August 16, 2020
Researchers from The Netherlands released a preprint* on April 25 that they then revised on May 29 suggesting that vitamin K, especially in the form vitamin K2, may benefit the lungs in severe COVID-19.
What They Studied
Their analysis included 134 subjects hospitalized for COVID-19 between March 12 and April 11. Their outcome was categorized as “good” if they were discharged without the need for ventilation and “poor” if they received ventilation and/or died. Their degree of lung damage was quantified on a 25-point scale depending on the percentage of the lungs affected. Since quarantining and social distancing precluded recruiting healthy non-infected patients for the same study, they compared the COVID-19 patients to 184 healthy, age-matched controls from a previous study.
They mainly quantified vitamin K status by measuring dp-ucMGP. MGP itself is a vitamin K-dependent protein made in the blood vessel wall, cartilage, and lungs. Its main purpose is to prevent calcium from depositing abnormally in soft tissues, and keep the calcium where it belongs, in the “hard tissues” of bones and teeth. When there is enough vitamin K to fully activate MGP, it is carboxylated. When there is not enough vitamin K, it is uncarboxylated MGP, or ucMGP. MGP is also phosphorylated during its activation and the non-phosphorylated form is known as desphospho-MGP or dp-MGP. If MGP gets phosphorylated or gets carboxylated, it usually winds up stuck to calcium deposits and does not freely circulate in the blood. 99.9% of inactive MGP in the blood is neither phosphorylated nor carboxylated. That is, it is dp-ucMGP. As a result, we can measure the dp-ucMGP in the blood, and the higher it is, the more deficient the blood vessels, lungs, or cartilage are in MGP.
In the first version of this paper, they did not measure any other markers of vitamin K status. However, in the second version, they added PIVKA-II. This is “protein induced by vitamin K absence or antagonists II” and it rises when the liver does not have enough vitamin K to activate all the factors in the clotting cascade. Generally if PIVKA-II is high, it means that there is not enough vitamin K to support blood clotting.
Finally, they measured desmosine and isodesmosine. These are formed when an elastic fiber known as elastin is degraded. Elastin is usually degraded by the enzyme elastase, which is normally kept in balance with alpha-1 anti-trypsin, the main inhibitor of elastase. Smoking oxidizes this inhibitor, leading to elastin degradation, which plays a major role in emphysema. Elastin degradation also plays a role in several other lung diseases, such as alpha-1 antitrypsin deficiency, bronchiectasis, COPD and cystic fibrosis.
Two of the authors of the paper we are discussing today, Rob Janssen and Cees Vermeer, put forward a hypothesis three years ago suggesting that vitamin K can prevent elastin degradation and help treat or reverse all of the diseases listed above, but the arguments in that paper are very circumstantial and no one has yet shown that to be true.
What is known, however, is that vitamin K is necessary to prevent elastin from calcifying, which is critical to the elasticity and function of blood vessels and lung tissue.
What They Found
In the healthy controls, dp-ucMGP was 471 pmol/L. In COVID-19 patients, it was 1482 pmol/L, over three times higher.
In COVID-19 patients with a good outcome, it was 1163 pmol/L. In COVID-19 patients with a bad outcome, it was 1998 pmol/L, 72% greater.
In patients who were not using vitamin K antagonists, the PIVKA-II levels were normal in 82%, mildly elevated in 14%, and elevated in 4%. They didn't report the mean PIVKA-II in each group, but they did show a figure comparing the distribution of PIVKA-II in good versus poor outcomes and the mean was actually lower in those with poor outcomes, suggesting that, if anything, their livers had better access to vitamin K. However, the overall interpretation of the PIVKA-II data is that COVID-19 patients in general had adequate vitamin K for clotting.
The reference value for plasma concentrations of elastin breakdown products desmosine and isodesmosine in age-matched never-smokers is 0.24 ng/mL; the reference value in in age-matched former or current smokers is 0.28 ng/mL. These values were higher in COVID-19 patients. In those with a good outcome, it was 0.34 ng/mL. In those with a poor outcome, it was 26% higher, 0.43 ng/mL.
Dp-ucMGP correlated with desmosine and isodesmosine. The variation in one explained 26% of the variation in the other.
These values did not correlate with the degree of lung damage.
Their Interpretation
The following is my summary of the authors' interpretation as described in the second version of the paper. I will describe my own thoughts in the section after this one.
Normal PIVKA-II suggests that the liver had adequate vitamin K to maintain clotting status, consistent with the increased clotting often found in COVID-19. By contrast, the elevated dp-ucMGP suggested that tissues outside the liver did not get adequate vitamin K.
