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Toggle Health Problems and D

Response to Vitamin D – 25% high, 24% low (ignores other than genes) – July 2024

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Steroids Volume 207, July 2024, 109437 https://doi.org/10.1016/j.steroids.2024.109437
Ulla M. Järvelin a b 1, Juho M. Järvelin c 2

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Highlights

  • Response to Vitamin D (VD) is a continuum, varying from VD resistance to VD hypersensitivity.
  • Low response to VD leads to autoimmunity. VD more than recommended is needed.
  • Strong response to VD leads to organ calcification. The sun and extra VD cause harm.
  • The prevalence of resistance or hypersensitivity to VD is undetermined.

Vitamin D resistance (VDRES) explains the necessity for higher doses of Vitamin D (VD) than those recommended for treatment success. VD receptor (VDR) signaling blockade, such as that caused by infections and poisons, is one basis for VDRES etiology. Mutations within genes affecting the VD system cause susceptibility to developing low VD responsiveness and autoimmunity.
In contrast, VD hypersensitivity (VDHY) occurs if there is extra VD in the body; for example, as a result of an overdose of a VD supplement. Excess 1,25(OH)2D3 is produced in lymphomas and granulomatous diseases. The placenta produces excess 1,25(OH)2D3. Gene mutations regulating the production or degradation of 1,25(OH)2D3 enhance the effects of 1,25(OH)2D3. Increased 1,25(OH)2D3 levels stimulate calcium absorption in the gut, leading to hypercalcemia. Hypercalcemia can result in the calcification of the kidneys, circulatory system, or placenta, leading to kidney failure, cardiovascular disease, and pregnancy complications. The primary treatment involves avoiding exposure to the sun and VD supplements. The prevalence rates of VDRES and VDHY remain unclear.
One estimate was that 25%, 51%, and 24% of the patients had strong, medium, and poor responses, respectively. Heavy-dose VD therapy may be a promising method for the treatment of autoimmune diseases; however, assessing its potential side effects is essential. To avoid VD-mediated hypercalcemia, responsiveness must be considered when treating pregnancies or cardiovascular diseases associated with VD. Furthermore, how VD is associated with the related disorders remains unclear. Investigating responsiveness to VD may provide more accurate results.
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Introduction

A noteworthy development in modern medicine is using vitamin D (VD) to treat and prevent rickets [1,2]. According to estimates, vitamin D deficiency (VDD) affects up to 40 % of people in the European Union and 24 % of Americans [3], and moderate cases of VDD are considered substantial health risks, even though severe cases are rare, and rickets is infrequent. VDD is associated with conditions such as cancer, connective tissue disorders, inflammatory bowel disorders, chronic hepatitis, food allergies, asthma, respiratory infections, and type 1 and 2 diabetes. However, most intervention studies have not proven a link between VDD and these conditions [4]. Calcitriol, a physiologically active VD,
mediates its action by binding to the vitamin D receptor (VDR) [5]. VDR is present throughout the body, including in cells involved in immune modulation [6-15]. The almost universal expression of the VDR implies that the VD/VDR axis controls genes associated with several processes, including energy metabolism, immunological responses, cell growth and differentiation, and calcium homeostasis [16]. However, most inter­vention studies have not proven a link between VDD and these processes [4]. VD supplementation can increase serum 25OHD3 concentration to a high normal range. However, this has not been associated with benefits for global health, major diseases, or medical events such as cancer, cardiovascular events, diabetes mellitus, falls, or fractures, at least in largely VD-replete adults [16]. The importance of VD substitution for preventing and treating rickets is indisputable. However, treatment re­sults for other diseases associated with VDD and VD are contradictory. This review attempts to determine the effects of VD responsiveness.

VD metabolism

A review of VD metabolism will help us understand the mechanisms associated with VD responsiveness and the utility of measuring VD metabolites when diagnosing VD responsiveness.
The skin synthesizes cholecalciferol (VD3), a secosteroid that func­tions as a prohormone. Although dietary VD supplements can also produce it, endogenous synthesis in the skin is the main source of VD3. In the skin, UVB causes the phototransformation of 7-dehydrocholesterol into pre-VD3, and heat promotes the conversion of pre-VD3 into VD3. VD3 is mostly transferred from the skin to the bloodstream by D-binding protein (DBP). Notably, 25-hydroxylases (CYP2R1 and CYP27A1) modify VD3 via hydroxylation in the liver, resulting in 25-hydroxyvita- min D3 (250HD3). Subsequently, la-hydroxylase (CYP27B1) performs a second hydroxylation to produce the active form, calcitriol [1,25 (OH)2D3], predominantly in the kidneys. [5] However, hydroxylation can also occur in other tissues and cells. The active form interacts with the VDR and affects biological processes [5,17]. Furthermore, 24-hy­droxylase (CYP24A1) converts 25(OH)D3 and l,25(OH)2D3 into inac­tive metabolites [5]. Additionally, l,25(OH)2D3 concentration, blood calcium levels, and parathyroid hormone (PTH) levels principally con­trol CYP27B1 and CYP24A1 activity. Furthermore, klotho and FGF23 negatively regulate CYP27B1 and positively regulate CYP24A1, linking VD metabolism to phosphate homeostasis (Fig. 1). [18] Free phosphate is filtered in the glomerulus of the human kidney before being reab­sorbed as it travels along the nephron. The sodium phosphate cotrans­porter (NaPi-IIa), which regulates phosphate reabsorption from primary urine in the proximal tubule, is encoded by SLC34A1. NaPi-Iia, Klotho, FGF23, PTH, and l,25(OH)2D3 control renal phosphate levels. [19] In­testinal l,25(OH)2D3 enhances calcium absorption. PTH increases cal­cium release from the bones into the circulation if the blood-ionized calcium content is low. PTH also accelerates the conversion of 25(OH)D3 to l,25(OH)2D3, which is then released into the bloodstream. PTH prevents phosphate reabsorption, resulting in larger quantities of ionized calcium and lower levels of water-soluble calcium phosphate salts. Consequently, the VD system has a direct feedback mechanism. PTH should be low in the lower third of the reference range if 25(OH)D3 levels are physiologically high and vice versa. [20].

