Vitamins D3 and K2: The Perfect Supplement Partners For Managing COVID19
Establishing Immune Resilience
Images used with permission from the International Science and Health Foundation
Diet alone vs. Dietary Supplementation
For many nutrients, a healthy diet supplies all that one needs for health maintenance. These dietary nutrients are delivered in an optimal form and at a proper dose. However, the human condition varies, as does the diet, and this results in gaps in natural product-driven health optimization. This is where supplementation provides some answers. For example:
Diet alone is not enough to provide adequate amounts of the nutrient
The form of the nutrient in a diet may not be optimized, or may have limited absorption/bioavailability
Variances in the health status of an individual dictates that additional help is needed for full optimization
There are genomic variances amongst individuals (e.g., polymorphisms) that limit the effectiveness of certain nutrients
Environmental factors, including pharmaceuticals, may create a demand for supplements
Examples of the later bullet would be the need to take additional Vitamin K if you on long term antibiotics or bile/fat sequestrants (Vit K Facts) CoQ10 if you are on a statin or a yeast-based probiotic to manage the gastrointestinal impact of antibiotics. Polymorphisms are examples of genetic variances and accounts for why 40% of the population struggles to activate folic acid, a problem solved by supplementing with the active form 5-MTHF (Gene Variants in Folic Acid)
This is a general description of health drivers at the intersection of natural products and diet. What is often not discussed is whether certain nutrients work best when paired, at least for specific conditions. In this article, I will focus on COVID19 as the health condition, given the current state of the pandemic, and to focus the scope of this article on the value proposition of pairing Vitamins D3 and K2.
Why Supplement with Vitamins D3 and K2?
For the vast majority blood levels of Vitamins D and K2 are not optimal. This becomes especially apparent as science reveals more details on the health benefits of these nutrients. Vitamin D inadequacy is a well-documented worldwide problem, but it becomes substantially worse in the winter months at high latitudes. In this situation access to sunlight is limited and this results in diminished Vitamin D3 generation, a problem easily addressed by supplementing with Vitamin D3. The amount of supplementation needed is elevated when one seeks to optimize health status beyond bones to include cardiovascular health and immunity (Vit D & Essential Nutrients in COVID19).
Added to this societal health dilemma is the slow and ultra-conservative approach of regulators. For example, EFSA advocates that the minimal plasma level of Vitamin D is 10ng/ml (25 nmol/L), which is woefully inadequate (Vitamins D & K2 & COVID19 Mortality). We recognize that at least 20ng/ml is required for bone health and to access benefits for cardiovascular health & immunity you need at least 50 ng/ml. In the context of COVID19 the goal is most certainly to have plasma levels at 50ng/ml. Hence, society is most certainly in need of Vitamin D supplementation (Global Vitamin D deficiency)
For Vitamin K this is a more complicated conversation, but the theme is consistent. Firstly, Vitamin K1 (phylloquinones) and the various forms of K2 (menaquinones) differ in their structure, actions and dietary sources. Vitamin K1 is usually obtained from vegetable sources and acts within the liver, whereas K2 usually comes from fermented foods, cheese and some oily fish with the microbiome also making a small contribution. Unlike K1 the actions of Vitamin K2 are extra-hepatic. Dietary intake of Vitamin K2 represents only 25% of the total ingested Vitamin K (Dietary Vitamin K2). Given these differences it has been suggested that Vitamins K1 and K2 should have their own separate Recommended Daily Intakes (RDI) (Sources & recommended intakes for K1 K2). From the NHANES dietary pattern study (Dietary sources of Vit K) it is apparent that only 43% of males & 62% of women have adequate K1 intake. This is degree of inadequacy is likely to be even greater for Vitamin K2.
Given the lifestyle and dietary patterns, major portions of societies have inadequate levels of Vitamins K2 and D. The solution is easy – supplementation.
Natural Products and COVID19
The potential for natural products to help optimize health outcomes upon SARS-CoV-2 infection is substantial but should be linked in partnership with vaccination and social distancing/masks as one prepared to battle the BEAST that is COVID19. Recently I outlined a case for Vitamin K2 as a critical tool in managing health outcomes in COVID19 (The Case for K2 & COVID19). Here I will highlight the links to the combination of K2 and D3. Nevertheless, there are solid scientific support for the potential use of a variety of natural products in managing outcomes experienced with COVID19, including:
Suppression of viral replication (xanthohumol, zinc)
Interference with viral docking mechanisms to infect cells (Cat’s claw, Curcumin)
Limiting the oxidative stress-driven inflammation and cytokine storm (astaxanthin, cat’s claw, curcumin, polyphenols, microbiome-related approaches).
Where does Vitamins D and K2 fit in?
