The MTHFR gene, short for methylenetetrahydrofolate reductase, is responsible for producing the MTHFR gene in the body. MTHFR dictates the levels of two B vitamins in your body – folate (vitamin B9) and cobalamin (vitamin B12). Both these vitamins are needed for a healthy immune system, new DNA production, and cell growth. Low levels of these vitamins cause pancytopenia (reduced red and white blood cell counts and platelets), and cognitive changes (fatigue, irritability, depression).
Homocysteine is another molecule that is related to the MTHFR enzyme, which usually converts excess homocysteine into methionine. Without MTHFR, homocysteine builds up in the body, leading to deleterious effects in the heart, blood vessels, brain, nerves, and bones.
Extremely high homocysteine levels increase the chances of the body forming a dangerous blood clot.
Low MTHFR enzyme activity leads to both low folate, low cobalamin, and high homocysteine levels (4). One way that leads to intrinsically low MTHFR enzyme activity is the presence of certain MTHFR polymorphisms that alter the amount of functional MTHFR enzyme that the body produces. The two most common polymorphisms are the C677T and A1298C mutations (5).
Interestingly, a study that compared the distributions of the C677T MTHFR polymorphism against COVID-19 incidence and mortality rates found that countries with the highest number of people with the C677T polymorphism (Latino and European countries) also had the highest numbers of recorded COVID19 cases and deaths (6).
‘Long COVID’ – a debilitating aftermath of acute COVID-19 infection
Before we piece together how folate, cobalamin, and homocysteine are involved in COVID-19, let’s talk about ‘long COVID’, also known as post-acute COVID-19 syndrome.
While fortunately a large proportion of patients breathe a sigh of relief after recovering from COVID-19, there are some who will be struggling to breathe for much longer. ‘Long COVID’ are persistent symptoms beyond 4 – 12 weeks after acute COVID, causing feelings of fatigue, difficulty concentrating (brain fog), and a myriad of symptoms such as breathlessness, cough, anxiety, depression, chest pain, chronic kidney disease, and thromboembolisms (7).
causing feelings of fatigue, difficulty concentrating (brain fog), and a myriad of symptoms such as breathlessness, cough, anxiety, depression, chest pain, chronic kidney disease, and thromboembolisms (7).
An Italian study reported up to 87% of 143 patients experiencing persistent symptoms nearly 2 months after acute COVID (8).
Researchers have drawn several parallels between the symptoms of long COVID and vitamin B12 deficient diseases like pernicious anemia and myalgic encephalitis/chronic fatigue syndrome (9). Could an imbalance of folate, cobalamin, and homocysteine be responsible for the debilitating sequelae of COVID?
COVID-19 – A methyl group assault?
Have a look at Figure 2. We see that homocysteine, folate, and cobalamin are linked by the MTHFR enzyme in processes collectively referred to as the one-carbon metabolism (9).
Figure 2: The one-carbon metabolism pathway
ATP, adenosine triphosphate; CBS, cystathionine beta synthase; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; THF, tetrahydrofolate
In the methionine cycle, pay attention to the SAM molecule, which acts as a universal methyl donor. SAM loses its methyl group, forming SAH, which becomes homocysteine and eventually methionine again.
How does COVID-19 fit into all this? Well, the SARS-CoV-2 virus is thought to interfere with the one-carbon metabolism by:
- Reducing SAM levels
- Using up methyl groups for viral replication
By simultaneously increasing demand and depleting supply of methyl groups, COVID-19 wreaks havoc with the body’s one-carbon metabolism pathways, ultimately leading to imbalanced folate, cobalamin, and homocysteine levels. As we’ll soon discuss, altered amounts of these nutrients may potentially influence how a person reacts to an infection.
Increased homocysteine levels and COVID-19
Doctors discovered early on that COVID-19 infections are notorious for causing blood clots throughout the body. They may occur in the brain (ischemic stroke), legs (deep vein thrombosis, DVT), and lungs (pulmonary embolism, PE). A meta-analysis on 102 studies including 64,503 patients with COVID-19 found that PE and DVT occurred at rates of 8% and 11%, respectively. COVID patients who needed intensive care had a 23% of developing any venous thromboembolism (which included PE and DVT) (10).
A meta-analysis on 102 studies including 64,503 patients with COVID-19 found that PE and DVT occurred at rates of 8% and 11%, respectively.
A number of studies suggest that high homocysteine levels put you at risk of getting blood clots (11). It remains plausible that having an MTHFR polymorphism that increases homocysteine levels could result in more severe COVID-19 infection, simply by raising the overall risks of a blood clot. What’s more, two MTHFR polymorphisms, A222V and E429A, were found to alter homocysteine levels (12).
Elevated homocysteine levels are also predictive of COVID-19 disease progression. In a study of 273 patients with mild COVID-19, homocysteine levels of more than 15.4 µmol/L had a three-fold increased risk of disease progression as evidenced by worsened CT lung images (13).
Low folate and cobalamin in COVID-19
Evidence is scarce on the direct relationship between B vitamins and COVID-19 infections. Nevertheless, there are no studies that show that being folate deficient results in worse COVID-19 clinical outcomes.
While a study on 333 patients hospitalised for COVID-19 found that 11% of them were folate deficient,
While a study on 333 patients hospitalised for COVID-19 found that 11% of them were folate deficient, researchers did not find any significant association between low folate levels and poor clinical outcomes (14).
On the other hand, a small clinical trial found that giving hospitalised COVID-19 patients aged 50 and above a combination of vitamin D, magnesium, and vitamin B12 supplements appeared to reduce the risk of needing oxygen or intensive care support (15). The authors postulate that these benefits may be due to vitamin D’s anti-inflammatory properties, magnesium’s role as a cofactor in vitamin D activation, and vitamin B12 as an essential immune system supporter.
Keeping homocysteine low and B vitamins high
The battle against COVID-19 looks to be a long one, and we need all the help we can get.
Your next steps are:
- Evaluate your risk – inflammation, Vitamin D, homocysteine, Vitamin B12 and folate levels
- Prepare for vaccination and support post vaccination if you decide to get it
- Provide antiviral and immune support on an ongoing basis