VD resistance and rickets

In the 1930s, some children with rickets were observed to require high doses of VD to alleviate their symptoms. In 1937, Albright, Butler, and Bloomberg introduced the concept of VD resistance (VDRES) [21]. Further research revealed that these children had either hereditary de­fects in la-hydroxylase, leading to decreased active VD (VD-dependent rickets type I [VDDR-I], or congenital defects in VDR. When VDR is defective, genetic VD-resistant rickets (HVDRR), also known as VD- dependent rickets type II (VDDR-II), develops. Both are rare autosomal recessive disorders characterized by hypocalcemia, secondary hyper­parathyroidism, and early onset severe rickets. [22] Rare instances of HVDRR defects have been detected to cause this issue. Only 70 items were discussed in the 2007 article “Vitamin D-resistant diseases” [23].
Although VDRES is rare (see 1.2.), the concept of acquired VDRES has been developed, which is more common and could be related to autoimmune diseases. This resistance results from mutations in the VD system that occur during aging and exposure to environmental factors, thereby impairing VD hormone signaling. These environmental factors include pathogens such as the Ebstein-Barr virus [24], cytomegalovirus [25], legionella, escherichia coli, and Yersinia. [26]. These pathogens can block the VDR and alter host immune responses. Glucocorticoids can also disturb the VDR gene [27]. Aluminum can decrease renal CYP27B1 activity in chickens [28] and has been found at high concentrations in the brain tissue of patients with multiple sclerosis (MS) [29]. Aging re­duces intestinal cholecalciferol absorption [30], decreases endogenous skin production [31] and VD hydroxylation [32]. The weakest link in the VD metabolic system is VDR, and the most significant indicators of ac­quired VDRES are mutations in the VDR [17,20]. The genes CYP2R1, CYP27A1, CYP27B1, and DBP (necessary for VD transport in circulation) and the cell-surface receptor megalin-cubilin, which is the membrane receptor for the l,25(OH)2D3/DBP complex, also have mutations asso­ciated with autoimmune diseases [20].
Autoimmune disorders occur when the immune system mistakenly attacks healthy cells and tissues. VD is vital for maintaining a strong and healthy immune system. Therefore, VDD can increase the risk of auto­immune disorders by weakening the adaptive immune system. [33,34] Several autoimmune conditions such as autoimmune thyroid disease [35], systemic lupus erythematosus [36], rheumatoid arthritis [37], inflammatory bowel disease (IBD) [38,39], MS [43], and insulin­dependent type 1 diabetes mellitus [6] have been associated with VDD. However, more research is needed to determine if VDD is the cause or effect of these autoimmune disorders [33,34]. Patients with IBD often have difficulty absorbing VD, necessitating higher doses of VD to ach­ieve normal serum 25(OH)D levels. This can prevent the development of bone fragility, osteoporosis, and osteomalacia [38]. However, few ran­domized controlled trials have examined the effects of VD supplemen­tation on disease occurrence and severity. One study found that a higher dose of VD (2000 IU) led to lower levels of proinflammatory markers in children and adolescents with IBD than a lower dose of 400 IU [39]. Children with rheumatic diseases, especially those treated with steroids, are recommended to receive at least double the daily recommended dose of VD for their age (approximately 2000 Ul/day) [40].

High-dose VD therapy

Recent studies on treating autoimmune diseases have revealed the clinical advantages of high-dose VD therapy. A single high dose of VD3 (100 000 IU) may positively affect health outcomes in older adults [41]. Large-dose, short-term VD supplementation has been shown to reduce insulin resistance compared to placebos in patients with type 2 diabetes [42]. Recommended serum 25(OH)D levels are usually 20 - 30 ng/ mL. In MS treatment, serum 25(OH)D levels of approximately 130 ng/mL are recommended for therapeutic effects. Clinical trials have shown that VD doses ranging from 10,000 to 40,000 IU/day are safe as an add-on therapy. In any case, these trials were relatively short in duration, had small sample sizes, and in many cases, were not placebo-controlled. The adverse effects during the trials were usually minor and manageable. The results of these trials are conflicting, and whether regular VD intake is reasonable beyond the correction of hypovitaminosis D remains un­clear. [43].
Dr. Cicero Coimbra, a neurologist from Brazil, used ultrahigh doses of VD to treat patients with autoimmune diseases [44,45]. This approach has been used in Germany to treat patients with autoimmune diseases since 2016. The fundamental idea behind high-dose VD3 therapy is that some patients have a non-hereditary, acquired type of VDRES and insufficient biological activity of l,25(OH)2D3. To overcome this resis­tance, high doses of VD3 are administered to patients to unblock VDRs. The initial doses of VD3 in the Coimbra protocol depend on the auto­immune disease being treated. For MS, doses of up to 1000 IU of VD3 per kg of body weight may be used, whereas other autoimmune disorders require smaller doses. [20] In rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, psoriasis, Crohn’s disease, and ul­cerative colitis, initial VD3 doses of 300-500 IU/kg of body weight are used. Systemic scleroderma, ankylosing spondylitis, and Hashimoto’s thyroiditis require VD3 doses of 300 IU/kg of body weight, whereas other autoimmune diseases require VD3 doses of 150 IU/kg of body weight. The doses are gradually adjusted (usually lowered) during follow-up, based on a standardized procedure that considers the pa­tient’s clinical condition, calcium levels, and PTH concentrations. [20] Studies have shown that the Coimbra protocol is safe for patients with autoimmune diseases when oral VD3 is administered in large doses with a strict low-calcium diet and daily fluid intake of 2.5 L. Owing to the underlying VDRES, patients are protected against what is typically considered a potentially toxic dose, and the doses used in this protocol only have physiological effects. [46] The Coimbra protocol is similar to insulin resistance therapy in which higher doses are administered to address resistance [47].

