Amidst the COVID pandemic, there has been a revival of the "Vitamin D hype", following previous Vitamin C, Resveratrol and Vitamin B hypes. First, let me say that no nutrition hype will prove to be effective to curb the pandemic. Expectations should not be elevated to unrealistic heights: no dietary nor supplementary intake of any nutrient will prevent diseases from occurring. Too many factors are involved, there is no such "one-size-fits-all"-solution as simple as "this supplement is a prodigy drug". It is not a complete novelty: the Hope-Simpson doctrine, established in 1981, reads that a seasonal stimulus related to UV-radiation is explanatory for the occurrence of seasonal epidemics (Epidemic influenza and vitamin D, Epidemiology & Infection 2006 Sep, 134).
Nevertheless, dietary habits are relevant with regards to inflammation and immunity-related diseases. Vitamin D is a notable regulator of immunomodulation and, as such, has been associated with modulation of inflammatory pathways in systemic and infectious diseases. Other well-documented immunomodulatory nutrients are zinc, selenium and vitamin A. In this message, I will discuss the immunomodulatory mechanisms of Vitamin D as well as presumed cardioprotective and antithrombotic properties of Vitamin D. Note that the modulatory effect on the Renin-Angiotensin Aldosterone System-Kallikrein System (RAS/KKS) remains controversial for the lack of human in vivo studies addressing questions of causality. One should always be cautious with regards to "promiscious" papers that do not actually address causality questions!
Another main topic is the bioavailability as well as the bioaccessibility of nutritients. It is inaccurate to say that nutrition is a minor topic according to scientists and medical professionals. To discriminate between natural sources and synthetic sources (pharmacological compound) makes no sense, as either compound exerts its molecular properties. What does actually make a difference, is that every nutrient has to meet the threshold of bioavailability and bioaccessibility: the nutrient must be able to be absorbed and remain available for use or storage. To date, no formula exists to ascertain the availability and accessibility of Vitamin D and other nutrients upon being transferred into the human digestive tract and blood serum.
1. Vitamin D;
1.1. Vitamin D metabolism;
1.2. The immune landscape of Vitamin D: innate and adaptive immunity;
2. Relationship between Vitamin D, the cardiovascular system and (deep venous) thrombosis;
2.1. Association of low serum 25-Hydroxyvitamin D with Venous Thrombosis and Embolism;
2.2. Low Vitamin D at presentation of ischemic stroke is associated with
elevated risk of Venous Thromboembolism and neurological deterioration;
2.3. Platelet aggregation disorders and anti-platelet aggregation properties of VitD;
2.4. Genetic indications for anticoagulatory properties of Vitamin D;
2.5. Endothelial function and antioxidative properties of Vitamin D;
2.6 A role for vitamin K2 (menaquinone);
3. Autoimmune diseases and Vitamin D deficiency;
3.1. Antiphospholipid (Antibody) Syndrome, thrombosis and Vitamin D;
4. The RAS and ROCK hypothesis;
5. Inhibitory and immunomodulatory properties of Vitamin D metabolites
1. Vitamin D
1.1 Vitamin D metabolism
Vitamin D is a noun for a group of steroid hormone compounds. Vitamin D is a lipophilic (fat-soluble) steroid. Vitamin D2 (ergocalciferol) is formed after ultraviolet-B (UVB) irradiation of plant ergosterol and Vitamin D3 (cholecalciferol) is generated in the skin from interaction of 7-dehydrocholesterol with UV radiation. Calcitriol (1,25-dihydroxycholecalciferol or 1,25(OH)2D3 (= 1,25 dihydroxyvitamin D3)) is the active form of Vitamin D following 25-hydroxyvitamin D3 (25(OH)D3) conversion in the kidneys and liver. While D2, ergocalciferol is mostly found in supplements, D3, cholecalciferol is regarded the most potential pharmacological agent (PubChem: Cholecalciferol compound summary).