In addition to dietary deficiency and use of vitamin K antagonists, the pathological processes involved in COVID-19 may increase the demand for vitamin K, causing a relative deficit even when dietary intake is normal. The comorbidities associated with COVID-19 also involve impaired vitamin K status.
That elastin breakdown correlated with dp-ucMGP is consistent with how soft tissue calcification correlates with elastin breakdown in lung fibrosis, emphysema, and COPD. Because of these associations and because calcified elastin is more likely to be broken down than non-calcified elastin, the authors group elastin calcification and degradation into “elastic fiber dysfunction” and suggest that “Vitamin K insufficiency could therefore represent a unifying risk factor for Covid-19 disease severity.” They further speculate that hypertension, diabetes, and cardiovascular disease all predispose toward worse COVID-19 outcomes because they involve preexisting elastic fiber dysfunction.
The authors take the high dp-ucMGP and normal PIVKA-II to suggest that vitamin K2, which more effectively reaches tissues outside the liver where MGP is found, would be more likely to help with COVID-19 than vitamin K1, which reaches the liver much more effectively than it reaches other tissues.
They speculate that in the context of COVID-19, vitamin K would be more effective at activating protein S, an anti-clotting factor, than factor II, a pro-clotting factor, and that vitamin K would act as an anticoagulant in this context. They acknowledge this “may sound paradoxical,” but support it with 1) the deep vein thrombosis found in COVID-19 patients, and 2) the coexistence of clotting, elevated dp-ucMGP, and soft tissue calcification found in calciphylaxis, a rare and life-threatening disorder.
Their overall conclusion is that we do not know whether vitamin K would help with COVID-19, but it should be tested:
It may be expected that vitamin K administration has an improving effect on vitamin K status in Covid-19 patients, this, however, has never been studied. Additionally, it remains to be evaluated whether improving vitamin K status would result in a better prognosis in Covid-19 patients.
… A proof-of-concept study on vitamin K1 supplementation in calciphylaxis is currently ongoing. We propose that such a trial should also be conducted in Covid-19.
My Comments
I wish that they had measured the vitamin K concentrations in the blood.
A May 16 letter to Thrombosis Research from physicians at a Kings College London anticoagulant clinic reported that during COVID-19, the INR, a metric of how long it takes the blood to clot, was elevated beyond the therapeutic level in nine times more patients than usual (0.9% vs 0.1%). They attributed this to frequent antibiotic use, which they measured, but also suggested other possibilities: liver impairment, increased use of alcohol or acetaminophen, reduced vitamin K absorption due to viral infection of the gut, and poor access to green vegetables due to stockpiling.
I agree with the authors of the Netherlands paper that the elevated dp-ucMGP may reflect increased demand for vitamin K rather than decreased supply. However, measuring vitamin K concentrations in the blood could have clarified whether decreased dietary intake or absorption had contributed.
My suspicion is that the pathological processes reflected in these associations is as follows:
In COVID-19, neutrophils increase in circulation and infiltrate the lung. Poorer outcomes are associated with more neutrophils.
Neutrophils are major producers of elastase, which breaks down elastin.
In version 1 of the paper, the authors spent a lot of room comparing their observations in COVID-19 to idiopathic pulmonary fibrosis (IPF). IPF does appear to involve increased neutrophils and MGP expression is increased almost 20-fold.
I don't know what it is about elastin degradation that increases MGP expression, but I would note that soft tissue calcification often occurs at sites of debris from damaged cells, and MGP increases in response. For example, in atherosclerosis, MPG accumulates at the sites of the debris of dead and dying cells.
The more MGP that is produced, the more likely its rate of production will exceed the rate at which it can be activated using vitamin K. Therefore, overproduction of MGP leads to increased amounts of dp-ucMGP in circulation.
In fact, in 2007 I put forward a hypothesis on the molecular mechanisms of vitamin D toxicity that involved overproduction of MGP. The following year, researchers from Tufts University confirmed some of the key predictions of my hypothesis.
Part of my hypothesis was that vitamin K2 would prevent vitamin D toxicity. However, no one has yet shown that to be the case, and while I consider it a strong hypothesis, there is one major point that could render it untrue:
The rate of MGP production and the rate at which it leaves the location of the cell where it gets activated (the endoplasmic reticulum) could exceed the maximal rate of the enzyme that uses vitamin K, known as the vitamin K carboxylase. It could be the case that the enzyme has all the vitamin K it can use, but there just isn't enough of the enzyme to keep up with activating all the MGP.
In short, at some some level of MGP overproduction, vitamin K may no longer be the limiting factor.
This exact obstacle to my own hypothesis is an obstacle for the hypothesis that vitamin K would help with COVID-19.
