Are Anemia and MTHFR Gene Mutations Connected?

Anemia is a common blood condition affecting around 1.62 billion people worldwide, or 24.8% of the global population.

Preschool-age children have the highest prevalence of anemia, but the demographic with the highest number affected is non-pregnant women at 468 million people worldwide.

Anemia occurs when the body’s iron stores are too low to produce hemoglobin, the substance in red blood cells that enables them to carry oxygen. 

Anemia is diagnosed when hemoglobin is less than 12 g per deciliter in women and less than 13 g/dL in men. 

Hemoglobin below these levels results in a lack of oxygen to cells where it is required for various metabolic pathways. Symptoms include fatigue, weakness, pale skin, chest pains, irregular heartbeat, and lightheadedness. 

The pathophysiology of anemia depends on the cause. It can include nutrient deficiency (especially iron, B12, and folate), blood loss, and various medical conditions that can lead to excessive breakdown of red blood cells, low red blood cell production, or a deficiency in the normal functioning of red blood cells.

Recent research suggests that genetic influences such as the MTHFR gene mutation may also contribute due to the role that MTHFR defects play in nutrient metabolism. 

This article will discuss how MTHFR is related to anemia and whether it can increase the risk of developing anemia. We will also explain treatment options for those with both MTHFR mutations and anemia and whether supplementation can help. 

The Methylenetetrahydrofolate reductase (MTHFR) enzyme is required for the conversion of 5, 10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF or methylfolate), the active form necessary for methylation. Methylfolate is involved in nucleotide synthesis, repair and formation of DNA and RNA, metabolism of homocysteine, and many other processes. 

Methylation dysfunction has been linked to a variety of health conditions, including elevated homocysteine, depression, cardiovascular disease, neural tube defects, and other conditions. 

Anemia can seriously affect health regardless of whether someone has MTHFR. If undiagnosed or left untreated, anemia can lead to multiorgan failure and even death. Anemia during pregnancy also increases the risk of early labor, low birth weight, anemia in the baby, and increased blood loss during pregnancy. 

In older people, anemia can lead to cardiovascular complications such as myocardial infarction, angina, high output heart failure, arrhythmias, and cardiac hypertrophy.

The MTHFR genetic mutation has been linked to an increased risk of anemia due to its impact on nutrient metabolism, particularly folate, vitamin B12, and homocysteine. 

MTHFR deficiency increases the likelihood of lower folate levels while also increasing the possibility of higher non-methylated forms of folate. Lower levels of vitamin B12 are also common in those with MTHFR mutations. 

B12 and folate are crucial in producing red blood cells (erythropoiesis). A deficiency of folate or vitamin B12 reduces the body’s ability to synthesize purines and thymidylate, reducing DNA synthesis. This leads to cell death (erythroblast apoptosis) and anemia from ineffective red blood cell production.

Vitamin-deficiency anemia is also known as megaloblastic anemia and is most often due to hypovitaminosis, specifically a lack of vitamins B12 and folate. These two nutrients are necessary for red blood cell production and maturation of the cell nuclei. 

In megaloblastic anemia, red blood cells are abnormally large and have underdeveloped nuclei. These cells are less effective in delivering oxygen and are more susceptible to premature apoptosis or cell death.

Hemolytic anemia is also linked to low folate and vitamin B12. In hemolytic anemia, red blood cells are destroyed (hemolysis) faster than they can be made. 

Hemolytic anemia may be more prevalent in patients with a coexisting MTHFR gene mutation and vitamin B12 deficiency, possibly due to high homocysteine levels. 

Elevated homocysteine may increase the risk of hemolysis in the presence of B12 deficiency, and there is a high frequency (30%) of vitamin B12 deficiency in people with the homozygous C677T mutation, a known cause of elevated homocysteine. 

This is because folate and B12 are both involved in recycling 5-methyl-tetrahydrofolate (5-MTHF) back to tetrahydrofolate (THF). Lack of vitamin B12 causes folate to become ‘trapped’ in the 5-methyl-THF form, and it also leads to a deficiency of methionine. 

The resulting B12 deficiency leads to an elevation in homocysteine (a common symptom of MTHFR) and potential hemolytic anemia. 

The A1298C polymorphism of the MTHFR gene has also been linked to a higher risk of iron deficiency anemia due to deficient regulation of iron. The MTHFR enzyme is required for the metabolism of cysteine, one of the essential factors in iron regulation.

Treating anemia begins with identifying the underlying cause. Nutritional replacements of (iron, B12, folate) should begin immediately. In iron deficiency, replacements must continue for at least three months after the normalization of iron levels to restore iron stores. In most cases, nutritional deficiencies can be resolved if treated adequately.

The most cost-effective means of restoring low iron levels is oral iron supplementation. The best forms include ferrous sulfate (20% elemental iron), ferrous gluconate (12% elemental iron), and ferrous fumarate (33% elemental iron). 

Depending on the severity of the deficiency and underlying cause, normalization of the hemoglobin level may take up to 3 months, and it may take longer to replace iron stores (ferritin >100 µg/L). 

Vitamin C assists with the uptake of iron by preventing the formation of insoluble and unabsorbable iron compounds and reducing ferric to ferrous iron, which is essential for the uptake of iron into the mucosal cells.

It is also important to note that conditions associated with B12 deficiency may be worsened by supplementing with folic acid due to unmetabolized folic acid circulating in the body. Folic acid does not occur naturally in the body’s tissues and cannot be properly metabolized by those with an MTHFR mutation. 

However, folate supplementation in the form of methylfolate can bypass folate insufficiency caused by MTHFR deficiency. Methylfolate supplementation is more efficient than folic acid supplementation, as it can enter the folate cycle directly without the need for enzymatic modification.

Methylfolate supplements are now available over-the-counter and online, often labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.

Methyl-life’s®  product range is formulated especially for people with a heightened need for bioavailable folate and B12 due to MTHFR/MTR/MTRR defects, nutritional deficiencies, vegans, vegetarians, or those with conditions in which nutritional absorption is impaired. 

Each product is made with the internationally-patented Magnafolate® PRO, clinically tested as the world’s purest methylfolate and the most active form of folate in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body.