Are Anemia and MTHFR Gene Mutations Connected?

Are Anemia and MTHFR Gene Mutations Connected?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 12, 2025

Table of Contents

    Are Anemia and MTHFR Gene Mutations Connected?

    Anemia is a common blood condition affecting around 1.62 billion people1 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 deciliter2 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 fatigue3, 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.

    How Can Anemia Impact the Symptoms of an MTHFR Gene Mutation?

    The Methylenetetrahydrofolate reductase (MTHFR) enzyme is required for the conversion of 5, 10-methylenetetrahydrofolate4 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 conditions5, 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 failure6 and even death. Anemia during pregnancy7 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.

    Can an MTHFR Gene Mutation Cause Anemia?

    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 levels8 while also increasing the possibility of higher non-methylated forms of folate. Lower levels9 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 thymidylate10, 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 hypovitaminosis11, specifically a lack of vitamins B12 and folate12. 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 deficiency13, 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%)14 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 tetrahydrofolate15 (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 homocysteine16 (a common symptom of MTHFR) and potential hemolytic anemia17.


    The A1298C polymorphism of the MTHFR gene has also been linked to a higher risk of iron deficiency anemia18 due to deficient regulation of iron. The MTHFR enzyme is required for the metabolism of cysteine, one of the essential factors in iron regulation.

    What Are the Treatment Options?

    Treating anemia begins with identifying the underlying cause19. 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

    Can Supplementation Help?

    The most cost-effective means of restoring low iron levels20 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 months21, and it may take longer to replace iron stores (ferritin >100 µg/L).


    Vitamin C assists with the uptake of iron22 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 acid23 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 insufficiency24 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 methylfolate25 and the most active form of folate in plasma circulation26. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body.

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    References

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      https://www.who.int/vmnis/anaemia/prevalence/summary/anaemia_data_status_t2/en/

    2. M Domenica Cappellini, Irene Motta; "Anemia in Clinical Practice-Definition and Classification: Does Hemoglobin Change With Aging?"; Seminars in hematology; 2015 Oct

      https://pubmed.ncbi.nlm.nih.gov/26404438/

    3. Jake Turner, Meghana Parsi, Madhu Badireddy; "Anemia"; StatPearls [Internet]; 2023 Aug

      https://www.ncbi.nlm.nih.gov/books/NBK499994/

    4. "Methylenetetrahydrofolic Acid"; Medicine and Dentistry, Women and Health; 2000

      https://www.sciencedirect.com/topics/medicine-and-dentistry/methylenetetrahydrofolic-acid

    5. Laura Dean; "Methylenetetrahydrofolate Reductase Deficiency"; Medical Genetics Summaries [Internet].; 2012 Mar

      https://www.ncbi.nlm.nih.gov/books/NBK66131/

    6. Jake Turner, Meghana Parsi, Madhu Badireddy; "Anemia"; StatPearls [Internet]; 2023 Aug

      https://www.ncbi.nlm.nih.gov/books/NBK499994/

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      https://www.ncbi.nlm.nih.gov/books/NBK499994/

    8. "Methylenetetrahydrofolate Reductase"; Medicine and Dentistry, Modeling Neuropsychiatric Disorders in Laboratory Animals; 2016

      https://www.sciencedirect.com/topics/medicine-and-dentistry/methylenetetrahydrofolate-reductase

    9. Zittan E, Preis M, Asmir I, Cassel A, Lindenfeld N, Alroy S, Halon DA, Lewis BS, Shiran A, Schliamser JE, Flugelman MY; "High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia"; American Journal of Physiology-Heart and Circulatory Physiology; 2007 Jul

      https://journals.physiology.org/doi/full/10.1152/ajpheart.01189.2006

    10. Palmer AM, Kamynina E, Field MS, Stover PJ; "Folate rescues vitamin B₁₂ depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability"; Proceedings of the National Academy of Sciences of the United States of America; 2017 May

      https://pubmed.ncbi.nlm.nih.gov/28461497/

    11. Hariz, A., Bhattacharya, P. T.; "Megaloblastic Anemia"; StatPearls; 2023 Apr

      https://www.ncbi.nlm.nih.gov/books/NBK537254/

    12. Gloria F. Gerber; "Vitamin Deficiency Anemia, (Megaloblastic Anemia)"; MSD Manual; 2024 Apr

      https://www.msdmanuals.com/en-nz/home/blood-disorders/anemia/vitamin-deficiency-anemia

    13. Acharya U, Gau JT, Horvath W, Ventura P, Hsueh CT, Carlsen W; "Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature"; Journal of Hematology & Oncology; 2008 Dec

      https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-1-26

    14. Zittan E, Preis M, Asmir I, Cassel A, Lindenfeld N, Alroy S, Halon DA, Lewis BS, Shiran A, Schliamser JE, Flugelman MY; "High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia"; American Journal of Physiology-Heart and Circulatory Physiology; 2007 Jul

      https://journals.physiology.org/doi/full/10.1152/ajpheart.01189.2006

    15. Tjong E, "Dimri M, Mohiuddin SS; Biochemistry, Tetrahydrofolate"; StatPearls; 2023 Jun

      https://www.ncbi.nlm.nih.gov/books/NBK539712/

    16. Varga EA, Sturm AC, Misita CP, Moll S; "Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease"; Circulation; 2005 May

      https://www.ahajournals.org/doi/10.1161/01.cir.0000165142.37711.e7

    17. Acharya U, Gau JT, Horvath W, Ventura P, Hsueh CT, Carlsen W; "Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature"; Journal of Hematology & Oncology; 2008 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626597/

    18. -

      https://www.geneticsmr.com/sites/default/files/articles/year2020/vol19-2/pdf/gmr18522_-_genotyping-a1298c-polymorphism-mthfr-gene-patients-iron-deficiency-anemia-institute.pdf

    19. Warner MJ, Kamran MT; "Iron Deficiency Anemia"; StatPearls; 2023 Aug

      https://www.ncbi.nlm.nih.gov/books/NBK448065/

    20. Nguyen, Minhthao, Tadi, Prasanna; "Iron Supplementation"; StatPearls; 2023 July

      https://www.ncbi.nlm.nih.gov/books/NBK557376/

    21. Ng, Kang S., Yu, Hyun H., Lee, Jung H.; "The Role of Methylation in the Inflammatory Response: A Study of DNA Methylation in Blood."; Scientific Reports; 2015 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836595/

    22. Nirenberg, V. S.; "The Discovery of the Genetic Code"; Proceedings of the National Academy of Sciences; 1990.

      https://pubmed.ncbi.nlm.nih.gov/2507689/

    23. Mills, K. C.; "Methylation of the Methylenetetrahydrofolate Reductase (MTHFR) Gene: Impact on Fertility and Pregnancy Outcomes"; Journal of Reproductive Medicine; 2010

      https://pubmed.ncbi.nlm.nih.gov/20357042/

    24. Mills, K. C.; "Methylation of the Methylenetetrahydrofolate Reductase (MTHFR) Gene: Impact on Fertility and Pregnancy Outcomes"; Journal of Reproductive Medicine; 2020

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

    25. Magnafolate®; "Magnafolate® PRO"; Lianyungang Jinkang Hexin Pharmaceutical Co.,Ltd.; 2021

      https://www.magnafolate.com/products/magnafolate-pro.html

    26. "Magnafolate Enhancing Immunity"; Trade Cloud; 2021 Sep

      https://i.trade-cloud.com.cn/upload/6405/file/20210929/english-version-magnafolate-enhancing-immunity_524485.pdf

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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