VD responsiveness range

Carsten Carlberg, a Professor of Biochemistry at the University of Eastern Finland, studied VD’s gene regulation and epigenetics. He found that people respond differently, molecularly and biochemically, to the same dosage of VD3. During the Finnish winter of 2015, 71 senior pre­diabetic participants in the VitDmet study received daily supplements of 0, 1600, or 3200 IU VD3. This study focused on the effects of VD3 sup­plementation on mRNA expression of 12 VD-regulated genes and several VD-affected laboratory parameters. This study demonstrated that even high doses of VD3 (3200 IU) did not always have the desired VD- regulatory effects in participants, with 25 % of patients failing to respond as expected. According to this study, patients were categorized as low (24 %), mid (51 %), and high responders (25 %). [48] Later, in 2017, the same research group conducted the VitDbol study, in which a group of healthy students received an 80,000 IU bolus dose of VD3. The results of the VitDbol study validated the findings of the VitDmet study. [49] To get an acceptable physiological response, such as lowering PTH concentrations or downregulating an activated adaptive immune sys­tem, patients with VDRES need substantial doses of VD3. Increased PTH levels, despite adequate 25(OH)D3 levels, are signs of acquired VDRES and can occur in patients with autoimmune diseases. In the VD system, PTH is essential for improving intestinal calcium absorption, triggering calcium release from the bones, boosting the conversion of 25(OH)D3 to l,25(OH)2D3, and preventing tubular phosphate reabsorption. An average 25(OH)D3 level should reduce the PTH levels to the lower third of the reference range. However, this negative feedback loop is dis­rupted in patients with autoimmune diseases. [20] On the VD respon­siveness continuum, individuals with VDRES fall at the low-response end [48,49].

VD hypersensitivity

Vitamin D hypersensitivity patients (VDHY patients) are on the opposite side of the VD responsiveness continuum. They have either excess VD in the body or their bodies are sensitized to VD Because of this, the effects of VD for them are stronger than average. They don’t need as much VD as others. On the other hand, extra sunshine or rela­tively low therapeutic doses of VD can increase the effects of VD in the body, leading to increased intestinal calcium absorption, calcium mobilization from the bones, and hypercalcemia. [51] The group “VD hypersensitivity” is divided into subgroups “exogenous and endoge­nous” based on its etiology.
Exogenous VDHY results from consuming extremely large amounts of pharmaceutical VD preparations. Values > 150 ng/mL (375 nmol/L) of serum 25(OH)D3 signify exogenous VDHY. The serum l,25(OH)2D3 levels are average. There is also hypercalcemia and low PTH [52]. Ac­cording to the 2011 recommendations of the Institute of Medicine, the maximum tolerated levels of VD intake is 1000 IU/d for newborns under six months of age, 1500 IU/d for infants of six to 12 months of age, 2500 IU/d for children of one to three years of age, 3000 IU/d for children of four-to eight years of age, and 4000 IU/d for adolescents and adults [55]. However, several studies have shown that VD is probably one of the least dangerous fat-soluble vitamins, far less dangerous than vitamin A [56].
Endogenous VD hypersensitivity syndrome was discovered more than 70 years ago. To treat rickets, children are administered high amounts of VD. While the majority of children responded favorably to this treatment, some displayed symptoms of hypercalcemia. This illness spread and became endemic in three distinct occurrences. The first occurred in Great Britain in the early 1950 s [57], the second in Poland in the 1970 s [58], and the third in East Germany in the 1980 s [59]. This syndrome was initially called idiopathic infantile hypercalcemia (IIH), but the name was misleading. It also occurs in adults, and its etiology is well-known.
One cause for endogenous VDHY is ectopic synthesis of 1,25 (OH)2D3. The placenta synthesizes extra l,25(OH)2D3 during pregnancy [76]. Sarcoid lymph nodes synthesize extra l,25(OH)2D3 [60-62]. Ectopic synthesis of l,25(OH)2D3 is also observed in tuberculosis [63], lymphomas [64,65], fungal infections, leprosy, and other granuloma­tous diseases [51].
Another cause of endogenous VDHY is mutations in the genes responsible for the synthesis or catabolism of VD. In 2011, Shlingmann et al. reported alterations in CYP24A1 expression in patients with idio­pathic infantile hypercalcemia (IIH). CYP24A1 catabolizes l,25(OH)2D3 into its inactive metabolites. Mutations in the CYP24A1 gene result in the build-up of l,25(OH)2D3 and a decrease in its degradation [Fig. 1]. [3,66] In 2017, Schlingmann et al. found that a mutation in the SLC34A1 gene results in hypophosphatemia [4] by impairing the proximal tu­bules’ ability to reabsorb phosphate from primary urine [4,66]. There­fore, hypophosphatemia concurrently inhibits CYP24A1 and stimulates la-hydroxylase (CYP27B1) (Fig. 1) [67]. The accumulation of 1,25 (OH)2D3 is also an outcome of this mutation. Nephrolithiasis, decreased PTH levels, hypercalcemia, and hypercalciuria are the hallmarks of both mutations. (Fig. 1) Besides, mutations in SLC34A1 [4,66] cause hypo­phosphatemia. Other yet unknown abnormalities in the genes control­ling VD metabolism are expected, except for in CYP24A1 and SLC34A1 [68].
In addition, an increase in the quantity of VDRs or saturation of the DBP capacity can lead to endogenous VDHY [52].
Endogenous VDHY, caused by gene mutations, constitutes a hered­itary risk factor because VD substitution can lead to the development of symptomatic hypercalcemia in otherwise healthy neonates [66]. Bial- lelic mutations result in the aforementioned clinical and biochemical phenotypes. Individuals carrying monoallelic gene mutations may exhibit hypersensitivity reactions to excess VD, have an attenuated disease, or be asymptomatic carriers [51].

