of any side effects.
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Vitamin D Supplementation 25
Contrary to the long-held belief of the medical establishment that adults should take no more than 400 IU of vitamin D daily, this study concludes that adults need at least 4,000 IU of vitamin D daily to achieve sufficient vitamin D levels and that even 10,000 IU of vitamin D daily is safe for adults. It takes long-term dosing of vitamin D in excess of 40,000 IU daily to develop vitamin D toxicity and hypercalcemia in adults. Lifeguards and outdoor workers often obtain very high natural vitamin D levels from their heavy sun exposure that would take long-term daily supplement doses in excess of 10,000 IU to achieve.
Elevated Blood Calcium Levels
Vitamin D helps your body absorb calcium from the food you eat. In fact, this is one of its most important roles.
However, if your vitamin D intake is excessive, your blood calcium may reach levels that can cause unpleasant and potentially dangerous symptoms.
The symptoms of vitamin D toxicity are primarily related to hypercalcemia, which means excessively high blood calcium levels (
Hypercalcemia typically develops after people take megadoses of vitamin D for a prolonged period of time.
For example, a 2015 case study reported that an older man with dementia who received 50,000 IU of vitamin D daily for 6 months was repeatedly hospitalized with symptoms related to high calcium levels .
In the 2020 case report mentioned earlier, the woman who took an average of 130,000 IU of vitamin D per day for 20 months was also hospitalized for symptoms related to hypercalcemia .
These included nausea, vomiting, muscle weakness, and kidney injury. Her blood calcium levels were 3.23 mmol/L (
However, not all people with hypercalcemia experience the exact same symptoms.
One woman experienced nausea and weight loss after taking a supplement that was later found to contain 78 times more vitamin D than stated on the label .
Importantly, these symptoms occurred in response to extremely high doses of vitamin D3, which led to calcium levels greater than 12 mg/dL.
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Reporting And Handling Of Pregnancies
Pregnant participants must immediately be withdrawn from the clinical study. Any pregnancy occurring during the treatment phase of the study and within 30days after discontinuation of study medication will be reported to the sponsor-investigator within 24h. The administration of vitamin D3 is not contraindicated in pregnancy, but hypercalcemia caused by long-term overdose can lead to various negative outcomes for the child. Furthermore, since the evidence for the effect of high-dose vitamin D in patients with COVID-19 remains uncertain, it was decided to exclude pregnant women. Pregnant women with a known vitamin D deficiency should be supplemented according to prescribing information or according to the recommendations of the treating gynecologist.
Acute Vitamin D Intoxication In A Child
This is a case study of a 2-year-old boy whos mother accidentally gave him 2,400,000 of vitamin D2 over the course of four days , which is 300x what is considered a safe daily dose for toddlers. The boys vitamin D level rose to an extremely high 470 ng/ml. Although he had to be hospitalized for two weeks for hypercalcemia, he made a full recovery.
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A Brief Algorithm For Vitamin D Dosing
As mentioned above, even for Vit. D risk group patients, recent measurements of serum 25-OH-D are not always available. Therefore, presuming that the true levels of 25OH-D for many individuals could be below 75 nmol/L, it is reasonable to suggest starting vit. D supplementation with 4000 IU/d or an equivalent weekly dose. For patients definitely belonging to Vit. D risk group, except those with or at high risk of hypercalcemia , the initial Vit. D dose might be doubled . For patients that are already taking Vit. D supplements without having performed 25OH-D measurements and without physicians advice before beginning of supplementation, it could be presumed that they might have low Vit. D status, i.e., they decided to start taking Vit. D on the grounds of their symptoms that potentially could have been caused by Vit. D insufficiency/deficiency. Therefore, it is reasonable to suggest doubling the Vit. D dose that they are currently using, but not exceeding the upper safe dose limits .
Brief algorithm for vitamin D dosing.
The suggested original, brief or working algorithm presented in Figure 1 also comprises the main principles of Vit. D dose selection discussed earlier in this paper when baseline 25OH-D levels are known .
Vitamin D Metabolism And Assessment Of Vitamin D Status
Vitamin D is essential for intestinal calcium absorption and for the prevention of rickets or osteomalacia. It also plays in role in calcium, phosphate, and bone metabolism in general besides having multiple extra-skeletal effects .
