What is homocysteine?
Homocysteine (Hcy) is a sulfur-containing amino acid (a building block of protein) that is used in the body to produce either methionine or cysteine, which are other amino acids. (2)(4) Hcy is involved in a process known as methylation, which impacts a broad range of functions such as cognition, detoxification, and cardiovascular function. (8)(16) Impaired methylation may result in adverse changes to gene expression, which is associated with negative health effects, including autoimmunity, cancer formation, and increased signs of aging. (13) In a healthy state, the body converts homocysteine to methionine or cysteine, depending on the body’s needs. In the case of methionine deficiency, Hcy can be re-methylated to form methionine. With sufficient methionine, Hcy is used to produce cysteine. (4) Homocysteine metabolism, which occurs primarily in the kidneys via the action of homocysteine-degrading enzymes, helps to maintain normal levels in the blood. The enzymes involved in breaking down Hcy include 5,10-methylenetetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CBS), methionine synthase (MS), and γ-cystathionase. Nutrients that act as essential cofactors of these enzymes include vitamins B6, B9 (folate), and B12. (3)
What is high homocysteine?
High homocysteine, referred to as hyperhomocysteinemia, is characterized by Hcy levels greater than 15 μmol/L. There are three classifications of high homocysteine, including:- Moderate, with levels >15 to 30 μmol/L
- Intermediate, with levels >30 to 100 μmol/L
- Severe or fatal, with levels >100 μmol/L (4)(9)
Signs, symptoms, and complications of high homocysteine
Research has found high Hcy to be correlated with vitamin B12 deficiency and its associated symptoms, including personality changes, psychosis, dementia, and ataxia (losing coordination of muscle movements). (2) High homocysteine levels is a risk factor for cardiovascular diseases, such as coronary artery disease, peripheral vascular disease, and stroke, and may be associated with neurodegenerative disorders such as Alzheimer’s disease. (2) Hcy is known to disrupt the blood-brain barrier and induce inflammation in nervous tissue, processes which are associated with overstimulation of the nervous system (3)(4), and potential neurological damage. (9) One study assessed the clinical characteristics of individuals with intermediate hyperhomocysteinemia (>30 to 100 μmol/L). The researchers found that these individuals were more likely to have hypothyroidism and kidney disease than individuals with Hcy levels below 30 μmol/L. Further, individuals with intermediate hyperhomocysteinemia were more likely to have a prescription for certain medications, including antidepressants, opioids, steroids, and thyroid hormones. (14) These findings suggest that high homocysteine may be associated with a variety of health conditions.Causes and risk factors of high homocysteine
There are several factors that may contribute to impaired homocysteine metabolism and high homocysteine, including:- Certain health conditions (e.g., cancer, diabetes, kidney dysfunction, thyroid dysfunction) (4)
- Certain nutrient deficiencies (e.g., folate, vitamin B6, vitamin B12) (3)
- Dietary factors (e.g., alcohol, coffee, (4) diet high in methionine) (3)
- Genetic factors affecting enzymes involved in Hcy metabolism (3)
- Older age (4)
- Sedentary lifestyle (3)
- Smoking (4)
Natural approaches to address high homocysteine
Scientific literature suggests that two of the causes of high Hcy are related to dietary factors, including certain nutrient deficiencies and a methionine-rich diet. (3) Fortunately, these factors may be addressed through dietary modifications and supplementation. Addressing additional risk factors may involve smoking cessation and increasing physical activity.Diet
Preventing or addressing high homocysteine through dietary modification may include moderating alcohol and coffee consumption, as well as adequately consuming the nutrients folate, vitamin B6, and vitamin B12. (4) It’s important to note that as vitamin B12 is primarily found in animal-based foods, vegetarians and vegans may be particularly at risk of vitamin B12 deficiency. (11) The table below summarizes dietary sources naturally high in these three vitamins.