Clinical signs of VD hypersensitivity and hypercalcemia

Clinical signs of hypercalcemia are similar, although the etiology varies [50,54]. Only a small percentage of patients exhibit significant symptoms, and most patients are asymptomatic and diagnosed through routine examinations [51]. In babies, in addition to weight loss, clinical symptoms include polyuria, dehydration, vomiting, and constipation [66].
VDHY may remain undetected until adulthood, and its clinical signs may emerge later in life, particularly in monoallelic mutations. Exces­sive sun exposure, high-VD food products, or VD supplements can induce increased levels of l,25(OH)2D3 and hypercalcemia in VDHY patients [51].
Chronic subclinical hypercalcemia and hypercalciuria result in kid­ney stones, adult renal insufficiency, and severely decreased kidney function. In addition to tubulointerstitial inflammation and fibrosis, mineral deposits associated with nephrocalcinosis play a role in devel­oping end-stage renal diseases [69-72]. Hypertension, arterial calcifications, and arterial vasoconstriction are cardiovascular symp­toms associated with hypercalcemia. Mutations in CYP24A1 have been associated with coronary artery calcification, which, in turn, leads to a higher risk of coronary heart disease. [73-75] Throughout pregnancy, the amount of l,25(OH)2D3 produced by the placenta increases [76]. Patients with VDHY do not experience an increased VD breakdown. Serious pregnancy consequences include pancreatitis, nephrolithiasis, arterial hypertension, potentially fatal hypercalcémie crises, and lethality for the mother and/or the fetus. [77-81] Additional clinical manifestations of hypercalcemia include neuropsychiatrie symptoms such as depression, hallucinations, anorexia, nausea, vomiting, con­stipation, peptic ulcer disease, pancreatitis, varying degrees of demin­eralization and fragility of the bone, and stupor and coma in severe cases [51].
Nonetheless, VDHY may remain undetected until adulthood, and its clinical signs may emerge later in life, particularly in monoallelic mu­tations. Excessive sun exposure, high-VD food products, or VD supple­ments can induce increased levels of l,25(OH)2D3 and hypercalcemia in VDHY patients [51].

Diagnosis of VD hypersensitivity

The diagnosis of VD hypersensitivity is challenging. Pregnancy, medication use, VD replacement, and related conditions such as lym­phomas, cancer, nephrocalcinosis, granuloma-forming illnesses, and hereditary diseases, as well as nephrolithiasis, decreased PTH levels, hypercalcemia, hypercalciuria, and hypophosphatemia should be care­fully considered. In the presence of excessive 25(OH)D3, the resulting hypercalcemia is known as exogenous VDHY. [51] In endogenous VDHY, elevated l,25(OH)2D3 concentrations have been associated with hypercalcemia. [51] If pathogenic CYP24A1 mutations are suspected, the 25(OH)D3 to 24,25(OH)2D3 ratio should be evaluated. The 25(OH) D3 to 24,25(OH)2D3 ratio is approximately < 30 in most heterozygotes and individuals without pathogenic CYP24A1 mutations; however, it is generally > 80 in individuals with harmful mutations. Genetic testing must be performed if the ratio of 25(OH)D3 to 24,25(OH)2D3 is > 80. [82,83].

Treatment of VD hypersensitivity

The primary course of hypercalcemia treatment is to reduce calcium intake and consume large amounts of water. Exogenous VDHY neces­sitates discontinuation of VD supplementation [51]. The central man­agement strategies for CYP24A1 mutations include reducing sun exposure and eliminating VD prophylaxis [3]. For SLC34A1 mutations, phosphate supplementation is the initial therapeutic option; reducing VD consumption does not normalize test findings [4]. Patients with genetic defects that cause hypercalcemia, granulomatous diseases, and lymphomas are advised to avoid exposure to sunlight [52]. Glucocorti­coids help reduce calcium levels by reducing intestinal calcium ab­sorption, increasing calcium excretion in the urine, and encouraging the creation of inactive metabolites [52]. Glucocorticoids have no thera­peutic effect in individuals with genetic defects that cause hypercalce­mia [51]. Patients with CYP24A1 mutations may need to be treated with rifampicin and azoles to treat hypercalcemia. Azole-containing medi­cations are CYP27B1 inhibitors. Rifampicin is a tuberculosis medicine that increases the activity of the enzyme CYP3A4, which, in this case, effectively inactivates VD metabolites compared to CYP24A1. [51].

Prevalence of VD hypersensitivity

The prevalence of VD hypersensitivity remains unknown. A Polish population survey revealed biallelic variations in CYP24A1 and SLC34A1 are found in one in 32,465 births [58]. Severe VDHY is asso­ciated with biallelic mutations in the SLC34A1 or CYP24A1 genes [51]. The identification of heterozygous SLC34A1 and CYP24A1 mutations can be challenging. As a result, heterozygous mutations often remain undetected and are not detected until the VD substitution is used. In otherwise seemingly healthy neonates, CYP24A1 or SLC34A1 mutations are familial risk factors for the development of symptomatic hypercal­cemia, which may be exacerbated by VD prophylaxis. Biallelic abnor­malities in the CYP24A1 gene may be present in 4-20 % of patients with calcium kidney stones [84]. Sarcoidosis frequently results in VDHY due to the ectopic synthesis of active VD [60]. The frequency of sarcoidosis varies significantly by region, ranging from one to five per 100,000 in­dividuals in South Korea, Japan, and Taiwan to 140-160 per 100,000 individuals in Sweden and Canada [85]. Furthermore, the real-world prevalence of VDHY remains unknown [52]. According to two accu­rate but narrowly sampled studies, about 25 % of Finns have VDHY [48,49].
The prevalence of new CYP24A1 and SLC34A1 mutations, VD sup­plementation, and recently identified differences in genes regulating VD metabolism contribute to increased VDHY. The administration of VD3 at doses higher than those advised may increase the risk of VDHY [51-53].
Table 1 shows the main differences between VD resistance and VD hypersensitivity.