1.2 The immune landscape of Vitamin D: innate and adaptive immunity
While the endocrine sites for calcitriol are the tubule cells of the kidneys, the paracrine and autocrine sites are macrophages, monocytes and dendrites of the innate immune system. The Vitamin D Receptor (VDR) regulates inflammatory genes such as CD14 and cathelicidin anti-microbial peptide (CAMP). Vitamin D is a key regulator of maturation, differentiation and stimulatory capacity of dendrites, derived from monocytes. Vitamin D antagonizes pro-inflammatory activity of Nuclear Factor activated T cells (NF-AT) and NF-kB in T cells (Vitamin D Signaling in the Context of Innate Immunity: Focus on Human Monocytes, Frontiers in Immunology 2019; 10: 2211). Humans with a genetic modification of the Vitamin D receptor, the C genotype (ACG instead of ATG) in which the VDR allele is shortened, show higher expression of NF-kB, NFAT and a higher IL-2 expression in dendrites and monocytes, thus a different immune profile (Vitamin D: Effect on Haematopoiesis and Immune System and Clinical Applications, International Journal of Molecular Sciences 2018 Sep; 19(9): 2663).
A 2013 study, focused on inflammation during pregnancy, offers some points as to how Vitamin D is involved in the regulation of innate immunity. Following stimulation of human myometrial cells with Lipopolysaccharides (LPS) and administration of 100nmol/L Vitamin D3, Vitamin D was shown to downregulate inflammatory cytokines IL-2, IL-9, IL-13 and TNF-α, chemokines MCP-1, CXCL-10 and CXCL-11, IL-1β, connexin 43, COX-2, Toll-like Receptor-4 and -5 (TLR-4 and TLR-5, see Toll-Like Receptors in Antiviral Innate Immunity, Journal of Molecular Biology 2014 Mar 20; 426(6): 1246-1264) and the prostaglandin receptor. Vitamin D3 increased anti-inflammatory IL-10 and upregulated anti-inflammatory activity through TLR-10 (Vitamin D Elicits Anti-Inflammatory Response, Inhibits Contractile-Associated Proteins and Modulates Toll-like Receptors in Human Myometrial Cells, Reproductive Sciences 2013 Apr;20(4): 463-475).
While correlation does not address causality questions, serum TNF-α concentrations were found to be negatively correlated with serum 25(OH)D concentrations in healthy females, indicating that Vitamin D decreases the highly inflammatory TNF-α (Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women, Journal of Inflammation 2008;5:10). Vitamin D is intrinsically linked to autophagy: TLR-8 activation in macrophages induces the expression of CAMP and the Vitamin D receptor, while TLR-8 agonists inhibit HIV through Vitamin D and CAMP autophagy (Toll-Like Receptor 8 Ligands Activate a Vitamin D Mediated Autophagic Response that Inhibits Human Immunodeficiency Virus Type 1, PLoS Pathogens 2012;8).
The innate immunity is a first line host defence against pathogens, comprising vascular endothelial cells, enzymes expressed by epithelial cells and phagocytes, cathelicidins (CAMP), complement factors, Toll-Like Receptor, mast cells, macrophages, dendrites, neutrophils and Natural Killer Cells. Interaction of TLR2/1 with Vitamin D 25(OH)2D3 stimulates expression of cathelecidin. 25(OH)2D3 upregulates CAMP and defensing β2. Vitamin 1,25(OH)2D3 modulates the physical epithelial barrier. Vitamin D decreases permeability of the intestines and cornea, thus protecting tissue integrity against migration of inflammatory cytokines. The adaptive immunity consists of T and B cells, constituting immunological memory (recognition of pathogens and adjusting an adequate response).
With regards to the adaptive immune system, the role of Vitamin D in suppressing Th1, Th17, subsequent blocking of Nuclear Factor Activated T Cells (NFAT) and induction of FOXP3 and Treg cells cannot consecutively proved by in vivo studies (Vitamin D: Nutrient, Hormone and Immunomodulator, Nutrients 2018 Nov; 10(11): 1656). An explanation might be that in vitro studies and animal profiles differ greatly from human in vivo Vitamin D interaction with T cells, Tregs (T regulators) and T-helper cells.
