Homocysteine is an amino acid derived from the metabolism of methionine, an essential amino acid obtained from the diet. In the body, homocysteine can be converted into other amino acids or recycled back to methionine with the help of certain B vitamins. Elevated levels of homocysteine in the blood are associated with an increased risk of cardiovascular and neurological health issues. Maintaining optimal homocysteine levels is important for overall health, as high levels can contribute to inflammation and affect blood vessels.
Elevated homocysteine levels can indicate potential vitamin deficiencies or genetic factors that may affect the body's ability to metabolize this amino acid properly. By identifying and addressing the root causes of elevated homocysteine, healthcare practitioners can develop personalized nutrition plans and supplementation strategies that may help maintain healthy homocysteine levels and support overall wellness. Understanding the importance of homocysteine in functional medicine allows healthcare providers to implement proactive measures, promoting overall wellness and supporting the prevention of serious health conditions.
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The Biochemical Role of Homocysteine
Homocysteine is a sulfur-containing amino acid produced through the metabolism of methionine, an essential amino acid obtained from the diet. Homocysteine is involved in methylation, the transfer of a methyl group from one molecule to another. Methylation reactions are involved in numerous biological processes, including gene expression, protein function, neurotransmitter synthesis, and detoxification. (32, 43)
The body tightly regulates the homocysteine levels in the body through the methionine-homocysteine cycle. Methionine is converted to S-adenosylmethionine (SAMe). SAMe, often called the body's universal methyl donor, donates its methyl group to various substrates and is converted to S-adenosylhomocysteine (SAH). SAH is then converted to homocysteine. (31)
Homocysteine has two possible fates. It can be remethylated to methionine in a reaction that requires vitamin B12 and folate. Alternatively, it can enter the transsulfuration pathway to be converted to cysteine, a reaction that requires vitamin B6 and leads to the synthesis of glutathione. (32, 43)
A balance between these pathways is essential for maintaining proper levels of methionine and homocysteine in the body. Disruptions in this cycle can lead to elevated homocysteine levels (hyperhomocysteinemia). High homocysteine levels are associated with an increased risk for cardiovascular, cerebrovascular, and thromboembolic health issues. Therefore, understanding how homocysteine is produced in the body and its role in the methylation cycle is essential for maintaining proper biochemical balance and overall health. (32)
Why Test for Homocysteine?
Serum homocysteine can be measured with a simple blood test. It can also be helpful to measure homocysteine in the context of a more comprehensive methylation panel, which measures other analytes involved in the methylation cycle and can help identify nutritional deficiencies contributing to abnormal homocysteine levels.
Homocysteine increases as we age. Studies have found elevated homocysteine levels in almost 30% of people older than 65 and more than 40% in people 80 and older. This is relevant to aging and wellness because hyperhomocysteinemia has long been established as a risk factor for ischemic heart health issues, heart attack, sudden cardiac events, premature coronary artery conditions, carotid artery narrowing, blood clots, stroke, and peripheral vascular concerns. Newer studies have also identified high homocysteine as an independent risk factor for cognitive health issues; homocysteine levels higher than 15 µmol/L are associated with nearly double the prevalence of cognitive decline. A 2017 study showed that patients with Parkinson's disease and cognitive dysfunction were more likely to have higher homocysteine levels.
By measuring homocysteine levels, healthcare providers can assess your risk factors, identify possible vitamin deficiencies, and develop targeted interventions to support healthy levels. Addressing elevated homocysteine through dietary changes, supplements, and lifestyle modifications may help support your overall health. Regular testing allows for proactive health management, aiding in the support of overall well-being.