Discussion

The treatment of autoimmune diseases can be complicated. High­dose VD therapy may be used to treat VDRES effectively. However, the outcomes and potential negative repercussions must be carefully evaluated.
VD has been shown to help treat or prevent cardiovascular disorders, and VDD has been recognized as a risk factor for these conditions in multiple trials [86]. In contrast, in individuals with VDHY, VD supple­mentation increases the prevalence of kidney disease and vascular calcification, which are risk factors for cardiovascular diseases [87-90]. Therefore, determining the responsiveness of each patient to VD is essential before treating or preventing cardiovascular diseases using VD.
VDD is believed to increase the risks of pregnancy, and VD supple­mentation is commonly advised [91]. Nevertheless, in pregnancy, the amount of 1,25(OH)2D3 produced by the placenta increases [76]. Excessive VD production in the placenta, together with VD supple­mentation, may manifest as symptoms of VDHY, such as hypercalcemia and unfavorable pregnancy outcomes. The VD response can be evalu­ated using laboratory assays (parathyroid hormone, calcium, phosphate, 25(OH)D3, and 24,25(OH)2D3) performed at the beginning and end of pregnancy. An analysis of the connections between difficulties during pregnancy and VD responses is possible.
Intervention trials have not demonstrated the effectiveness of VD supplementation in treating extraskeletal VD-dependent disorders or a causal relationship between VDD and these diseases. The results of these studies were contradictory. Therefore, considering the VD response in this study may produce more accurate findings.
Given the rarity of inborn resistance or hypersensitivity, adminis­tering the recommended amount of VD in neonates is desirable. How­ever, if newborns’ growth and development are unsatisfactory, their response to VD needs to be considered.
Few studies concerning the responsiveness to VD have used small sample sizes. Based on these studies, the number of VD-sensitive and —resistant individuals in the population could reach up to 25 % in both groups. Therefore, studies with larger sample sizes are required to assess the importance of VD responsiveness in this population.
Closing words
VDD affects people worldwide. On the other hand, the risk of hy­percalcemia in individuals with VDHY caused by VD supplementation may increase as more people become aware of the health benefits of VD.


Study appears to ignore 2 genes, form of Vitamin D, VDR activators, and poor gut


See also VitaminDWiki

Response to Vitamin D - many studies
Comparing High-dose vitamin D therapies
High-dose Vitamin D is safe and effective – review of 10 studies – Sept 2021
Coimbra protocol using high-dose Vitamin D is safe – April 2022
Can reduce risk of hypercalcemia by:

  • Reducing Calcium
  • Increasing Water
  • Increasing Magnesium
  • Increasing Vitamin K2

Personalized treatment of Vitamin D
Table of Contents as of May 2024
23+ Personalization factors for Vitamin D treatment:
VitaminDWiki – Vitamin D: not one size, type, form, route for all - Jan 2022
VitaminDWiki – Increased Vitamin D response if take cofactors, etc
VitaminDWiki – Reasons for low response to vitamin D
VitaminDWiki – PTH and Vitamin D - many studies
VitaminDWiki – How you might double your response to vitamin D
Personalized dosing: 70 to 1 differences in doses for vitamin D treatment of Breast Cancer
VitaminDWiki – Forms of Vitamin D category has 108 items
The Power of Vitamin D: Is the Future in Precision Nutrition through Personalized Supplementation Plans? - April 2024
Factors to take into account when interpreting 25-hydroxy-vitamin D serum levels – March 2024
Perhaps 100X difference in BLOOD-Level responses to identical Vitamin D dosing
Perhaps a 500X difference in CELL-Level responses to identical Vitamin D dosing


2 additional Vitamin D genes are described in VitaminDWiki - Genetics

CYP3A4, Vitamin D Binding

in Visio for 2023


183+ VitaminDWiki pages with RESPONSE OR RESPONDER

This list is automatically updated NOT "vaccine OR virus OR vaccination OR COVID")