2. Relationship between Vitamin D, the cardiovascular system and (deep venous) thrombosis
2.1 Association of low serum 25-Hydroxyvitamin D with Venous Thrombosis and Embolism
Vitamin D is speculated to have anticoagulant properties. Due to inconsecutive research papers, conclusions upon the role of Vitamin D in preventing thrombotic events cannot be drawn. One main objective is that the role of Vitamin D suppletion has been focused on markers of coagulation instead of causative factors. One study found that a low 25(OH)D level was not a risk for Venous Thromboembolism (VTE), while reviews suggest that a low 25(OH)D level might modestly increase VTE risk in white people (Serum 25(OH)D and risk of Venous Thromboembolism: The Atherosclerosis Risk in Communities (ARIC) Study, Journal of Thrombosis and Haemostasis Vol. 12, Issue 9, September 2014). A cohort study involving 18791 participants proves a correlation (not causality!) between decreasing levels of 25(OH)D and incidence of Venous Thromboembolism (25-Hydroxyvitamin D concentrations and risk of venous thromboembolism in the general population with 18791 participants, Journal of Thrombosis and Haemostasis Vol. 11, Issue 3, March 2013).
While one study found that normal serum levels of 25(OH)D were not associated with future risk of Venous Thromboembolism (VTE), a major limitation of said study is that subjects with Vitamin D deficiency were not included (Serum levels of Vitamin D are not associated with the future risk of venous thromboembolism. The Tromso Study, Thrombosis and Haemostasis 2013 May;109(5)). On the other hand, a large cohort study and meta-analysis of 18 studies, comprising 29 years of clinical follow-ups, observed increasing risk of ischemic heart disease, myocardial infarction and early death with decreasing plasma 25-hydroxyvitamin D levels. The probable mechanisms of Vit D deficiency increasing the risk of ischemic heart disease and infarction are elevated parathyroid hormone release levels, inflammation, thrombogenicity, dyslipidemia and progression of Extracellular Matrix Remodeling as well as increased renin gene transcription, subsequent hypertension, atherosclerosis and ischaemia (25-Hydroxyvitamin D Levels and Risk of Ischemic Heart Disease, Myocardial Infarction and Early Death, Arteriosclerosis, Thrombosis and Vascular Biology Vol. 31, Issue 11, November 2012).
Anti-thrombotic actions carried out by vitamin D are reported to be a strengthening of the anticoagulant effect of warfarin following 3 months of vitamin D supplementation as compared to the placebo group. In another study, cholecalciferol supplementation resulted in reduced levels of E-selectin, VCAM and ICAM-1, indicating improvement of endothelial function. While inactive, cholecalciferol might contribute to endothelial stabilization through vitamin D-receptor (VDR) indepedent mechanisms (Emerging
Role of Vitamin D and its Associated Molecules in Pathways Related to
Pathogenesis of Thrombosis, Biomolecules 2019 Nov;9(11):649)
2.2 Low Vitamin D at presentation of ischemic stroke is associated with elevated risk of Venous Thromboembolism and neurological deterioration
Likewise, a 2018 report found associations between low serum Vitamin D levels and the development of Venous Thromboembolism (VTE) in patients presenting with ischemic stroke during an inpatient rehabilitation stay (Low Vitamin D Levels Are Associated With the Development of Deep Venous Thromboembolic Events in Patients with Ischemic Stroke, Clinical and Applied Thrombosis/Hemostasis 2018 Dec;24(9 Supplement)).
It is hypothesized that decreasing serum 25(OH)D is associated with Early Neurological Deterioration (END) following acute ischemic stroke (Decreasing serum 25-hydroxyvitamin D levels and risk of early neurological deterioration in patients with ischemic stroke, Brain and Behavior Vol. 9, Issue 3, March 2019).
2.3 Platelet aggregation disorders and anti-platelet aggregation properties of VitD
Notably, platelet aggregation disorders, loss of vascular wall integrity (endothelial dysfunction) and low Vitamin D serum concentration are associated with the Vascular Wall-type Ehlers-Danlos Syndrome (Vascular type Ehlers-Danlos syndrome is associated with platelet dysfunction and low Vitamin D serum concentration, Orphanet Journal of Rare Diseases 2016; 11: 111).
