The connection between MTHFR, B12, iron deficiency and anemia

Anemia is a reduction in hemoglobin, the protein contained in red blood cells that allows oxygen to be delivered to tissues, or reduced hematocrit, the percentage of red blood cells (RBCs) in the blood. The term literally translates to ‘without blood’ (an- means without, and -aemia means blood).

The most common cause of anemia worldwide is iron deficiency, which causes cells to be microcytic (low mean cell volume) or hypochromic (deficient in hemoglobin). Anemia is a sign of an underlying condition rather than a diagnosis in itself. These conditions can include nutrient deficiencies (iron, B12, folate), chronic diseases, blood loss or impairments in bone marrow function¹.

Anemia is classified by mean cell volume (MCV) because this reflects the underlying causes. 

• Microcytic anemia (low MCV) most commonly due to iron deficiency, but can also occur with chronic inflammation or inherited hemoglobin disorders.
• Macrocytic anemia (large MCV) most often caused by folate or B12 deficiency, but may also result from liver disease, alcohol intake and certain medications.

• Fatigue and lack of energy
• Pallor (pale skin)
• Reduced cognitive function
• Dyspnea (shortness of breath)
• Weakness
• Lightheadedness or loss of balance
• Headaches
• Heart palpitations
• Cold hands and feet

Pernicious anemia is an autoimmune condition in which the body’s immune system attacks the cells in the gut that produce intrinsic factor (IF). Intrinsic factor is the protein required for absorbing vitamin B12. Lack of intrinsic factor typically leads to vitamin B12 deficiency.

Pernicious anemia is one of the main causes of B12 deficiency as it impairs the body’s ability to absorb B12 in the small intestine.

People with B12 deficiency due to pernicious anemia are usually treated with intramuscular B12 injections or sublingual B12 supplements. Sublingual B12 is often used when gastrointestinal absorption is impaired. Studies suggest that sublingual B12 improves B12 levels by allowing passive diffusion via the mucous membranes in the mouth.

MTHFR variants are not known to cause iron-deficiency anemia. Iron deficiency is caused by low intake, blood loss (especially in older patients), increased requirements (such as during pregnancy) or malabsorption.

However, some forms of anemia have been impaired DNA synthesis, which may occur when MTHR function is reduced. An MTHFR mutation means that the body cannot properly convert folic acid to methylfolate, which is required for methylation and thymidine synthesis. When this process slows, developing red blood cells cannot divide normally and become enlarged (macrocytic), especially when overall folate or B12 intake is low.

Elevated homocysteine - which is common among those with MTHFR mutations - has been linked to impaired iron metabolism. Homocysteine causes oxidative stress which may impair the function of specific heme proteins. A 2021 study found that oxidative stress from excess homocysteine leads to loss of activity in iron-containing enzymes, suggesting a direct toxic effect on heme proteins². While this does not cause iron-deficiency anemia, it indicates that impaired methylation can place additional stress on pathways that involve iron-containing proteins.

Several studies have found an increased prevalence of the MTHFR C677T mutation in people with vitamin B12 deficiency. A 2024 study showed that people with homozygous (TT) or heterozygous (CT) MTHFR variants had statistically significant lower hemoglobin than controls. Researchers have suggested that individuals with MTHFR mutations are already more prone to functional deficiencies, and tend to have lower levels of active folate even if their dietary intake is adequate. Reduced MTHFR enzyme function may then lead to a metabolic imbalance, exacerbating anemia⁴.

Deficiency in folate and vitamin B12 has been linked to megaloblastic anemia, in which red blood cells are abnormally large and immature. Megaloblastic anemia occurs when folate or vitamin B12 deficiency impairs DNA synthesis in rapidly dividing cells. Developing red blood cells in the bone marrow are unable to divide properly and instead become abnormally large, resulting in anemia⁵.

Folate and B12 work together in the methylation cycle. When B12 is low, folate becomes ‘trapped’ in a form that cannot be used for DNA synthesis - this is known as the methyl-folate trap. Both deficiencies impair cell division in the bone marrow, producing enlarged and ineffective red blood cells.

The first step in treating anemia is to identify the underlying cause, as this can vary from case to case and will significantly impact recovery.

Iron deficiency may result from low dietary intake, poor absorption (due to celiac disease, gastric surgery or low stomach acid), or increased loss of blood (due to gastrointestinal bleeding or heavy menstruation).

Each of these causes should be addressed before supplementing with bioavailable iron. 

Supplementation is generally advised for at least three months to replenish iron stores, and should continue for about a month after hemoglobin returns to normal⁶. Supplementation options usually include ferrous sulfate in daily divided doses. People who are unable to absorb oral iron supplements (due to celiac disease, surgery or lack of stomach acid) may require intravenous iron⁷.

Deficiency in folate or B12 also requires targeted supplementation. Active forms of these nutrients are considered most effective for restoring healthy levels in people with impaired conversion.