Items found: 185
Title Modified
1 year to respond to monthly Calcifediol – June 2024 20 Jun, 2024
50,000 IU Vitamin D once every 2 weeks – response was 34 ng – RCT April 2017 12 Jun, 2024
Some ICU patients got 540,000 IU of Vitamin D: good responders lived longer than controls or poor responders – RCT June 2024 07 Jun, 2024
Response to Vitamin D – 25% high, 24% low (ignores other than genes) – July 2024 02 Jun, 2024
Vitamin D response varies from resistance that increases through life to hypersensitivity – May 2024 09 May, 2024
Oral Vitamin D had a bigger response that injection in obese women - Jan 2024 02 Feb, 2024
People with Multiple Sclerosis have blunted responses to Vitamin D supplementation - Jan 2024 17 Jan, 2024
Vitamin D response: 800 IU: 20 ng, 3200 IU: 45 ng – RCT March 2012 06 Jan, 2024
Beans etc, can cut in half the response to fat-soluble Vitamin D and K - June 2019 01 Jan, 2024
Vitamin D response in post-menopausal women: weekly better than monthly, notice benefit in 3 months – Jan 2021 23 Dec, 2023
1.77 nmol response to 100 IU of Vitamin D (46 RCTs) – meta-analysis Sept 2023 16 Dec, 2023
Psoriasis and Eczema Respond Well to Vitamin D Treatment - Renu Oct 2023 16 Dec, 2023
Autistics have half of the response to Vitamin D – RCT Oct 2018 08 Nov, 2023
Vitamin D given daily, weekly, or monthly has similar response (116 RCTs) – meta-analysis Aug 2023 02 Oct, 2023
Response to Vitamin D fortification varies from 1 to 10 nmol per 100 IU daily – review Aug 2023 18 Sep, 2023
V-safe - 7% had emergency medical after vaccination - CDC response, cancel V-safe - Sept 2023 07 Sep, 2023
Smoking does not decrease response to monthly Vitamin D – RCT July 2020 03 Aug, 2023
Vitamin D response independent of dosing interval – meta-analysis July 2023 03 Aug, 2023
Gene variants can reduce Vitamin D response by 1.7X (14,000 IU daily, Multiple Sclerosis) – Dec 2021 15 Jul, 2023
Vitamin D which dissolves in mouth for those having poor response due to poor guts, HSCT etc.- June 2023 08 Jun, 2023
Response to infant 2,000 IU Vitamin D daily was in 194 ng, monthly dosing was 20% less – RCT May 2023 17 May, 2023
Fast responses to Vitamin D – loading dose, nanoemulsion and Calcifediol – April 2023 15 Apr, 2023
Response to Vitamin D - many studies 07 Apr, 2023
No response to vitamin D 7X more likely if poor CYP24A1 or VDBP genes - Feb 2023 11 Feb, 2023
Vitamin D non-responders may have one or more poor genes: GC, LIPC, CYP24A1, and PDE3B – Oct 2022 10 Feb, 2023
Poor CYP2R1 gene reduces blood response to Vitamin D supplementation – Aug 2019 10 Feb, 2023
CYP2R1 gene reduces response to Vitamin D - many studies 10 Feb, 2023
Co-factors increase Vitamin D response for the GRH cohort - Jan 2023 21 Jan, 2023
Antibody response to COVID vaccination appears independent of Vitamin D levels – Nov 2021 07 Dec, 2022
Vitamin D spray results in bigger response than drops – Jan 2021 07 Dec, 2022
The vitamins and minerals that help the immune system respond to respiratory viruses – Dec 2022 06 Dec, 2022
Colorectal Cancer – vitamin D did not help (too small of a response) – RCT Oct 2022 29 Oct, 2022
Responses to 3600 IU Vitamin D or Calcifediol – Oct 2022 05 Oct, 2022
No response to Vitamin D was 11 X more likely to have if poor Binding gene – Sept 2022 27 Sep, 2022
Australia’s COVID Response resulted in 31 X more life years lost than were saved - Sept 2022 26 Sep, 2022
Poor or no response to vitamin D was associated with poor genes (cystic fibrosis, 4 genes) Sept 2022 07 Sep, 2022
Better response 6 months after Pfizer vaccinations if higher vitamin D – Aug 2022 27 Aug, 2022
Vitamin D improves Sinovac vaccine (fast innate response) - July 2022 24 Aug, 2022
Better response to shingles virus after 6,400 IU Vitamin D raised above 40 ng – Jan 2021 20 Aug, 2022
Cancers are associated with low vitamin D, poor vaccination response and perhaps poor VDR – July 2022 15 Aug, 2022
Surgeries often deplete Vitamin D - 300,000 IU resulted in little response – Nov 2018 02 Aug, 2022
Multiple Sclerosis treated by Vitamin D (includes dose-response) - July 2022 11 Jul, 2022
Wheezing and asthmatic children have weaker Vitamin D responses - May 2022 19 May, 2022
Short-term response to 1,000 IU of Vitamin D tripled in obese when Magnesium was added – RCT April 2022 17 May, 2022
Response to 1,000 IU of vitamin D daily for 6 months – 40 percent above 30 ng (small study) – Feb 2022 26 Apr, 2022
COVID vaccination: 29 percent higher antibody response if more than 20 ng of vitamin D – March 2022 23 Mar, 2022
Response to Vitamin D varies with genes (3,000 IU, weight loss in this RCT) – March 2022 22 Mar, 2022
Responses by healthy individuals to 2,000 IU vitamin D daily – Feb 2022 03 Feb, 2022
COVID, influenza, hepatitis B, measles, etc. vaccine responses vary with Vitamin D and its receptor 08 Dec, 2021
On-line Vitamin D response simulation – July 2021 24 Oct, 2021
Stoss (loading) dose of vitamin D resulted in bigger response at 30 days (again) – RCT April 2021 14 Oct, 2021
Reasons for low response to vitamin D 22 Sep, 2021
Vitamin D injections should not be used if fast response is needed (COVID-19 in this case) 02 Sep, 2021
Vitamin D, C, A, and E, as well as Iron, Se, and Zinc each augment vaccine response – July 2021 20 Jul, 2021
Poor response to Asthma inhaler if poor Vitamin D Receptor – Dec 2019 01 Jul, 2021
Parathyroid response to Vitamin D among obese 27 Jun, 2021
Based on PTH response, obese adolescents may not need and much vitamin D as non-obese (12 ng vs 16.5 ng) – June 2021 12 Jun, 2021
Poor response to vitamin D supplementation if poor level of B Vitamins (rats in this case) March 2021 22 May, 2021
Cytomegalovirus downregulates Vitamin D receptor, but tissues respond by increasing production – Sept 2016 19 May, 2021
Overweight elderly respond well to 3600 IU Vitamin D daily for a year – RCT May 2021 07 May, 2021