Note that there is a distinction between clots in thrombus formation as well as the location of thrombus formation (underlying thrombosis): thrombi can consist of "white clots" (= platelet-rich clots, which are found in arteries) or "red clots" (= red blood cells and fibrin accumulation, found in veins) (Thrombosis and platelets: an update, European Heart Journal Vol. 38, Issue 11, 14 March 2017). This, however, does not mean that venous and arterial thrombosis are entirely distinct.
The presence of Vitamin D Receptors (VDR) on platelets has been discovered only recently. Mean platelet volume (MPV) and platelet distribution width (PDW) are reportedly elevated and increased in vitamin D deficient and insufficient patients with stable coronary artery disease (Mean platelet volume is associated with serum 25-hydroxyvitamin D concentrations in patients with stable coronary artery disease, Heart and Vessels 2018; 33(11): 1275-1281). In 2020, it has been confirmed that platelet aggregation amounting to an increased risk of cardiovascular events is associated with vitamin D deficiency. Platelet activation and megakaryocytopoiesis are calcium-dependent mechanisms modulated by VDR. Of relevance is the finding that uric acid and estrogens are associated with platelet activation and reactivity (Hydroxyvitamin D Serum Levels are Negatively Associated with Platelet Number in a Cohort of Subjects Affected by Overweight and Obesity, Nutrients 2020 Feb; 12(2): 474).
In 2017, a cohort study found that calcitriol, a vitamin D analogue, diminished platelet aggregation in Diabetes Mellitus type 2 patients. Glycemic control was inversely associated with high platelet aggregation and low vitamin D25 levels. This effect of calcitriol was hypothesized to be of benefit to treat vascular complications related to diabetes (Vitamin D diminishes the high platelet aggregation of type 2 diabetes mellitus patients, Platelets Journal Vol. 30, Issue 1, 2019).
2.4 Genetic indications for anticoagulatory properties of Vitamin D
Tissue Factor (TF) and Thrombomodulin (TM) are contributors to thrombosis. Tissue Factor Pathway Inhibitor (TFPI) and antithrombin (AT) are antithrombotic factors. While human in vivo studies addressing causality questions on the role of vitamin D on thrombosis are lacking, there is biological evidence suggesting a thrombomodulatory role of vitamin D (Emerging Role of Vitamin D and its Associated Molecules in Pathways Related to Pathogenesis of Thrombosis, Biomolecules 2019 Nov;9(11):649). The regulation of the Antithrombin (AT) gene by vitamin D is documented (Identification of Regulatory Mutations in SERPINC Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency, PLoS One 2016; 11(3)). Mutations affecting the vitamin D response are associated with a higher risk of thrombotic activity.
2.5 Endothelial function and antioxidative properties of Vitamin D
Like polyphenols, quercetin, kaempferol, flavonoids and other nutrients that will be discussed in the following features, vitamin D exerts antioxidative mechanisms to protect the integrity of endothelial cells. Vitamin D increases the vasodilator Nitric Oxide (NO) and decreases Reactive Oxygen Species(ROS)/Oxidative Stress. NO is required to maintain integrity of endothelial cells. Calcitriol Vitamin D analogues inhibit the expression of highly inflammatory IL-6 and IL-8, as well as adhesion molecules ICAM-1, PECAM-1 (Platelet-endothelial cell adhesion molecule), E-selectin and VCAM-1 (Vascular cell adhesion molecule). In addition, vitamin D reduces prostaglandin by repressing COX-2 (cyclo-oxygenase-2) (The Role of Toll-Like Receptors and Vitamin D in Cardiovascular Diseases- A Review, International Journal of Molecular Sciences 2017 Nov;18(11): 2252).
2.6 A role for vitamin K2 (menaquinone)
The role of vitamin K2 in preventing cardiovascular diseases, as well as the interplay of vitamin K2 with vitamin D needs further investigation. Animal studies proved that K2 suppresses the expression of Toll-like receptors TLR-2 and TLR-4 and inhibits calcification of the aorta and smooth muscle cells. In vitro menaquinone treatment of human macrophages and stimulation with TLR-agonists resulted in reduction of inflammatory cytokine production (The
Role of Toll-Like Receptors and Vitamin D in Cardiovascular Diseases- A
Review, International Journal of Molecular Sciences 2017 Nov;18(11):
2252). Furtermore, vitamin K2 in the form of MK-7 regulates osteoporosis, atherosclerosis, cancer and cardiovascular diseases without risk of overdosing. MK-7 modulates expression of TNF-α, IL-1α and IL-1β. Both K1 and K2 are involved in maintaining healthy hemostasis and coagulation (coagulants Factor II, VII, IX, X and anticoagulants protein C, protein S and protein Z). Vitamin K-hydroquinone (KH2) exerts anti-oxidative activity.
