Homocysteine

Homocysteine is a naturally occurring amino acid that plays a crucial role in various biochemical processes within the body. 

While it is essential for certain functions, elevated levels of homocysteine have been associated with an increased risk of cardiovascular disease, neurodegenerative disorders, and other health issues. 

Homocysteine is a sulfur-containing amino acid formed during the metabolism of methionine, an essential amino acid obtained from dietary sources. It exists in two forms: free homocysteine and protein-bound homocysteine.

In the body, homocysteine plays a critical role in methylation reactions, DNA synthesis, and the metabolism of neurotransmitters such as serotonin. 

It is involved in the synthesis of cysteine, another amino acid necessary for the production of glutathione, an important antioxidant. 

However, elevated levels of homocysteine can be harmful and have been linked to various health conditions.

Understanding homocysteine, its sources, recommended intake, and ways to optimize its levels is vital for maintaining overall health and well-being.

Definition and Function

What is Homocysteine?  [13., 14., 16.]

Homocysteine, a non-protein amino acid, is not obtained directly from the diet but instead made inside the body as a byproduct of methionine metabolism.  Homocysteine plays a crucial role in the body's metabolism. 

Homocysteine can be converted into cysteine or recycled into methionine, an essential amino acid, with the assistance of specific B vitamins. 

While some homocysteine is essential for overall health, elevated homocysteine levels have been linked to increased risks of cardiovascular, cerebrovascular, and thromboembolic diseases. However, in many ways the functions of homocysteine in health and disease remain a mystery.  

While some studies have shown benefits of lowering homocysteine levels, others have yielded conflicting results regarding its impact on cardiovascular and cerebrovascular risks.  [14.]

The metabolism of homocysteine involves various enzymes and B vitamins, and disruptions in this process can lead to elevated levels. 

While homocysteine itself can be directly toxic to cells by interfering with protein synthesis and damaging DNA, its elevation is also a marker of dysfunctional metabolism. Many nutritional, hormonal, and genetic factors that raise homocysteine levels are associated with common pathological conditions.

What Does Homocysteine Do in the Body?

Homocysteine plays a crucial role in the body as a storage molecule for sulfur and a transfer molecule for methyl metabolism. It enables the transfer of single carbon units from the reduced folate pool to the principal methyl donor in the cell.

Low levels of homocysteine, known as hypohomocysteinemia, are associated with metabolic dysfunction and disease. For example, low homocysteine levels are strongly linked to peripheral neuropathy, with 41% of patients with idiopathic peripheral neuropathy exhibiting hypohomocysteinemia.  [13.] 

Additionally, low homocysteine levels may indicate excessive conversion to cystathione for use in the production of glutathione, taurine, and sulfate, suggesting impaired ability for de novo production of glutathione and increased susceptibility to oxidative stress.

Elevated levels of homocysteine have been associated with various diseases, including cardiovascular disease, cancer, autoimmune diseases, endothelial dysfunction, and neurodegenerative diseases.  [13.] 

To reduce homocysteine levels, there are three pathways: two for homocysteine remethylation to methionine and one for conversion into cystathione for transsulfuration. The remethylation pathways depend on the folate coenzyme 5-methyltetrahydrofolate and betaine as methyl group donors, while the transsulfuration pathway uses cystathione as a precursor.

Overall, homocysteine plays a crucial role in metabolism, and its levels are tightly regulated. Abnormalities in homocysteine metabolism can lead to various diseases, making it an important marker for metabolic dysfunction and overall health.

Laboratory Assessment of Homocysteine Levels

General Lab Test Information and Sample Type

Homocysteine levels are commonly assessed in blood plasma or serum; a venipuncture is required to obtain the sample.  No special preparation is required.  

Interpreting Homocysteine Test Results

Reference Range for Homocysteine in Blood Tests

It is important to consult with the ordering laboratory company for their recommended reference range.  Reference ranges vary according to age; typical reference ranges for homocysteine in adults are reported as:  [11.]

Adults: 0-12 micromol/L 

However, another lab company reports normal values as:  [1.] 

18 to 60 years:  0.0–14.5 micromol/L

61 to 70 years: 0.0–17.2 micromol/L

71 to 80 years: 0.0–19.2 micromol/L

>80 years:  0.0–21.3 micromol/L

What is the Optimal Range for Homocysteine in Blood Tests?

Some experts liken homocysteine to blood glucose: both play a crucial metabolic role, and either excess and deficiency can lead to metabolic and health issues.  [13.] 

This pattern is common among many body metabolites, which are beneficial within a narrow range but problematic outside it.  The real issue arises when these molecules are damaged or present in excessive amounts, leading to physiological alterations. 