Vaccine response improved by Vitamin D (Shingles in this case) – Jan 2021 06 May, 2021
Hemodialysis associated with very poor mRNA response (wonder if low vitamin D) – March 26, 2021 31 Mar, 2021
Response to vitamin D increased 30 percent with Magnesium - Nov 2018 07 Mar, 2021
Poor protein binding gene associated with poor Vitamin D response – RCT Nov 2019 02 Mar, 2021
Boron improves magnesium absorption and may help vitamin D non-responders – Aug 2015 25 Feb, 2021
Response to weekly Calcifediol in 4 months - RCT Aug 2022 03 Feb, 2021
Weekly response to semi-activated vitamin D slightly better than standard – RCT Nov 2019 21 Jan, 2021
Obese children had 2.2 X less response to a single dose of Vitamin D – Oct 2020 14 Oct, 2020
Response to 150,000 IU vitamin D once vs 5,000 IU daily – RCT May 2014 10 Jul, 2020
Those with Asthma or COPD had half the response to Vitamin D – March 2020 19 Mar, 2020
Response to Vitamin D increased if take Magnesium and Vitamin K2 – Grassroots March 2020 10 Mar, 2020
Response by obese to weekly 50,000 IU of Vitamin D – May 2018 12 Feb, 2020
Less response to 800 IU of Vitamin D by Africans than natives in Finland – RCT March 2018 25 Dec, 2019
Increased Vitamin D response if take cofactors, etc 05 Nov, 2019
UV helped EAE mice (MS) designed to not respond to Vitamin D – Oct 2019 23 Oct, 2019
Sublingual vitamin D gave similar response as oral for most, and better for some – RCT Sept 2019 17 Oct, 2019
Poor ovarian response (poor IVF) associated with low vitamin D – Sept 2019 28 Sep, 2019
Obese responded to weekly vitamin D better than non-obese – RCT March 2018 22 Aug, 2019
Poor responses to UV and Vitamin D were correlated to just 4 poor genes – June 2019 19 Jul, 2019
Response to Vitamin D varied by 12 ng due to gene variants (CYP2R1) – Aug 2019 15 Jun, 2019
Single dose of Vitamin D as gummies resulted in higher blood response than hard tablets – May 2019 07 May, 2019
Sepsis reduced the Omega-3 response and half life – April 2019 14 Apr, 2019
Poor Vitamin D response 4X more likely if poor Vitamin D binding proteins - July 2019 09 Apr, 2019
25 minutes of daily sun provided less than half of the response as 500 IU of vitamin D (Korea) – RCT March 2019 26 Mar, 2019
Response to UV varies more with pigment genes and age than skin color – Jan 2019 24 Mar, 2019
Response to UV varies more with pigment genes and age than skin color – Feb 2019 24 Mar, 2019
Vitamin D Nutrigenomics - High, Medium, and Low Responders - March 2019 22 Mar, 2019
Decreased response to vitamin D in white children having poor Vitamin D binding gene – Feb 2019 20 Mar, 2019
Monthly Vitamin D had a 20 percent better response than quarterly – small RCT April 2019 06 Mar, 2019
Vitamin D response time is 3-6 months, not much benefit in first 4 months – RCT July 2017 17 Feb, 2019
Poor Vitamin D binding had 30 percent less response to Vitamin D (50,000 IU weekly) – Feb 2019 04 Feb, 2019
Fat loss, etc. if respond well to 3 years of Vitamin K2 (MK-7, 180 ug) – RCT Jan 2018 09 Jan, 2019
Respond to daily Vitamin D in 2-12 months 07 Jan, 2019
7 ng less response by Multiple Sclerosis patients to 5,000 IU of vitamin D – Aug 2015 30 Dec, 2018
2 month response time to Vitamin D (Grassroots Health) 08 Dec, 2018
Response to Vitamin D varies with Vitamin D Binding Protein gene – RCT May 2018 06 Jun, 2018
Poor response to Osteoporosis medicine (risedronate) if vitamin D less than 16 ng – May 2018 09 May, 2018
No genetic response to 4,000 IU of Vitamin D (other studies disagree) – RCT April 2018 15 Apr, 2018
Vitamin D – individual responses to 100,000 IU – March 2017 11 Feb, 2018
Monthly vitamin D dosing had higher response than 3 per month – RCT Jan 2018 28 Jan, 2018
Multiple Sclerosis patients need more vitamin D to get same blood level response – Aug 2015 27 Jan, 2018
Vitamin D injection helped migrants a bit, but some had poor or even negative responses – Dec 2017 19 Jan, 2018
Vitamin D injection of 300,000 IU helped a bit, but many had a very small response – Dec 2017 19 Jan, 2018
Vitamin D injection of 600,000 IU (response by 10 individuals)– Sept 2017 29 Dec, 2017
10 reasons for poor response to Vitamin D (race, binding protein, etc.) – Nov 2017 24 Dec, 2017
Inflammation and immune responses to Vitamin D (perhaps need to measure active vitamin D) – July 2017 22 Nov, 2017
Low response to vitamin D for some people – genes are one of the causes – Nov 2014 22 Nov, 2017
Response to a large dose of vitamin D (80,000 IU) typically varied by 2 X – June 2016 14 Nov, 2017
Monsanto banned from EU parliament (they refused to respond to Glosophate safety questions) – Oct 2017 10 Oct, 2017
Estrogen contraception pill doubled the response to 1,000 IU of vitamin D – RCT Sept 2017 04 Sep, 2017
Immune response was poor in mice and humans with low vitamin D and low vitamin A – May 2015 17 Aug, 2017
Vitamin D daily or weekly dosing resulted in similar response -RCT Jan 2016 20 Jul, 2017
Huge variation in response to vitamin D supplementation – personal vitamin D response index – Dec 2016 27 Jun, 2017
Vitamin D responses to as much as 15,000 IU per day – Feb 2017 20 Jun, 2017
Spray and oral forms of 3000 IU vitamin D provide similar long-term response – RCT Oct 2016 20 May, 2017
Overview Vitamin D Dose-Response 19 Apr, 2017
UVB 50 percent more response in obese than normal weight (other study disagrees) – Feb 2017 02 Mar, 2017
UVB 50 percent more response in obese than normal weight (yet response to Vitamin D is 50 percent less) – Feb 2017 28 Feb, 2017
Critically ill injected with 300,000 IU of vitamin D, 3X more likely to die if PTH did not respond - RCT July 2015 22 Jan, 2017
Vitamin D injection lasts longer and has bigger response than weekly oral – Jan 2017 24 Dec, 2016
Graph of weekly response to monthly vitamin D supplementation – Aug 2015 17 Sep, 2016