Evidence for a Role for Vitamin D in Managing COVID19
One aspect that limits a definitive guideline as to advocating that COVID19 patients receive Vitamin D, is the lack of interventional trials in a placebo controlled RCT format. There are several reasons for this.
One the COVID19 symptoms vary over time and hospitalization usually occurs when the disease is advanced.
Raising plasma Vitamin D levels with supplementation takes some time, and the ability oral dosing to raise levels is not easily predictable under the best of circumstances. If the goal is to reach a certain blood level e.g., 50ng/ml the dose required to do so may vary substantially from individual to individual based on baseline level, absorption and disposition.
While most clinical trial design focuses on results from a specific dose, a superior clinical trial design would involve supplementing with Vitamin D to achieve a certain blood level, independent of the dose required to get there. Further, it would need to be a pretreatment regimen as opposed to therapeutic intervention as establishing desired blood levels may require 1-2 weeks to achieve (Vitamins D & K2 & COVID19 Mortality).
Achieving critical blood levels of Vitamin D is important as its benefits vary markedly. At the low end, a blood level of 20ng/ml offers protection against rickets, a disease where bone calcification and strength are compromised. For many years, this was the sole focus of Vitamin D, however now we know there is a lot more to the story.
Given the challenges facing the performance of classic interventional RCTs to evaluate the potential benefits of Vitamin D in COVID19, Borsche et al (Mortality analysis of COVID19 with Vitamin D) took a different approach. They noted that there was a negative correlation between Vitamin D levels measured upon admission, and mortality with COVID19 (P=0.019). They noted that the median Vitamin D levels of COVID patients was 23.2 ng/ml (range of 17.4 – 26.8) which maybe adequate for bone health but insufficient for immunity.
Using a regression analysis, Borsche et al. asked a critical question “What is the Vitamin D blood level where mortality would be ZERO?”
The answer was 50ng/ml which is nearly double the blood levels of hospitalized COVID patients.
While this is a mathematical prediction, albeit based on a large pool of patients, it does set the stage for supplementation. Ideally, supplementation should be routine in society i.e., before acquiring the infection, with the focus on achieving a blood level of at least 50 ng/ml. To put it another way, what is the minimum blood level of Vitamin D that assures survival? The answer is 50 ng/ml, a result that strongly contrasts the EFSA recommendations of 10ng/ml. In the current pandemic vitamin D should be taken as a promoter of immune resiliency, a preventative approach used in conjunction with social actions (masking, distancing) as well as all the important use of vaccines.
Supporting this mathematical conclusion based on regression analysis is a retrospective study from Iran (Vit D status and Survival from COVID19). They noted that inpatients hospitalized with COVID19 there was ZERO mortality in patients under 80 years old whose vitamin D levels were above 41 ng/ml.
Source: Maghbooli et al PLOS ONE 15(10): e0240965. https://doi.org/10.1371/journal.pone.0240965
This coronavirus is a BEAST.
To WIN the BATTLE bring ALL the WEAPONS you can.
Another aspect to consider, beyond survival is the duration of COVID19 symptoms. In other words, can higher blood levels of Vitamin D lower the number days with active infection, hospitalization and potentially limit the Long COVID syndrome? Reis et al (COVID19 Hospital stay influenced by Vit D status) evaluated this possibility in Brazilian patients, and while there was a trend to have fewer days in hospital with higher vitamin D levels, all patients in the study were had very low levels while attempting to differentiate between <10 and >10ng/ml, which is far below the immune resiliency blood level of 50ng/ml. This potential benefit of Vitamin D on the duration of hospital stays and symptoms of Long COVID requires further research.
Evidence for the Impact of Vitamin K2 on COVID19
There is strong mechanistic evidence that supports a role for Vitamin K2 based on its impact on cardiovascular & lung health, and inflammation (Rotterdam study on K2 & Coronary Artery Disease). Vitamin K2 levels are often assessed indirectly given the difficulty in measuring the forms of K2 directly. This is one reason why the importance of Vitamin K2 has gone under the radar. One of the surrogates for the active status of Vitamin K2 is the plasma levels of dp-uc MGP, the inactive form of MGP (matrix Gla protein), an enzyme that suppresses the calcification of elastic fibers in arteries and lung tissue. High levels of dp-uc MGP reflects inadequate levels of Vitamin K2, resulting in excess of elastic fiber mineralization (harder, less flexible arteries and lungs).
Another surrogate marker for Vitamin K2 status is desmosine, a breakdown product of elastin. When elastin is mineralized, losing its inherent elastic characteristics, it is then chopped up by matrix metalloproteinases (MMPs) and appears in plasma where it may contribute to clot formation. Incidentally, MMPs are normally dormant but are raised during inflammation and cytokine surges that accompany COVID19.
