What is homocysteine? banner

What is homocysteine?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

January 22, 2025

Table of Contents

    But what is homocysteine?

    Homocysteine is a naturally occurring amino acid that’s created when your body breaks down the essential amino acid methionine. Methionine is broken down into homocysteine, and then homocysteine is ‘recycled’ back to become methionine again. Methionine is a sulfur-containing amino acid involved in building proteins and producing certain substances in the body, including the antioxidant glutathione and the molecule SAMe.

    A host of important nutrients are created throughout the methionine-homocysteine pathway; all of which play a part in various other biochemical reactions such as detoxification, healthy immune function, the formation of connective tissues, as well as brain and cardiovascular function.

    The specific enzymes required for this pathway require many important nutrients, especially B vitamins. A lack of any particular nutrient can lead to an undesirable elevation in homocysteine levels. It’s for this reason that the level of homocysteine in your blood plasma becomes an important indicator of overall health.

    The metabolism of homocysteine

    Normally, homocysteine is broken down by your body’s stores of vitamin B12, vitamin B6, and methylfolate and changed into substances that your body actually needs.


    There are two pathways through which the methylation cycle can convert homocysteine to methionine.

    The re-methylation pathway that regenerates methionine requires vitamins B12, B6 and folate. When your levels of these B vitamins are sufficient, there should be very little homocysteine left in your bloodstream. But if you are deficient in B12, B6 or methylfolate - or all three - you may be at risk of elevated homocysteine. 5

    Why is high homocysteine so bad?

    If untreated, hyperhomocysteinemia can lead to vascular damage, cognitive impairment, neurological complications, congenital defects, and pregnancy complications. 6

    Homocysteine causes artery walls to become tough and thickened, increasing the risk of cardiovascular disease. 7 The higher the homocysteine level, the higher the prevalence and progression of calcification in the vascular system.8

    What is considered high homocysteine?

    There is some conflict over what is considered ‘high’ homocysteine. Some medical researchers say that any level higher than 10 µmol/higher may benefit from intervention, however, any level higher than 5 µmol/l increases the risk of death. Levels continue to increase as the homocysteine increases.14


    However, according to current guidelines, a normal level of homocysteine in the blood is less than 15 micromoles per liter (µmol/L) of blood. Higher levels of homocysteine are ranked by severity:


    • Moderate: 15-30 µmol/L
    • Intermediate: 30-100 µmol/L
    • Severe: greater than 100 µmol/L

    Symptoms of high homocysteine

    Hyperhomocysteinemia typically doesn’t produce any noticeable symptoms. Most people will only have their homocysteine levels tested if they appear to have symptoms of a vitamin deficiency. That’s why it’s important to be aware of the signs of deficiency in B12, folate or both. 


    People with B vitamin deficiencies may experience symptoms such as:

    • Fatigue or chronically low energy
    • Numbness/tingling in the limbs
    • Unexplained weight loss
    • Dizziness
    • Muscle weakness
    • Pale complexion
    • A sore tongue or mouth
    • Anemia (in the case of vitamin B12 deficiency) 15

    Causes of high homocysteine levels and MTHFR

    Homocysteine concentration is affected by many factors including age, gender, ethnicity, nutritional deficiencies like folate and Vitamin B12, as well as renal and liver function. 16


    Besides deficiency in folate or B12, other risk factors for hyperhomocysteinemia include:

    • Low thyroid hormone levels
    • Psoriasis
    • Kidney disease
    • Genetics
    • Certain medications

    B vitamin deficiencies can occur for many reasons. Diet is a common cause, particularly in vegans or vegetarians, as foods with the highest content of B vitamins are animal products. Deficiencies can also occur due to poor nutrient absorption, stress, and/or medications.

    However, a common cause of both folate deficiency and high homocysteine is the MTHFR genetic mutation. The MTHFR enzyme helps convert homocysteine to methionine, and a mutation on the MTHFR gene reduces the enzyme’s function by up to 65%. Depending on the variant of the mutation, the loss of enzyme function can cause homocysteine levels to rise by around 25%. 17 People with the homozygous 677TT gene tend to have higher homocysteine levels and lower serum folate levels. 18

    • Raised homocysteine affects the way cells use oxygen, resulting in a build-up of damaging free radicals. Oxidation has already been linked to the onset of numerous diseases of the heart, brain, and immune system. Reactive chemical forms such as free radicals can oxidize low-density lipoproteins, which then accumulate as plaque within the arteries. 9
    • It’s estimated that 10% of all coronary artery disease is attributed to high homocysteine levels, and that a level higher than 5 μmol/l raises the risk of ischemic heart disease by 84%. 10
    • Homocysteine can also cause apoptosis (death) of endothelial cells and alters lipid metabolism, causing loss of function in cellular membranes.11
    • High homocysteine has also been linked to neurodegenerative disorders such as Alzheimer’s Disease and Parkinson’s Disease, particularly when vitamin B12 deficiency is involved. 12
    • Elevated homocysteine is also strongly associated with metabolic syndrome and hypertension, which is correlated with type II diabetes mellitus (T2DM).13

    What is homocysteine?