For homocysteine, the ideal range is estimated to be 5.0 to 7.0 mmol/L.  [13.] 

Clinical Significance of High Levels of Homocysteine

Elevated homocysteine levels have been associated with a range of conditions, including hip fracture, cognitive decline, osteoporosis, chronic kidney disease, hypothyroidism, Alzheimer's disease, and schizophrenia.  [14.]

Pathophysiologically, elevated homocysteine levels can lead to endothelial injury, inflammation, oxidative stress, and alterations in collagen cross-linking, contributing to atherosclerosis, bone fragility, and neurological disorders.  [14., 16.]

Hyperhomocysteinemia

High homocysteine in the blood is also known as hyperhomocysteinemia.  Causes of hyperhomocysteinemia include:  [1., 10., 14.]

• Genetic defects in enzymes like Methylene Tetrahydrofolate Reductase (MTHFR)
• Deficiencies in vitamins B12, B6, and folate
• Certain medications, such as methotrexate, nitrous oxide, and some antiepileptic drugs
• Chronic kidney disease
• Hypothyroidism
• Irritable bowel disease  [3.] 
• Smoking  [12.] 
• Excessive alcohol consumption  [9.]
• High levels of coffee consumption  [15.]

Homocystinuria  [8.]

Homocystinuria is a rare genetic disorder characterized by the body's inability to break down the amino acid methionine. This leads to the accumulation of homocysteine and its metabolites in the blood and urine. 

Homocystinuria is typically caused by mutations in genes that encode enzymes involved in the metabolism of homocysteine, such as cystathionine beta-synthase (CBS) or methionine synthase (MTR). Symptoms of homocystinuria can vary but often include developmental delays, intellectual disability, eye problems, skeletal abnormalities, and an increased risk of blood clots and heart disease. 

Treatment usually involves a special diet low in methionine, along with vitamin B6 supplements and other medications to help lower homocysteine levels. Early diagnosis and management are important to prevent or minimize complications associated with the condition.

Clinical Significance of Low Levels of Homocysteine

Typically lower levels of homocysteine are recommended, as higher homocysteine levels have been associated with an increased risk of disease.   [14.] 

However, some experts report that a very low level of homocysteine, or hypohomocysteinemia, results in reduced levels of antioxidants, as the sulfur-containing compounds produced as part of homocysteine metabolism are required for glutathione production.  [13.]

Hypohomocysteinemia has been associated with idiopathic peripheral neuropathy, Alzheimer’s disease and dementia.  [2., 5.]

Reduced levels of homocysteine have also been noted in pregnancy, hormone replacement therapy, and overuse of homocysteine-lowering supplements.    [2., 7.]

Related Biomarkers

When testing for homocysteine levels, it can be beneficial to also test for other biomarkers related to cardiovascular health and metabolism. Some of these biomarkers may include:

• Lipid panel (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)

• hs-C-reactive protein (hs-CRP), a marker of inflammation

• Fasting blood glucose or HbA1c, markers of glucose metabolism

• Vitamin B12 and folate levels, to assess for deficiencies that can contribute to high homocysteine

• Creatinine and estimated glomerular filtration rate (eGFR), to assess kidney function

• Thyroid function tests including TSH and free T4, as thyroid dysfunction can affect homocysteine levels  [17.] 

• Liver function tests, including ALT and AST, to assess liver health

• Iron studies, including ferritin, to assess for iron deficiency or overload, which can affect homocysteine levels

• MTHFR gene mutation testing, especially if there is a family history of hyperhomocysteinemia or cardiovascular disease

Natural Ways to Optimize Homocysteine Levels

Currently, elevated homocysteine is a greater problem than low homocysteine.  

Individuals with high levels of homocysteine may consider the following:

• Increase intake of foods rich in vitamins B6, B12, and folate, such as leafy greens, legumes, eggs, and fortified cereals.

• Consume foods high in betaine, such as beets, spinach, and whole grains.  [4.]

• Increase intake of foods rich in choline, such as eggs, lean meats, and cruciferous vegetables: choline is a precursor to betaine, which helps lower homocysteine levels.  [6.]

• Eat foods rich in antioxidants, such as fruits, vegetables, and nuts, to reduce oxidative stress.  The Mediterranean diet shows promise in reducing homocysteine levels.  [13.]

• Limit intake of alcohol and caffeine, as they can interfere with homocysteine metabolism.

• Maintain a healthy weight and engage in regular physical activity.

• Consult with a healthcare professional about the appropriate use of supplements, such as vitamin B complex, to help lower homocysteine levels.

Low homocysteine: if homocysteine is excessively low, supplementation with methionine, N-acetylcysteine, and taurine is indicated.  [13.] 

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