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 diseases. Maintaining optimal homocysteine levels is crucial for overall health, as high levels can lead to inflammation and damage to blood vessels.

Elevated homocysteine levels can indicate potential vitamin deficiencies or genetic factors that impair the body's ability to metabolize this amino acid properly. By identifying and addressing the root causes of elevated homocysteine, functional medicine practitioners can develop targeted interventions, such as personalized nutrition plans and supplementation strategies, that optimize homocysteine levels and reduce the risk of related health issues. Understanding the importance of homocysteine in functional medicine allows healthcare providers to implement proactive measures, promoting overall wellness and preventing the onset 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 diseases. 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 disease prevention because hyperhomocysteinemia has long been established as a risk factor for ischemic heart disease, heart attack, sudden cardiac death, premature coronary artery disease, carotid artery stenosis (narrowing), blot clots, stroke, and peripheral vascular disease. Newer studies have also identified high homocysteine as an independent risk factor for dementia and cognitive impairment; homocysteine levels higher than 15 µmol/L are associated with nearly double the prevalence of dementia. 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 optimize your levels. Addressing elevated homocysteine through dietary changes, supplements, and lifestyle modifications may reduce your risk of developing chronic health conditions. Regular testing allows for proactive health management, aiding in the prevention of serious medical conditions and promoting 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 disease, 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 disease. Factors that can impair homocysteine metabolism and contribute to elevated levels include (16, 43):

• Comorbid medical conditions: cancer, diabetes, kidney disease, 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 damage the inner endothelial lining of blood vessels, promoting inflammation and oxidative stress in the vasculature. This increases the risk of atherosclerosis, a thickening and hardening of arteries caused by plaque buildup, and blood clots. Atherosclerosis is a primary cause of cardiovascular disease, including coronary artery disease (CAD), heart attack, heart failure, and stroke. (32) 

Studies show that nutritional interventions with homocysteine-lowering B vitamins slow the rate of brain atrophy in elderly with mild cognitive impairment. It is unclear if homocysteine directly causes brain atrophy or if these findings are related to vitamin deficiencies. Nevertheless, the evidence does support that homocysteine is neurotoxic and decreases blood perfusion to the brain. Elevated levels are associated with neurodegeneration progression, as observed in diseases like Alzheimer's disease. (32) 

There is also a correlation between high homocysteine levels and depression. 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 depression 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 also interferes with collagen cross-linking, altering the bone matrix composition and increasing bone fragility. (3) 

Strategies to Lower Homocysteine

If you have been diagnosed with hyperhomocysteinemia, the fortunate news is that there are many natural ways to reduce homocysteine levels. Dietary factors that cause 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 diseases. In addition to the therapeutic interventions discussed below, you can reduce your risk of heart and neurological disorders by quitting smoking, managing blood pressure and diabetes, getting adequate sleep, and exercising regularly. 

Nutrition to Lower 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 prevent hyperhomocysteinemia. 

Supplements to Lower 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 effectively reduce 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 preventing vascular events and treating hyperhomocysteinemia. 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 functional medicine provider to create personalized treatment plans, including nutritional, supplemental, and lifestyle interventions, helps to optimize homocysteine levels by addressing the root causes related to the elevation.