Possible Reduction of Coronavirus Lymphopenia: Supplying 5-Methyltetrahydrofolate and Pyridoxine, and Reducing Folic Acid Supplementation in Hospital Bread and Other Grain Products
Abstract:
Lymphopenia was the most common clinical laboratory finding in coronavirus patients. Folate deficiency is generally accepted as causing lymphopenia. People with the methylenetetrahydrofolic acid reductase (MTHFR) polymorphism, inability to convert folic acid to the form used at the cellular level, 5-methyltetrahydrofolate, are at a higher risk from Coronavirus. In the lab, providing 5-methyltetrahydrofolate brings these low activity cells up 10 times overs folate deficiency cells, whereas folic acid only brings normal activity cells up two and a half times. Under certain circumstances excess folic acid supplementation can mimic folate insufficiency; theoretically, folic acid could compete with dietary folate and natural folate supplementation. Therefore it might be useful not only to supplement with 5-methyltetrahydrofolate to reduce lymphopenia, but also to reduce or remove folic acid from the diets of patients suffering from lymphopenia, and any patient with coronavirus who has the methylenetetrahydrofolic acid reductase (MTHFR) polymorphism.
Hospitals are providing folic acid supplementation in the bread and other grain products, but may be completely unaware that they are giving folic acid as a nutritional supplement in the food.
Metformin is an incidental antiolate, which may be part of its benefits to coronavirus patients, since folic acid found unconverted in human blood may be competing with 5-methyltetrahydrofolate, and causing leukopenia. Since the elderly have been hit particularly hard by coronavirus and since pyridoxine has been found to be deficient in up to 50% of nursing home residents and also appears to improve folate recycling, testing could confirm if it also could benefit reducing lymphopenia with minimal side effects.
It is suggested to consider reducing folic acid to patients with coronavirus including folic acid supplementation in grain products in the diet in the hospital which are not considered to be nutritional supplements, and providing 5-methyltetrahydrofolate or other available natural forms of B9 two patients suffering lymphopenia with Coronavirus, and if it is found beneficial, possibly providing it to patients who might have subclinical lymphopenia with Coronavirus in the hopes of improving outcomes.
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Background:
A cluster of pneumonia was reported in Wuhan, Hubei China for the first time in December of 2019[1]. A corona virus was identified as the pathogen - SARS Cov 2 - and the disease it caused was designated Covid 19. The disease emerged in China and has spread rapidly throughout the world.
A meta-analysis of clinical, laboratory and imaging features of Covid 19 described fever, cough and myalgia as the most common clinical features. Regarding the laboratory findings, lymphopenia was the most common, in almost one quarter of the patients (23.8%)[2].
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Research and discussion:
Folate deficiency is closely associated with lymphocytopenia; it is generally accepted that folate deficiency leads to lymphocytopenia[3].
Another link between folate Coronavirus is that people with methylenetetrahydrofolic acid reductase (MTHFR) polymorphism, having low MTHFR activity cells, are at a higher health risk from Coronavirus[4].
When lymphoblastoid cell lines cultivated in a folate-deficient medium for one week were treated with either folic acid or 5-Methyltetrahydrofolate, supplying folic acid resulted in a 2.5-fold increase in 5-Methyltetrahydrofolate in cells with normal MTHFR activity, but did not increase 5-Methyltetrahydrofolate in low MTHFR activity cells. However, when cells with low MTHFR activity were exposed to 5-Methyltetrahydrofolate, a 10-fold increase in intracellular levels of this 5-Methyltetrahydrofolate was determined[5]. (Unfortunately, the study did not see if normal cells exposed to 5-Methyltetrahydrofolate would increase similarly.)
Folic acid is a synthetic form of B9 which lacks coenzyme activity[6], which is provided in grain products in many countries to prevent spina bifida and other neural tube defects[7]. External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). (Naturally occurring 5-MTHF has another advantage over folic acid in that it is also well absorbed even when gastrointestinal pH is altered[7].)