Vitamin K1 is found in cabbage, Brussel sprouts, green grapes, kiwi fruit and avocado; K2 is found in fermented soy beans, cheese, chicken meat, pork and salmon. The highest levels of K1 are found in leaf vegetables, while K2 is highest in fermented soy. Moderate levels of K1 are found in green asparagus, sprouts and cabbage, while moderate K2 is found in cheese, chicken, beef and zuurkool (Vitamin K: Double Bonds beyond Coagulation, Insights into Differences between K1 and K2 in Health and Disease, International Journal of Molecular Sciences 2019 Feb;20(4): 896).
3. (Auto)immune diseases and Vitamin D deficiency
3.1 Antiphosholipid (Antibody) Syndrome, thrombosis and vitamin D
Antiphospholipid Syndrome (APS) is an autoimmune disorder, characterized by thrombosis and the presence of antiphospholipid antibodies (APS, in: The Autoimmune Diseases, Fifth Edition, 2014). Catastrophic ADS is known as a manifestation of Disseminated Thrombosis in large and small vessels, resulting in Multiple Organ Failure (MOF) (L.R. Wolgast MD, "Antiphospholipid Syndrome", in: Transfusion Medicine and Hemostasis, Third Edition 2019).
A retrospective cohort study reports a significant frequency of vitamin D deficiency among patients with APS (Vitamin D and antiphospholipid syndrome: A retrospective cohort study and meta-analysis, Seminars in Arthritis and Rheumatism Vol. 47, Issue 6, June 2018, P877-882). With regards to lupus, patients were shown to have a higher prevalence of vitamin D deficiency even without classic risk factors (The anti-thrombotic effects of vitamin D and their possible relationship with antiphospholipid syndrome, Lupus Vol. 27, Issue 14, 2018). In vitro studies show the inhibition of Tissue Factor (TF) expression induced by anti-β2GPI-(antiphospholipid) antibodies (Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression, Annals of the Rheumatic Diseases Vol 70, Issue 1, 2011).
A 2009 study reports suppression of antirenal autoimmunity through inhibitory effects of calcitriol (vitamin D) on the Th17 effector response. Calcitriol inhibits the priming of Th17 cells by splenic dendritic cells in vivo, the ability of CD4+ T cells to commit to Th17 activity and the ability of Th17 to produce IL-17 (Calcitriol Suppresses Antirenal Autoimmunity through inhibitory effects on the Th17 effector response, Journal of Immunology 2009 Apr 15; 182(8): 4624-4632). IL-17 and IL-23 play an important role in some autoimmune diseases (Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category, Journal of Experimental Medicine 2008 Apr. 14;205(4): 799-810). A low vitamin D level, elevated markers of Th1 response, increased levels of C-reactive protein (CRP), elevated sCD14, Interferon-γ (IFNγ) are associated with Immune Reconstitution Inflammatory Syndrome (IRIS) (Vitamin D, d-dimer, Interferon γ and sCD14 levels are independently associated with Immune Reconstitution Inflammatory Syndrome: A prospective, International Study, EBioMedicine 2016 Feb; 4: 115-123). Low 25 Hydroxyvitamin D levels are also independently associated with autoimmune inlammation of the thyroid gland in healthy obese people (Low 25 Hydroxyvitamin D Levels are Independently Associated with Autoimmune Thyroiditis in a Cohort of Apparently healthy Overweight and Obese Subjects, Endocrine, metabolic and immune disorders drug targets 2018; 18(6):646-652).