Vitamin D is a fat-soluble secosteroid produced by the skin after exposure to sunlight. The photolytic reaction is induced by irradiation of 7-dehydrocholesterol in the skin, by an energetic UV-B wavelength of approximately 280 to 310 nm) .
UV-B irradiation of 7-dehydrocholesterol promotes a photochemical cleavage between carbons 9-10 of the steroid ring generating the pre-vitamin D3 hormone. Through a time and temperature-dependent molecular isomerization, pre-vitamin D2 is converted to vitamin D3 , as well as to two biologically inert products, tachysterol and luminosterol. Dermal synthesis of vitamin D depends upon the intensity of UV radiation and air pollution .
The first hydroxylation step at C-25 occurs in the liver by the vitamin D-25-hydroxylase , a mitochondrial cytochrome P450âlike enzyme, converting cholecalciferol into 25D). The half-life of 25 D is approximately 2-3 weeks. The final hydroxylation step occurs in the renal proximal convoluted tubules by the vitamin D-1-hydroxylase , a cytochrome P450âlike oxidase, converting 25D to 1,25-dihydroxycholecalciferol , the active form of vitamin D. The half-life of calcitriol is very short, approximately 6-8 hours.
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Consequences Of Vitamin D Resistance
There also is an epigenetic influence of the VDR on genes of the immune system. An in vivo proof-of-principle study investigated chromatin accessibility in monocytes obtained from a human subject before and after a vitamin D bolus dose of 2000 µg . The bolus dose, which raised 25D3 levels by 7.6 ng/ml after two days, resulted in a significant opening or closing of hundreds of gene loci, the most prominent of which belonged to the human leucocyte antigen system coded on chromosome 6. With the help of antigen-presenting proteins of the HLA system, the immune system is able to differentiate between endogenous and exogenous proteins. Therefore, a dysfunction within the HLA system predisposes for the development of autoimmune diseases. Polymorphisms of the HLA system for example constitute the most significant genetic influence on MS . Interestingly, a vitamin D responsive element could be identified at a gene within the HLA-DRB1 region, which is closely associated with the development of MS . Besides the epigenetic influence, this finding also underlines the transcriptional effect of vitamin D on the pathogenesis of this disease.
In summary, there is much plausibility for acquired vitamin D resistance playing a pathological role in the development of autoimmune diseases, in this way providing an important component for our understanding and explanation of these diseases.
Annual Injection Of Vitamin D And Fractures Of Aged Bones
Over a 5-year period 341 elderly people were given annual vitamin D megadose injections and their fracture rate during that period was compared to a group of 458 matched controls not receiving vitamin D. The vitamin D group experienced 6% fewer fractures than the control group. This is actually impressive considering that an annual dose of 150,000-300,000 IU amounts to only about 400 IU 800 IU per day, which leading vitamin D experts agree is completely inadequate for adults, possibly even inadequate for infants, and even more inadequate for seniors. Vitamin D2 has also been found to be only about 25% as effective for raising human vitamin D levels than vitamin D3 and the half life of vitamin D is only a few months max, making an annual megadose the least reliable way of maintaining year-round adequate vitamin D status. Despite the vitamin D group receiving essentially meaninglessly insufficient vitamin D treatment, they experienced measurably superior health outcomes and no signs of vitamin D toxicity were observed following the 300,000 IU megadoses.
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The Vitamin D Hammer: Beating The Flu In 72 Hours
Recently, when my father came down with a bad cold, we made use of the Vitamin D Hammer along with our secret weapon vitamin C. The improvement was clear.
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But, what is this hammer and how can you use it to get rid of influenza-like symptoms fast?