Contrariwise, folic acid supplementation can metabolically mimic dietary folate insufficiency[8], which could therefore include lymphopenia.
From this information, I postulate there for that giving 5-MTHF could reduce lymphopenia and thereby have a benefit for people suffering with coronavirus with low MTHFR activity cells.
I also postulate that for anyone suffering from lymphopenia, a benefit might be derived from taking 5-MTHF, because the 2.5 increase for normal cells from exposure to folic acid might have an increase similar to the tenfold increase in the low activity MTHFR cells, thereby reducing the lymphopenia.
Theoretically, folic acid could interfere with normal folate metabolism through competition with reduced, coenzymatic folates for transporters, binding proteins, and folate-dependent enzymes, so patients with lymphopenia, and especially those with the MTHFR gene variations with low MTHFR activity cells, might benefit from having folic acid removed from their diet (as versus merely supplying 5-methyltetrahydrofolate)[9].
That including food given patients in the hospital including folic acid fortified cereal-grain products[10] such as bread, rolls, crackers, rice, noodles, and breakfast cereal.
These foods are often provided in the hospital instead of 100% whole grain products (which are not generally fortified is folic acid) without the awareness of the doctors or hospital staff that they are also supplying nutritional supplements in the process.
Further, folic acid has been expected to be converted as it absorbs through the intestinal wall[11]. However unconverted folic acid has been found in human blood with higher intakes (400μg or more)[12], and has been found to have adverse effects in the human liver[13]. So it is possible that removing folic acid from the diet of someone with coronavirus with normal cell activity would have a benefit of allowing the body to absorb more of the natural forms of folate without competition[9], and thereby increase activity and reduce lymphopenia, so a change in diet and in addition 5-Me-THF could reduce lymphopenia and improve outcomes for not only people with low activity MTHFR but also people with normal MTHFR activity or those who might be suffering from an undiagnosed or subclinical folate deficiency.[3]
Metformin has an antifolate activity[14,15] which could explain its benefit against coronavirus, strengthening the case that even people without low MTHFR activity or lymphopenia could find a benefit from 5-Me-THF supplementation.
Pyridoxine appears to improve folate recycling[16], so B6 could be tested for an adjunctive therapy for lymphopenia. Elderly people are hit especially hard with coronavirus, especially those in nursing homes. One study found that half of the residents of nursing homes had vitamin B6 deficiency, and that since supplement was effective prophylaxis for deficiency, recommended it to all elderly people in nursing homes[17]; however, B6 is toxic in excess, so it must be monitored to avoid exceeding safe parameters[18].
Conclusion:
Lymphopenia, methylenetetrahydrofolic acid reductase (MTHFR) polymorphism being an increased risk factor for Coronavirus severity, excess folic acid in certain circumstances mimicking folate deficiency, and metformin's benefit against Coronavirus all meet at the crossroads of supplementation with natural forms of B9 such as 5-methyltetrahydrofolate, the form used at the cellular level, and possible reduction of folic acid in hospital diets to reduce lymphopenia and improve coronavirus outcomes there thereby.
Hospitals need to be aware that they are often providing nutritional supplements, including folic acid, when they feed their patients grain products. With Coronavirus patients, they may find a benefit from avoiding these food products along with supplementing with the form of B9 that the cells can use directly. Considering that a significant number of elderly people in nursing homes have a B6 deficiency and that B6 has been found to help recycle folate through the system, pyridoxine should also be tested to see if it is beneficial.
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Author Contributions:
D.B. performed literature research, wrote this article, and did all the editing.
Corresponding email address: acctdmail@aol.com
This is a pre-publication version of this manuscript.
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Funding:
There has been no funding.
Conflict of interest statement:
The author declares no conflict of interest.
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Deborah Barges is an independent researcher, initially studying one of the causes of fibromyalgia, having isolated it by experience and accident, and the zinc-copper-iron homeostases as a result.
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Pre-publication version
©Deborah Barges Apr 2019 - Apr 2021. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