4. The RAS and ROCK hypothesis *Renin-Angiotensin Aldosterone (RAS/RAAS)
To date, no human in vivo trial has shown the actual role of vitamin D on regulation of the Renin-Angiotensin-Aldosterone System. In vitro, calcitriol has been shown to impair the effect of Lipopolysaccharides (LPS) on the expression of ACE and ACE2. LPS is a proinflammatory molecule attached to the outer membrane of pathogens, known for its induction of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) through damage of endothelial pulmonary microvascular cells. Its actions increasing the permeability of the capillary membrane result in edema and hypoxia. LPS proved to induce ACE expression and to suppress ACE2, in order to induce ALI. The AT1R receptor induces ACE expression, while Ang II regulates the ACE/AT1R Receptor axis. Renin induces conversion of Ang I and Ang II, contributing to Lung Injury.
Vitamin D inhibits renin, ACE and Ang II and induces ACE2 in LPS-induced Lung Injury. While Ang II promotes ALI, Ang 1-7 decreases severity of ALI and inflammation. ACE2 is known to convert Ang II to Ang 1-7. The protective properties of vitamin D might be the induction of Ang 1-7 and ACE2, inhibition of renin and the ACE/Ang II/AT1R axis (Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin-angiotensin system, Molecular Medicine Reports Vol. 16, Issue 5, November 2017). Thus: the ACE2/Ang 1-7-axis has vasodilatory and anti-inflammatory effects, while the ACE/Ang II axis is vasoconstricting and pro-inflammatory, of which the latter contributes to Acute Lung Injury and hyperinflammatory states.
In addition to the ACE/Ang II axis, the RhoA/Rho Kinase (ROCK) pathway is vasoconstrictive, pro-inflammatory and pro-oxidative. A remarkable report reads that of 100 patients with Bartter's and Gitelman's tubulopathies, living in a COVID-19 hotspot, none was infected with SARS-CoV-2 (Rho kinase inhibitors for SARS-CoV-2 induced acute respiratory distress syndrome: Support from Bartter's and Gitelman's syndrome patients, Pharmacological Research 2020 Aug; 158: 104903). Barrter's and Gitelman's patients have increased levels of ACE2 and Ang 1-7 and reduced ROCK activity. In addition to Angiotensin Receptor (AT1R/AT2R) blockers and/or ROCK inhibitors, vitamin D supplementation might be of benefit (Letter: ACE2, Rho kinase inhibitors and the potential role of Vitamin D against COVID-19, Alimentary Pharmacology & Therapeutics 2020 Aug; 52(3):577-578).
A randomized trial found no benefit of correcting vitamin D (25(OH)D) deficiency in obese without hypertension. Neither RAS activity nor blood pressure was corrected by the increase of serum vitamin D 25(OH)D. Participants were given ergocalciferol, the least potent vitamin D analogue. The conclusion of this placebo-control trial is that vitamin D is not a modifiable factor in RAS activity. However, participants were not hypertensive nor severly vitamin D deficient and levels of bioactive vitamin D were not measured, leaving open the possibility that participants were not actually vitamin D deficient (The Effect of Vitamin D on Renin-Angiotensin-System (RAS) Activation and Blood Pressure- A Randomized Control Trial, Journal of Hypertension 2017 Apr; 35(4): 822-829).
5. Inhibitory and immunomodulatory properties of Vitamin D metabolites: confusion follows contradiction?
Calcitriol, the active metabolite (1,25(OH)2D) was reported to have direct effect on T-cells, independent of Dendritic Cell activity. Through inhibition of Interferon-gamma, production of IL-2, TNF-alpha, IL-17 and IL-21 is inhibited. Calcitriol inhibits T-helper-1 (Th1-)priming cytokines in favor of Th2, increasing production of IL-4, IL-5 and IL-10 (Vitamin D and 1,25(OH)2D Regulation of T cells, Nutrients 2015 Apr;12(4): 988). While IL-10 is an anti-inflammatory cytokine, IL-4 is a pro-inflammatory cytokine with profibrotic properties. On the other hand, calcitriol was found to reduce Th2 response in CD4+ T-cells. Inhibition of Th1 cytokines might be detrimental for the immune response to pathogens (Modulation of the Immune Response to Respiratory Viruses by Vitamin D, Nutrients 2015 Jun;7(6)). The effect of vitamin D on Th1 and Th2 as well as on cytokine secretion, is differentiation. From what has been regarded "contradictory studies" can be gathered that vitamin D does not either favor Th1 or Th2, but its mechanism is characterized by differentiation of the immune response dependent on the immunological context (for example, the pathogen involved).