    Key Takeaway

    If you have an MTHFR genetic mutation or a family history of cardiovascular issues, you need to know about homocysteine.

    Homocysteine is an amino acid that occurs naturally in the body during the metabolism of methionine to cysteine. If in excess, homocysteine can cause serious damage to the heart and blood vessels. Both markedly and mildly elevated circulating homocysteine concentrations are associated with increased risk of vascular occlusion (blockage of a blood vessel) and all-cause mortality.1 This risk persists even when factors such as physical activity, smoking status, alcohol consumption, BMI, and other metabolic diseases are taken into account.2


    Elevated homocysteine is also linked to migraines, dementia, poor memory function, cognitive decline, and low mood.3 Women with high homocysteine levels may struggle to conceive and are at risk of recurrent miscarriage. 4

    • Icon Homocysteine is a naturally occurring amino acid that can cause serious harm to your blood vessels if levels are too high
    • Icon Methylfolate, B12 and B6 are required to convert homocysteine to methionine, a beneficial amino acid
    • Icon High homocysteine levels can indicate that you are low in folate and B12
    • Icon MTHFR is the most common genetic cause of high homocysteine
    • Icon Supplementing with methylfolate, NAC, glutathione, and TMG (betaine) may help to reduce high homocysteine.

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    Frequently Asked Questions about Homocysteine

    What does it mean when your homocysteine is high?

    High homocysteine means that your levels are above the healthy range of 5-15 µmol/L. This could be because your body isn’t processing homocysteine as it should. You could be low in folate and/or B12, because these two nutrients are essential for processing homocysteine. There can be many reasons for folate or B12 deficiency, including diet and malabsorption syndromes. The most common genetic cause of high homocysteine is the MTHFR genetic mutation, which can lead to folate deficiency.19

    How do you treat homocysteine levels?

    Methylfolate and B12 are key to reducing homocysteine levels and supporting heart health. Methylfolate, a bioactive form of folate, directly assists with the remethylation of homocysteine to methionine. This process is critical for people with MTHFR genetic variations as their bodies are unable to convert folate to its active form, leading to elevated homocysteine levels. By supplementing with the readily available methylfolate, this metabolic block is bypassed, ensuring that homocysteine is converted to methionine. 20 A 2020 study found that taking methylfolate for three months had significantly reduced blood homocysteine levels. 21

    What do homocysteine levels tell you?

    Homocysteine levels tell you how efficiently your body is processing homocysteine, an amino acid that can be harmful at high levels. If your homocysteine is elevated, it could mean that you are deficient in folate and/or vitamin B12.

    What vitamin deficiency causes high homocysteine?

    Folate deficiency is commonly associated with high homocysteine levels because folate is an essential part of the homocysteine conversion process. Deficiencies in Vitamins B12 and B6 can also lead to high homocysteine. In many cases, low levels of these vitamins (especially folate) are caused by the MTHFR genetic mutation. 22

    References

    1. Lars Brattström, David EL Wilcken; "Homocysteine and cardiovascular disease: cause or effect?"; The American Journal of Clinical Nutrition; 2000 Aug

      https://www.sciencedirect.com/science/article/pii/S0002916523066984

    2. Minyoung Kim, Sujeong Shin, Eunsol Yoo, Jae-Heon Kang, Eunju Sung, Cheol-Hwan Kim, Hocheol Shin, Mi Yeon Lee; "Serum Homocysteine Levels and All-Cause and Cause-Specific Mortality in Korean Adult Men: A Cohort Study"; Nutrients; 2024 Aug

      https://www.mdpi.com/2072-6643/16/16/2759

    3. Rita Moretti, Paola Caruso; "The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice"; International Journal of Molecular Sciences 20, no. 1: 231; 2019 Jan

      https://www.mdpi.com/1422-0067/20/1/231

    4. Priyanka Thakur, Anuja Bhalerao; "High Homocysteine Levels During Pregnancy and Its Association With Placenta-Mediated Complications: A Scoping Review"; Cureus; 2023 Feb