Supplements
Dietary supplementation of vitamins B6, B12, and folic acid (a form of folate) have been studied for their effects on homocysteine levels. In a randomized controlled trial in adults with at least one sign of metabolic syndrome, two-month supplementation of B vitamins with vitamin C was shown to reduce Hcy levels from 9.8 to 8.2 µmol/L in the first study group and 10.8 to 7.4 µmol/L in the second study group. (7) While these supplements have been shown to lower Hcy levels, this change does not necessarily result in a reduced risk of cardiovascular disease. (4) Researchers have stated that identifying the individuals who are most likely to benefit from this combination of B vitamins requires further investigation with key groups, such as those with moderately or severely elevated homocysteine levels. (6) Interestingly, there may be additional supplement ingredients that affect Hcy levels in certain individuals. For example, an eight-week trial assessed the effects of creatine supplementation compared to control (no intervention) and placebo (placebo supplementation) groups in resistance-trained men. The study found that Hcy levels were significantly lower compared to baseline in men with creatine supplementation with resistance training. (1)Caution with supplementation
If you are considering supplementation, working with an integrative healthcare provider can help to establish your nutrient needs and an appropriate supplement protocol. Caution should be exercised with B vitamin supplementation as supplementing with high amounts of folate may conceal symptoms of a vitamin B12 deficiency, and vice versa. (9)(10)The bottom line
Homocysteine is an amino acid found naturally in your blood that is involved in methylation reactions. Individuals with high homocysteine may have an increased risk of cardiovascular and neurological conditions. Elevated homocysteine may be prevented or addressed through dietary modifications and supplementation of folic acid, vitamin B6, and/or vitamin B12. We always recommend consulting with your integrative practitioner before making changes to your wellness plan.References
- Bereket-Yücel, S. (2015). Creatine supplementation alters homocysteine level in resistance trained men. The Journal of Sports Medicine and Physical Fitness, 55(4), 313–319.
- Diaz-Arrastia, R. (2000). Homocysteine and neurologic disease. Archives of Neurology, 57(10), 1422-1427.
- Djuric, D., Jakovljevic, V., Zivkovic, V., & Srejovic, I. (2018). Homocysteine and homocysteine-related compounds: An overview of the roles in the pathology of the cardiovascular and nervous systems. Canadian Journal of Physiology and Pharmacology, 96(10), 991–1003.
- Ganguly, P., & Alam, S. F. (2015). Role of homocysteine in the development of cardiovascular disease. Nutrition Journal, 14, 6.
- Hannibal, L., & Blom, H. J. (2017). Homocysteine and disease: Causal associations or epiphenomenons? Molecular Aspects of Medicine, 53, 36–42.
- Maron, B. A., & Loscalzo, J. (2009). The treatment of hyperhomocysteinemia. Annual Review of Medicine, 60, 39–54.
- Maruyama, K., S Eshak, E., Kinuta, M., Nagao, M., Cui, R., Imano, H., Ohira, T., & Iso, H. (2019). Association between vitamin B group supplementation with changes in % flow-mediated dilatation and plasma homocysteine levels: A randomized controlled trial. Journal of Clinical Biochemistry and Nutrition, 64(3), 243–249.
- Moore, L. D., Le, T., & Fan, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38(1), 23–38.
- Moretti, R., & Caruso, P. (2019). The controversial role of homocysteine in neurology: From labs to clinical practice. International Journal of Molecular Sciences, 20(1), 231.
- National Institutes of Health Office of Dietary Supplements. (2019, July 19). Folate. Retrieved from https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
- National Institutes of Health Office of Dietary Supplements. (2019, July 19). Vitamin B12. Retrieved from https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/
- National Institutes of Health Office of Dietary Supplements. (2019, September 19). Vitamin B6. Retrieved from https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/
- Richardson, B., & Yung, R. (1999). Role of DNA methylation in the regulation of cell function. Journal of Laboratory and Clinical Medicine, 134(4), 333–340.
- Sellos-Moura, M., Glavin, F., Lapidus, D., Evans, K. A., Palmer, L., & Irwin, D. E. (2020). Estimated prevalence of moderate to severely elevated total homocysteine levels in the United States: A missed opportunity for diagnosis of homocystinuria? Molecular Genetics and Metabolism, S1096-7192(20), 30051-2.
- Verhoef, P., van Vliet, T., Olthof, M. R., & Katan, M. B. (2005). A high-protein diet increases postprandial but not fasting plasma total homocysteine concentrations: A dietary controlled, crossover trial in healthy volunteers. American Journal of Clinical Nutrition, 82(3), 553–558.
- Zhong, J., Agha, G., & Baccarelli, A. A. (2016). The role of DNA methylation in cardiovascular risk and disease: Methodological aspects, study design, and data analysis for epidemiological studies. Circulation Research, 118(1), 119–131.