A 2017 meta-analysis concerning 11321 participants concludes benefit for patients with severe vitamin D deficiency not receiving a bolus dose of vitamin D (Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of indivual participant data, BMJ 2017; 356). The trials assessed in this analysis are too inconsistent to draw conclusions with regards to the preventive effect of vitamin D supplementation on respiratory infections, however: data relating to adherence were not available for all participants, no distinction is drawn with regards to the pathogenic nature of respiratory infections and confirmation was only obtained in a minority of cases. Actually, the main question "Does vitamin D supplementation prevent respiratory tract infections?", does not seem to be addressed. In other words, the net effect of vitamin D supplementation on prevention of respiratory viruses remains unclear, while this analysis is referred to as "evidence" for the benefits of vitamin D.
Calcitriol did not show direct effect on Rhinovirus replication, but was shown to potentiate secretion of CXCL8 and CXCL10 (Effects of Vitamin D on Airway Epithelial Cell Morphology and Rhinovirus Replication, PLoS One 2014; 9(1)). CXCL10 exerts both pro-fibrotic and anti-fibrotic properties. Like vitamin D, CXCL10 is able to exert a differentiation of effector responses, depending on immunological context.
Caution
A 2017 paper noted that many interventional studies in inflammatory and immune diseases with Vit D supplementation have proven to be inconclusive, possibly for measuring the 25-hydroxyVitaminD instead of calcitriol (Modulation of inflammatory and immune responses by Vitamin D, Journal of Autoimmunity Vol. 85, December 2017). The main factor for the amount of contradictory and confusing studies might be that Vitamin D metabolites differ with regards to endocrine systems and diseases. There is no general base-level to decide whether Vitamin D insufficiency contributes to a certain disease: the serum level is, in other words, tissue-dependent and disease-dependent (Does Vitamin D Sufficiency Equate to a Single Serum 25-Hydroxyvitamin D Level or are Different Levels Required for Non-Skeletal Diseases?, Nutrients 2013 Dec;5(12)). Some diseases, such as chronic inflammation, are correlated with slightly decreased serum levels of 25(OH)D.
Toxicity
Increasing VitD intake through supplementation is contraindicated in some specific situations. A 2017 study found that Vitamin D3 supplementation reduced the risk of advanced adenomas in individuals of the rs7968585 AA Vitamin D receptor gene who recently had colorectal adenomas by 64%, while D3 supplementation increases the risk of advanced colorectal adenomas in individuals with 1 or 2 G alleles by 41% (Vitamin D Receptor Genotype, Vitamin D3 supplementation and Risk of Colorectal Adenomas, JAMA Oncology 2017;3(5):628-635).
Hypercalcemia
Increasing vitamin D intake promotes serum calcium and phosphorus levels, which can result in hypercalcemia and hyperphosphatemia, posing a risk for the development of cardiovascular calcification. Using newer vitamin D analogs other than calcitriol, such as paricalcitol, might reduce this risk (The influence of selective vitamin D receptor activator paricalcitol on cardiovascular system and cardiorenal protection, Clinical Interventions in Aging 2013; 8: 149-156). The concentration associated with hyperphosphatemia and hypercalcemia is > 150 ng/mL (Optimal Vitamin D Supplementation Doses that Minimize the Risk for Both Low and High Serum 25-Hydroxyvitamin D Concentrations in the General Population, Nutrients 2015 Dec;7(12)).
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Broccoli, cauliflower, green Granny Smith apples are a source of Vit K
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Freaky leaves: Vitamin K, an essential amino acid that cooperates with Vitamin D, is found in green leaves, cabbage, sprouts, kiwi fruit and other green legumes
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Metabolism of forming menaquinone (K2) out of K1 (phylloquinone) in broccoli
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Food illustration by Mercedes Bouter
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Member of the brassica family
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