The Hypothesis Of Acquired Vitamin D Resistance
In two intervention studies, Carlberg and colleagues found evidence that different individuals display a different molecular and biochemical response to the same dose of either long-term or single-bolus vitamin D3 supplementation . Initially, in the VitDmet study, 71 elderly prediabetic individuals were supplemented with either 0, 1600 or 3200 I.U. vitamin D3 daily over 5 months of Finnish winter . The focus of this work was on the effects of vitamin D3 supplementation on mRNA expression of twelve of the vitamin D-regulated genes and several vitamin D-affected laboratory parameters. With the help of these biomarkers, the group was able to show in 2015 that even supposedly adequate high vitamin D3 doses were not able to exert the expected vitamin D-regulatory effects in all subjects. Focusing on the PTH feedback system alone, a total of 25% of the patients showed no adequate response of this laboratory parameter. Regarding all 36 tested parameters, Carlberg et al. could cluster their patients in 24% low responders, 51% mid responders and 25% high responders. In 2017, the group was able to reproduce these findings in the VitDbol study, in which a cohort of healthy Finnish students received a 80,000 I.U. bolus dose of vitamin D3 with similar low responder rates .
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Reporting Of Suspected Unexpected Serious Adverse Reactions
A SUSAR needs to be reported to the ethics committee via BASEC and to Swissmedic for category B and C studies within 7 days if the event is fatal, or within 15days .
The sponsor-investigator must inform all investigators participating in the clinical study of the occurrence of a SUSAR. According to the exact timelines, all in the trial involved ethics committees will be informed about SUSARs in Switzerland via the sponsor-investigator via BASEC.
Safety Of Vitamin D Supplementation In Children: A Massive Vitamin D Overdose With No Apparent Hypercalcaemia
A 12-year-old girl was accidentally prescribed 100,000 IU of vitamin D3 daily for a period of three months. She consumed at least 150 50,000 IU D3 capsules, totaling up to 7.5 million IU for the period. Her vitamin D blood level after this was found to be an extremely high 268 ng/ml. Amazingly, after a thorough evaluation, no symptoms of vitamin D toxicity were observed in her.
Universal intake of up to 40,000 IU vitamin D per day is unlikely to result in vitamin D toxicity.
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Variability In The Form Of Vd That Is Needed For Specific Situations
Use of calcidiol versus calcitriol
Calcitriol is the most active metabolite of vitamin D. Alfacalcidol is a synthetic calcitriol analogue which is 25-hydroxylated in the liver into calcitriol, avoiding the need for enzymatic conversion by the renal 1alpha-hydroxylase enzyme . Not surprisingly, therefore, alfacalcidol increases calcitriol levels independently of renal function. The effects on intestinal calcium absorption and on bone turnover of oral or parenteral administered calcitriol and alfacalcidol are very similar . In general, the use of 1-alpha-hydroxylated forms is hampered by the higher risk of developing hypercalcemia and/or hypercalciuria . However, the biochemical safety of calcitriol and alfacalcidol is similar. Alfacalcidol has been shown to prevent falls and fractures in women with postmenopausal osteoporosis and also in elderly individuals of both sexes . Some possible differences on vertebral fracture risk between calcitriol and alfacalcidol may be related to the populations enrolled in the trials .
When to use active vitamin D analogues versus 25D versus vitamin D-alone or in various combinations
The Amount Of Vitamin D To Reach A Desired Level Varies According To The Clinical Conditions
Exogenous and endogenous glucocorticoid excess
A meta-analysis of observational studies has found that most adult subjects administered pharmacological amounts of glucocorticoids had low 25D levels, irrespective of what threshold value was used to define hypovitaminosis D . The bone loss associated with glucocorticoids include distorted PTH pulsatility and pathophysiological perturbations in vitamin D synthesis, metabolism, and action. Interference with vitamin D synthesis occurs at separate steps leading to impaired production of active vitamin D. Vitamin D metabolism, furthermore, is heavily influenced by chronic exposure to either endogenous or exogenous glucocorticoid excess. Glucocorticoids are also associated with target tissue resistance to vitamin D .
It is, therefore, important to consider vitamin D supplementation when patients are exposed to glucocorticoid excess . Therapeutic goals should take into account two particular points . Resistance to vitamin D dictates a higher level of 25D level to ⥠32 ng/mL. Daily administration of 2,000 IU often will reach and maintain this goal . A second therapeutic point relates to synthetic interference with production of active vitamin D, necessitating in some situations the use of active forms of vitamin D, such as calcidiol or calcitriol .
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