RF from mobile phones reduced immune response in rats, unless they had vitamin D – Sept 2016 10 Sep, 2016
Burn patients have little vitamin D and uncertain response to supplementation – Dec 2014 04 Sep, 2016
Response to Vitamin D - Grassroots 01 Sep, 2016
Response to Vitamin D: summary chart of 8 studies – March 2013 01 Sep, 2016
Large variability in response to UV (more than response to oral Vitamin D) – March 2016 22 Jun, 2016
Large variability in response to UVB (similar to that of oral Vitamin D) – March 2016 22 Jun, 2016
Large variability in response of people to UVB (similar to that to oral Vitamin D) – March 2016 22 Jun, 2016
Dengue fever immune response and micronutrients (vitamins D, E, A, and Zinc, Iron, Chromium) – Nov 2015 11 Jun, 2016
Immune response to respiratory viruses – vitamin D connection – review May 2015 17 May, 2016
3X variation in response to dose of vitamin D – meta-analysis June 2012 24 Apr, 2016
PTH boosts immune response when vitamin D levels are low – May 2012 29 Mar, 2016
CYP2R1 and GC variations decrease vitamin D response – PHD thesis Nov 2015 18 Feb, 2016
Pigs have about 2X less variation in response to calcidiol as humans do to vitamin D – 2015 07 Dec, 2015
Vitamin D response reduced if taken with Calcium – meta-analysis Oct 2015 01 Dec, 2015
Response to Vitamin D supplementation – July 2015 25 Nov, 2015
How you might double your response to vitamin D 31 Oct, 2015
600,000 vitamin D loading doses – good response to both oral and muscular – Oct 2015 13 Oct, 2015
Different response by Vitamin D Receptor to Vitamin D vs Vit. D analogs – Sept 2015 24 Sep, 2015
If at high risk of vitamin D deficiency, get a higher response if take more Magnesium – Sept 2013 12 Sep, 2015
Response to 1000 IU of vitamin D varies by about 4 percent due to gene variants – RCT July 2014 09 Aug, 2015
More muscle response when have adequate vitamin D 27 Jul, 2015
Familial Mediterranean fever – poor response to colchicine if low vitamin D – June 2015 13 Jun, 2015
CYP2R1 gene probably responsible for low vitamin D response – RCT April 2014 02 Jun, 2015
Better response to Inflammatory Bowel Disease drug if more than 30 ng of vitamin D – March 2014 18 Apr, 2015
Anorexia nervosa patients have low vitamin D levels, but respond well to supplementation – Meta-analysis Nov 2014 15 Apr, 2015
Vitamin D-binding protein controls T cell responses to vitamin D in the lab – Sept 2014 01 Apr, 2015
Low dose Vitamin D during pregnancy and infancy results in strange acute respiratory infection response – April 2015 24 Mar, 2015
Obese need 2X as much vitamin D to get the same response – June 2012 14 Mar, 2015
Is too much vitamin D bad (U-shaped response) – possible causes and cures 10 Mar, 2015
Response and adverse effects of 20,000 and 30,000 IU Vitamin D weekly - Feb 2015 09 Mar, 2015
24 ng lower response to Vitamin D due to obesity, low initial Vitamin D, and genetics – RCT Feb 2015 24 Feb, 2015
Genes are one of the reasons for low response to vitamin D – Nov 2014 24 Feb, 2015
Some people need more vitamin D to get the same response – perhaps due to genes – Nov 2014 24 Feb, 2015
Activation (methylation) of CYP2R1 and CYP24A1 predict response to dose of vitamin D – Oct 2013 24 Feb, 2015
89 percent of respondents were aware that vitamin D had health benefits – Jan 2014 23 Jan, 2015
Transdermal Magnesium Chloride spray - variable responses, removed toxic metals - 2010 21 Jan, 2015
Solutions if have poor response to conventional vitamin D 14 Dec, 2014
Immune System response of infants is associated with higher levels of vitamin D – RCT Nov 2014 08 Nov, 2014
How to predict response to a vitamin D dose – RCT April 2014 06 Nov, 2014
Not as much dark skin vitamin D response from single UV dose (no surprise) – Oct 2013 13 Aug, 2014
Dose response equations for Vitamin D 02 Aug, 2014
Response to vitamin D dose, overview of 25 studies - Feb 2014 02 Aug, 2014
Similar response to Vitamin D supplements by senior white and black women – Feb 2013 08 May, 2014
U-shaped response to vitamin D – possible causes 24 Apr, 2014
Response to high dose vitamin D is limited by vitamin A - July 2013 13 Apr, 2014
Hearts responded to stress better after 5,000 IU of vitamin D for a month - March 2014 11 Mar, 2014
Hypothesis: Low vitamin D is responsible for many recent increases in health problems 01 Jan, 2014
Hypothesis: Magnesium accounts for some of the variation in vitamin D response – Oct 2013 16 Nov, 2013
40 percent less likely to get adequate vitamin D response if have certain genes – Jan 2013 10 Sep, 2013
Increased D levels responsible for Dead Sea therapy – May 2011 16 Aug, 2013
Response to vitamin D related to DBP and CYP2RI genes – Aug 2013 10 Aug, 2013
Response to Vitamin D3 varied with rs4588, D2 less response than D3 and did not change – April 2013 13 Jul, 2013
Higher BMI decreased response to 700 IU vitamin D – RCT 2008 26 Feb, 2013
Difference in Fok gene reduced response to vitamin D by 35 percent – Nov 2012 17 Nov, 2012
Response by Masterjohn on vitamin A thwarting vitamin D – Mar 2010 26 Oct, 2012
Is Vitamin D Supplementation Responsible for the Allergy Pandemic – May 2012 27 Jun, 2012
Metabolites and genes may predict responses to Calcium and Vitamin D – Jan 2011 24 Jun, 2012
40 ng response plateau to 2000 to 4,000 IU of vitamin D – June 2012 19 Jun, 2012
More response to 1100 IU vitamin D in cold season or less BMI – May 2012 15 May, 2012
IOM finally responds to Endocrine Society on Vitamin levels – March 2012. 25 Mar, 2012
Miss Ohio Teen USA on responsible tanning 29 Sep, 2010
Genetics Determines Vitamin D Response 19 Aug, 2010
Hormesis: response to dose may not be linear 16 Jun, 2010
Would be nice to capture and share vitamin D dose /response / benefit information 24 May, 2010




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