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034471

    5. Yuka Hama, Tadanori Hamano, Norimichi Shirafuji, Kouji Hayashi, Asako Ueno, Soichi Enomoto, Miwako Nagata, Hirohiko Kimura, Akiko Matsunaga, Masamichi Ikawa, Osamu Yamamura, Tatsuhiko Ito, Yohei Kimura, Masaru Kuriyama, Yasunari Nakamoto; "Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment"; Nutrients; 2020 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602498/

    6. Domingo González-Lamuño, Francisco Jesús Arrieta-Blanco, Elena Dios Fuentes, María Teresa Forga-Visa, Monstserrat Morales-Conejo, Luis Peña-Quintana, Isidro Vitoria-Miñana; "Hyperhomocysteinemia in Adult Patients: A Treatable Metabolic Condition"; Nutrients; 2024 Dec

      https://www.mdpi.com/2072-6643/16/1/135

    7. Paul Ganguly, Sreyoshi Fatima Alam; "Role of homocysteine in the development of cardiovascular disease"; Nutrition Journal; 2015 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326479

    8. Susie Jung, Beom-Hee Choi, Nam-Seok Joo; "Serum Homocysteine and Vascular Calcification: Advances in Mechanisms, Related Diseases, and Nutrition"; Korean Journal Of Family Medicine; 2022 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9532189/

    9. Mi-Sun Lee, Kofi Asomaning, Li Su, John C Wain, Eugene J Mark, David C Christiani; "MTHFR Polymorphisms, Folate Intake, and Carcinogen DNA Adducts in the Lung", International Journal Of Cancer; 2012 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293105/

    10. Nicholas J. Wald, Hilary C. Watt, Malcolm R. Law; "Homocysteine and Ischemic Heart Disease"; Arch Intern Med; 1998

      https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/191864

    11. Ruben Esse, Madalena Barroso, Isabel Tavares de Almeida, Rita Castro; "The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art", International Journal Of Molecular Sciences, 2019 Feb

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412520/

    12. Marika Cordaro, Rosalba Siracusa, Roberta Fusco, Salvatore Cuzzocrea, Rosanna Di Paola, Daniela Impellizzeri; "Involvements of Hyperhomocysteinemia in Neurological Disorders"; Metabolites; 2021 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825518/

    13. Daniel E Platt, Essa Hariri, Pascale Salameh, Mahmoud Merhi, Nada Sabbah, Mariana Helou, Francis Mouzaya, Rita Nemer, Yasser Al-Sarraj, Hatem El-Shanti, Antoine B Abchee, Pierre A Zalloua; "Type II diabetes mellitus and hyperhomocysteinemia: a complex interaction", Diabetology Metabolic Syndrome; 2017 Mar

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359933

    14. Paul Ganguly, Sreyoshi Fatima Alam; "Role of homocysteine in the development of cardiovascular disease", Nutrition J= , 2015 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4326479/

    15. Bamini Gopinath, Elena Rochtchina, Victoria Flood; "Association of Elevated Homocysteine Level and Vitamin B12 Deficiency With Anemia in Older Adults"; Arch Intern Med; 2009

      https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/414924

    16. Helga Refsum, A David Smith, Per M Ueland, Ebba Nexo, Robert Clarke, Joseph McPartlin, Carole Johnston, Frode Engbaek, Jørn Schneede, Catherine McPartlin, John M Scott; "Facts and recommendations about total homocysteine determinations: an expert opinion"; Clinical Chemisty; 2004 Jan

      https://pubmed.ncbi.nlm.nih.gov/14709635/

    17. Bradley A Maron, Joseph Loscalzo; "The Treatment of Hyperhomocysteinemia", Annu Rev Med., 2009

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716415

    18. Laura Dean, "Methylenetetrahydrofolate Reductase Deficiency", Medical Genetics Summaries, 2024 Nov

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

    19. Bradley A MaBradley A Maron, Joseph Loscalzo; "The Treatment of Hyperhomocysteinemia", Annu Rev Med., 2009ron, "The Treatment of Hyperhomocysteinemia", Annual Review Of Medicine; 2009

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716415

    20. Nutrients; 2023

      https://www.mdpi.com/2072-6643

    21. Doreen Schmidl, Kinga Howorka, Stephan Szegedi, Kristina Stjepanek , Stefan Puchner, Ahmed Bata, Ulrike Scheschy, Gerold Aschinger, René M Werkmeister, Leopold Schmetterer, Gerhard Garhofer; "A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes"; Molecular Vision: Biology And Genetics In Vision Research; 2020 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190578/

    22. Bradley A Maron, Joseph Loscalzo; "The Treatment of Hyperhomocysteinemia", Annu Rev Med., 2009

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716415

    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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