Understanding Homocysteine Test Results
Normal and optimal homocysteine levels should be less than 10 µmol/L. Levels between 10-15 µmol/L are considered borderline. (15) Hyperhomocysteinemia is diagnosed with a serum homocysteine level greater than 15 µmol/L. There are three classifications of hyperhomocysteinemia, as follows (32):
- Moderate: 16-30 µmol/L
- Intermediate: 31-100 µmol/L
- Severe: > 100 µmol/L
In a study of over 57,000 American adults, 1.8% of individuals had intermediate or severe hyperhomocysteinemia. This same study found that patients with homocysteine greater than 30 µmol/L were more likely to have hypothyroidism, kidney health issues, and a prescription for an antidepressant, opioid, steroid, or thyroid hormone medication. (29)
Causes of Elevated Homocysteine Levels
Elevated homocysteine levels do not necessarily mean you have a cardiovascular or neurological condition. Factors that can affect homocysteine metabolism and contribute to elevated levels include (16, 43):
- Comorbid medical conditions: cancer, diabetes, kidney health issues, thyroid dysfunction, homocystinuria
- Folate, vitamin B6, and vitamin B12 deficiencies
- Dietary factors: excess consumption of alcohol, coffee, and methionine-rich foods
- Genetic variations of the cystathionine β-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes
- Older age
- Male sex
- Sedentary lifestyle
- Smoking
Health Implications of High Homocysteine
Elevated levels of homocysteine may affect the inner endothelial lining of blood vessels, potentially contributing to inflammation and oxidative stress in the vasculature. This may increase the risk of atherosclerosis, a thickening and hardening of arteries caused by plaque buildup, and blood clots. Atherosclerosis is a primary concern for cardiovascular health, including coronary artery conditions (CAD), heart attack, heart failure, and stroke. (32)
Studies show that nutritional interventions with homocysteine-lowering B vitamins may support brain health in elderly individuals with mild cognitive concerns. It is unclear if homocysteine directly causes brain changes or if these findings are related to vitamin deficiencies. Nevertheless, the evidence does suggest that homocysteine may affect brain health and blood flow to the brain. Elevated levels are associated with neurodegeneration progression, as observed in conditions like Alzheimer's disease. (32)
There is also a correlation between high homocysteine levels and mood concerns. In a study including over 900 middle-aged men, researchers found that individuals in the upper tertile for homocysteine levels had more than a two-fold increased risk for mood concerns than those in the lowest tertile. Another study found that individuals with homocysteine levels greater than 12 µmol/L had significantly lower SAMe, mood-enhancing neurotransmitters, and red blood cell folate levels.
Osteoporosis and hip fracture are correlated with elevated homocysteine. Not only does homocysteine promote oxidative stress, but it may also interfere with collagen cross-linking, altering the bone matrix composition and potentially increasing bone fragility. (3)
Strategies to Support Healthy Homocysteine Levels
If you have been diagnosed with hyperhomocysteinemia, the fortunate news is that there are many natural ways to support healthy homocysteine levels. Dietary factors that contribute to high homocysteine may be addressed through dietary modifications and supplementation. However, it's important to remember that increasing your intake of vitamins does not wholly reduce the risk of chronic health issues. In addition to the therapeutic interventions discussed below, you can support your heart and neurological health by quitting smoking, managing blood pressure and diabetes, getting adequate sleep, and exercising regularly.
Nutrition to Support Healthy Homocysteine Levels
Addressing high homocysteine through dietary modifications includes moderating alcohol and coffee consumption and adequately consuming foods rich in folate, vitamin B6, and vitamin B12. Some of the foods with the highest content of these vitamins are listed below:
- Folate: spinach, liver, asparagus, and brussels sprouts
- Vitamin B6: fish, organ meats, potatoes, non-citrus fruits
- Vitamin B12: fish, meat, poultry, eggs, dairy
Eating a high-protein diet has also been shown to elevate homocysteine levels. Methionine is found in high quantities in the standard American diet, concentrated in foods like meat, fish, poultry, dairy, and eggs. Limiting the intake of these foods may help manage homocysteine levels.
Supplements to Support Healthy Homocysteine Levels
Dietary supplements may be required in addition to dietary modifications for correcting identified nutrient deficiencies. Studies have demonstrated the efficacy of B vitamin supplementation in reducing homocysteine levels; however, these studies have been unsuccessful at reducing cardiovascular disease risk. (5, 19, 42)
Research suggests that omega-3 fatty acids may help support healthy homocysteine levels, especially when simultaneously dosed with B vitamins. The exact mechanisms by which omega-3 fatty acids influence homocysteine metabolism are not fully understood, but it is believed that they might impact the enzymes involved in the methionine-homocysteine cycle. (26)
Oral N-acetyl cysteine (NAC) supplementation may be considered for supporting vascular health and managing homocysteine levels. Four weeks of oral NAC dosed at 1.8 grams daily resulted in reductions of serum homocysteine by 11.7% and significant reductions in systolic and diastolic blood pressure. (14)
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Summary
Homocysteine is an amino acid naturally found in the blood that is involved in essential methylation reactions. Individuals with hyperhomocysteinemia (levels greater than 15 µmol/L) may have an increased risk of cardiovascular and neurological conditions. Measuring and monitoring homocysteine levels, therefore, can be an important aspect of preventive healthcare. Working with a healthcare provider to create personalized plans, including nutritional, supplemental, and lifestyle interventions, helps to support healthy homocysteine levels by addressing the root causes related to the elevation.
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