To determine if VitamIn K2 levels are altered in COVID19 Dofferhoff 2020 et al (Vit K status as a modifiable prognosticator of COVID19) noted:
3.1 fold increase in plasma dp-uc-MGP. These are levels that exceed that seen in hypertension, diabetes & COPD patients – known conditions exacerbated by low vitamin K2 levels
Significantly elevated plasma desmosine (56% higher than uninfected patients)
Levels of desmosine and dp-uc MGP were highly correlated affirming the linkage of their actions and COVID19 severity.
Raised arterial calcification in COVID19 patients; those with severe disease displaying the greatest arterial calcification.
These authors concluded that inadequate Vitamin K2 leads to enhanced elastin fiber mineralization & breakdown, which in turn promotes thrombus formation and a worsening of the disease outcomes. Further, they proposed that levels of dp-uc MGP would serve as a prognostic risk factor for COVID19 and an assessment of disease status.
By contrast, COVID19 did not affect levels of PIVKA-II which is a marker for Vitamin K1 levels, narrowing the issue to the extrahepatic actions driven by vitamin K2 not K1.
There are related Vitamin K2-dependent biochemical pathways that are compromised in COVID19. Tutusaus 2020 (Vit K processes & COVID19 immunothrombosis) noted that Protein S and Growth-arrest-specific gene 6 (GAS6) are compromised. These elements also contribute the degradation of elastin and the promotion of inflammation, vascular damage, and thrombus formation.
Inflammation & Cytokine Storms
One of the features of COVID19, particularly in those displaying severe disease, is the profound inflammation and cytokine storm that is apparent. Sparked by oxidative stress that then activates epigenetic mechanisms that drive excessive production of MMPs, adhesion molecules, nitrosative stress, chemokines and Th1 cytokines. Both Vitamin D (Vit D Deficiency & the Morbidity of COVID19) and K2 (Vit K Missing Link to Managing COVID19) display actions (direct and indirect) that serve to restore balance to these processes.
Why combine K2 and D3?
Advocating for a combined approach with nutrient supplementation assumes the actions of D3 and K2 are both separate and yet complementary, and perhaps even synergistic (Vitamins K2 and D as pleiotropic nutrients with synergistic actions). Certainly, the K2 and D3 share a link to how the body handles calcium. Vitamin K2 limits calcification of arteries, lungs and heart and assists Vitamin D into redirecting calcium to bones. There has been a reluctance in advocating supplementing with high doses of Vitamin D based on concerns over possible vascular calcification resulting from high blood levels of calcium. The reality is that if there is adequate Vitamin K2 then this will not occur. Here K2 and D3 work synergistically to achieve balance to calcium tissue localization. Both vitamins also target optimal immunity and suppress chronic inflammation.
Currently global populations harbor inadequate levels of both vitamins, a situation that COVID19 appears to exacerbate. The targeted nature of K2 and D3 biological actions are directly related to COVID19 pathology – immunity, vascular health, thrombus formation. Further the links between D3 and K2 to risk factors associated with poor outcomes in COVID19 suggests a functional interaction.
The other critical element for advocating dietary supplementation with vitamins K2 and D3 as we face the continued burden of the pandemic, is that supplementation is easy and massively cost-effective as compared to hospitalization, use of monoclonal antibodies and antiviral pharmaceutical approaches. Supplements should not be used to forgo the use of vaccines, and social distancing measures, but supplementing with vitamins K2 and D3 optimizes your ability to battle the virus and survive.
Conclusion
Levels of Vitamin D and K2 are largely inadequate for comprehensive health optimization in most societies world-wide. The SARS-CoV-2 virus exploits these limitations hence one must consider that the status of Vitamin D and K2 is both a predictor of outcomes in COVID19 but also a site of intervention. A limitation to be considered is that the aggressive time course of the COVID19 pathology given that Vitamins D and K2 based interventions may be more effective when delivered in a prevention modality. In other words, supplementation is likely to be more effective when given before an infection occurs as opposed to once the disease is firmly established. The upside of this approach is that there is a litany of aging related diseases that would be benefited by these K2 and Vitamin D supplementation, independent of the current pandemic (Lowered ALL cause Mortality with Vit K).
In terms of specific recommendations, I advocate that the vitamin D3 levels be monitored to confirm that plasma levels are at least 50ng/ml. The dose of Vitamin D3 needed to achieve this is subject to inter-personnel variations, but 4000 IU is a decent starting point. Check our Vitamin D levels before and after supplementation to determine you have the correct levels. For Vitamin K2, the MK7 form of menaquinone is preferable based on superior absorption and longer half-lives. A dose of 150 -200 mcg is recommended.