In the case of hemodialysis patients, dp-ucMGP reaches higher levels than in COVID-19, around 3000 pmol/L, versus close to 2000 in severe COVID-19. As much as 1080 micrograms of K2 per day has been used, 5-10 times what most people need, but only brings the value down to ~1700 pmol/L. Would even more help? If so, it would probably require 3000-4000 micrograms, whereas most people only need 100-200 micrograms. But it is also quite possible that no dose would fully normalize the level when it gets that high.
I personally am very skeptical that vitamin K could be used as an anticoagulant in the context of COVID-19. While it deserves to be tested, vitamin K has never been shown to be an anticoagulant in any context. Calciphylaxis is very complicated and often involves hypercalcemia, which can cause both soft tissue calcification and blood clotting. That these two things occur together does not suggest that vitamin K would treat both of them.
The Bottom Line
I believe most people should aim for 120 micrograms per day of vitamin K1 and 100-200 micrograms per day of vitamin K2. The Ultimate Vitamin K2 Resource covers how to do that with food and supplements.
Will vitamin K2 help prevent or treat COVID-19? I don't yet see any reason to think it would serve as prevention, but I do find it plausible that poor vitamin K status leading into the illness would predispose towards worse lung damage. I also find it plausible that high doses of vitamin K2 could limit the lung damage. Based on the high concentrations of dp-ucMGP in this study, I believe that would require around 3000 micrograms per day, and I would prefer that to be a mix of MK-7 and MK-4.
I consider it harmless for most people to get the maintenance dose described above, and I think short-term use of the higher dose is unlikely to cause problems for most people. However, high doses could increase the turnover of other fat-soluble vitamins, could lower glutathione levels, and some people report them to cause heart palpitations. The rationale for these concerns is described in detail in The Ultimate Vitamin K2 Resource.
Critical safety information: People who use anticoagulant medications must discuss any change to their vitamin K intake with the physician prescribing the medication. If the medication targets vitamin K metabolism, the dose will have to be adjusted to accommodate any vitamin K.
Overall I consider it wise to get the maintenance dose from food or supplements year-round, and I consider using the higher dose in the case of severe COVID-19 to be a speculative approach that is worth trying under medical supervision, and I would love to see its use tested in a randomized controlled trial.
Stay safe and healthy,
Chris
Discuss!
Here are three ways to discuss this topic, including asking me questions and getting a response:
The Masterpass FREE Forum. This forum is free and open to anyone to participate. Anything related to health and nutrition, including all aspects of the coronavirus, is welcome. I will do my best to participate several times a week, though I expect this to eventually be very large and may at some point have to participate on a weekly basis if it starts to take on a life of its own.
The Coronavirus Forum. This is for anyone who purchases The Food and Supplement Guide for the Coronavirus, pre-orders my upcoming Vitamins and Minerals 101 book, or joins the CMJ Masterpass (if you join, use the coupon code NEWSLETTER for 10% off the membership price). This forum is dedicated specifically to the coronavirus, has subsections based on topics (nutrition, medicine, lifestyle, mechanisms of disease), and has a section where the archive version of this newsletter is directly linked and each newsletter can be discussed as an individual thread. I consistently participate in this forum 3-5 times a week.
The Masterpass Discussion Group. Preserved for those who join the CMJ Masterpass, it's the best place to ask me questions in a fairly intimate environment and get a rapid response. All topics I cover are fair game, and I consistently participate approximately five times per week. The Masterpass also has monthly live Zoom Q&As that are even more intimate.
Please Support This Service
These research updates are made possible by purchases of The Food and Supplement Guide to the Coronavirus. The guide contains my most up-to-date conclusions about what we should be doing for nutritional and herbal support on top of hygiene and social distancing for added protection. Due to the absence of randomized controlled trials testing nutritional or herbal prevention, these are my best guesses for what is likely to work without significant risk of harm, based on the existing science. By purchasing the guide, you are enabling me to continue devoting my skills to the most important issue we now face. I am genuinely grateful for your contribution. You can purchase the guide using this link.
You can get the guide for free if you pre-order my upcoming book, Vitamins and Minerals 101: How to Get the Nutrients You Need on Any Diet (to be released when the COVID-19 crisis subsides) or when you join my membership program, the CMJ Masterpass, which is meant to help people with significant health and wellness expenditures consistently save money by returning marketing cost of the companies involved back to the members as rebates.
For other ways to support my work, please see here.
Disclaimer
I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
Subscribe
If you aren't subscribed to the research updates, you can sign up here.
Archive
You can access an archive of these updates here.
*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.